Context
Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown.
Objective
To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems.
Design
Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652) and 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables.
Setting
Participants recruited from the community.
Participants
Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects.
Results
Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P < .05, corrected). Specifically, the reduction in the anterior and posterior cingulate cortices was associated with the impairment of social cognition in the autistic subjects (P < .05, corrected). A significant correlation was also found between repetitive and/or obsessive behavior and interests and the reduction of serotonin transporter binding in the thalamus (P < .05, corrected). In contrast, the dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P < .05, corrected in voxelwise analysis). In the orbitofrontal cortex, the dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = −0.61; P = .004).
Conclusions
The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.
Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests.1 There is no established treatment or cure for the disorder. Recent population-based surveys showing that autism is more common than previously believed have aroused serious public concern worldwide.2 In addition, genome-wide linkage scans and copy-number analyses have revealed “hot spots” on several chromosomes.3-5 To clarify the pathophysiologic mechanism of autism, the neuroimaging approach is a fruitful method. In this study, we used positron emission tomography (PET) to focus on neurotransmitter alterations in the autistic brain.
A wide array of transmitter systems has also been studied with respect to autism. Initial studies on the pathophysiologic mechanism of autism have focused on the serotoninergic system. Prior studies consistently found elevated serotonin levels in the whole blood cells and platelets of patients with autism6-10 and their relatives.11-13 Short-term dietary depletion of tryptophan (ie, the serotonin precursor) has been shown to exacerbate repetitive behavior and to elevate anxiety and feelings of unhappiness in autistic adults.14 Conversely, treatment with selective serotonin reuptake inhibitors—commonly used antidepressants—has been shown to be effective in ameliorating the repetitive and/or obsessive behavior and interests in some but not all autistic individuals.15 Genetic studies have yielded evidence of a critical role for the serotonin transporter gene (SLC6A4; OMIM d182138), which is located on chromosome 17q11.5,16 Several SLC6A4 polymorphisms have been found to be associated with autism.17,18 Furthermore, SLC6A4 promoter polymorphisms may influence the gray matter volume of cerebral cortical structures in young male autistic individuals.19 It has also been shown that SLC6A4 modulates the function of social brain systems when healthy control subjects process facial emotions.20 Neuroimaging studies with PET have provided further evidence that the levels of serotonin synthesis in autistic children aged 2 to 5 years are significantly lower than those in control children.21,22 A recent single-photon emission computed tomography study has shown that autistic children, under light sedation, have a reduction in serotonin transporter binding in the medial frontal cortex, midbrain, and temporal lobe areas.23
Interest in the role of dopamine has been stimulated by the observations that dopamine blockers (ie, antipsychotics) are effective in treating some aspects of autism, such as hyperactivity, aggression, and self-injury.24,25 In addition, some direct evidence suggests that levels of the principal dopamine metabolite homovanillic acid are elevated in the cerebrospinal fluid of autistic individuals,26 although this has not been consistently reported.27 Previous genetic studies have demonstrated that the prevalence of the A1 allele of the dopamine D2 receptor is significantly increased in autism,28 whereas the dopamine D1 receptor gene may be a risk gene for core symptoms of autism in male-only affected sibling-pair families.29 Furthermore, it has been suggested that the 9- and 10-repeat alleles of the dopamine transporter may be associated with hyperactivity, impulsivity, social anxiety, and tic symptoms in autistic children.30 In a PET study of autistic children, low levels of medial prefrontal dopaminergic activity were observed under anesthesia,31 whereas increased dopamine D2 receptor binding in the whole caudate and putamen has also been demonstrated.32 These findings suggest that the alteration of both the serotonin and the dopamine systems is a feature of autism, although these findings remain equivocal and inconclusive.
Taking these results together, we hypothesized that alterations in both the serotoninergic and the dopaminergic systems exist in the brain of autistic individuals, and that the changes are associated with the clinical features of autism. To examine this hypothesis, we used PET to measure the binding of the serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems, in adults with high-functioning autism. We also examined the relationships between some of the clinical symptoms of autism and the binding levels of both transporters.
Twenty men with autism (mean [SD] age, 21.2 [2.0] years; age range, 18-26 years) and 20 healthy male controls (mean [SD] age, 21.9 [2.0] years; age range, 18-26 years) participated in this study. All participants were right-handed and had an IQ of greater than 70 (estimated using the Wechsler Adult Intelligence Scale–Revised). The IQ did not differ significantly between the 2 groups (mean [SD], 99.3 [18.1] for the autistic group and 104.6 [15.2] for the control group; P = .30) (Table 1). An autism diagnosis was based on the following: the DSM-IV-TR1; the Autism Diagnostic Interview–Revised33; and the Autism Diagnostic Observation Schedule–Generic.34 All of the autistic individuals and controls underwent screening to exclude comorbid psychiatric illnesses (ie, schizophrenia, affective disorders, mental retardation, and personality or behavioral disorders) by means of the Structured Clinical Interview for the DSM-IV.35 Individuals with a history of neurological disorders (eg, epilepsy or head injury) or genetic disorders (eg, fragile X syndrome or tuberous sclerosis) were also excluded. In addition, controls were excluded if they had a family history of psychiatric illness, measured using the Family History Research Diagnostic Criteria.36 All autistic participants were drug naive. The present study was approved by the local ethics committees. Written informed consent was obtained from each of the participants.
To assess social cognitive ability, we used the Faux Pas Test.37-39 A low score on this test indicates poor social cognition. This test is appropriate for the measurement of theory-of-mind impairment at a higher level. To evaluate the degree of repetitive and/or obsessive behavior and interests, we used the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).40,41 We also assessed anxiety and depressive symptoms using the 17-item Hamilton Anxiety Scale (HAM-A)42 and the 17-item Hamilton Scale for Depression (HAM-D),43 respectively. Aggression was evaluated using the Aggression Questionnaire (AQ).44 These evaluations were performed on the day of the PET examination with radioactive carbon (11C)–labeled trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([11C](+)McN-5652).
Imaging procedures and data analysis
All participants underwent 3-dimensional magnetic resonance imaging (MRI) with a static magnet (MRP7000AD; Hitachi, Tokyo) just before the PET measurement. The MRI and PET examinations were performed under sedation-free conditions. The PET scans were conducted with a high-resolution brain-purpose unit (SHR12000; Hamamatsu Photonics K.K.). The MRI measurements and a mobile PET gantry allowed us to reconstruct PET images parallel to the anterior-posterior intercommissural line without resectioning. Using this approach, we were able to allocate a region of interest (ROI) to the target area of the original PET image. In quantitative PET brain imaging, the partial volume effect is an important degrading factor.45,46 To reduce the partial volume effect, we set ROIs on the MRIs and transferred them onto PET images as described elsewhere.47,48 Participants in both groups underwent 38 serial PET scans during a period of 92 minutes with periodic arterial blood sampling after an intravenous injection of [11C](+)McN-5652 to determine their serotonin transporter binding.49,50 The reproducibility of PET images with [11C](+)McN-5652 was reported in Papio anubis baboons51; when the primates underwent scanning with [11C](+)McN-5652 at 3- to 4-week intervals, good test-retest reliability was obtained. Accordingly, within 4 weeks of the initial PET scan, a second PET measurement with [11C]-labeled 2β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([11C]WIN-35,428) was performed under the same protocol as in the [11C](+)McN-5652 study to measure dopamine transporter binding.52-54 As described previously,49 we estimated [11C](+)McN-5652 binding on the basis of a single-tissue–compartment 3-parameter model. Because the distribution volume of [11C](+)McN-5652 estimated by this model correlated with the binding of the serotonin transporter in the brain,49 we constructed parametric images of the [11C](+)McN-5652 distribution volume for all participants with the use of biomedical imaging software (PMOD, version 2.5; PMOD Technologies Ltd, Zurich, Switzerland) (Figure 1A and B). Similarly, applying a 3-compartment 4-parameter model to the [11C]WIN-35,428 data allowed us to estimate the binding potential of the tracer47,53 to evaluate the dopamine transporter binding. This curve-fitting model cannot generate the distribution volume directly. In our voxelwise imaging analyses, we instead calculated the ratio index for subsequent use with statistical parametric mapping (SPM) software (SPM99; Wellcome Department of Cognitive Neurology, Institute of Neurology, London, England). Because this binding potential has been shown to correlate well with the reference tissue-derived ratio index (ie, the ratio of the PET binding value in the target region to the PET binding value in the cerebellum in the late integrated image),53 we constructed parametric images of the [11C]WIN-35,428 ratio index (Figure 1E and F) for subsequent voxelwise analysis. These voxelwise image analyses of the serotonin and dopamine transporter binding were conducted using the SPM software.49,53
Demographic and clinical variables were compared between the autistic and control groups using the t test, in which a 2-tailed α level of .05 was set as the level of significance (SPSS software, version 11.0J; SPSS Japan Inc, Tokyo). In the SPM analysis, voxelwise between-group comparisons were performed to investigate regional differences in the binding levels of [11C](+)McN-5652 and [11C]WIN-35,428. Correlation analyses were conducted between the 5 clinical behavior scores (Faux Pas Test, Y-BOCS, HAM-A, HAM-D, and AQ) and the total voxel analysis of the whole brain by using SPM analysis within the autistic group. To avert the risk of a type I error, the levels of statistical significance for the voxel and cluster analyses were set at P < .05 after allowing for multiple comparisons. In addition, we performed ROI analysis to examine whether regional serotonin and dopamine binding covaried in autistic individuals. Based on the results of the SPM analysis, we restricted the ROI analysis to the orbitofrontal area, where pronounced disturbances were present in the binding of serotonin and dopamine transporters (Table 2). In this analysis, the Pearson product moment correlation coefficient was computed. P < .05 was considered statistically significant.
The demographic and clinical variables of the participants are shown in Table 1. The mean Faux Pas Test score was significantly lower in the autistic participants than in the controls (P < .001).
Comparison of serotonin transporter binding between groups
The SPM results showed significant reductions in the [11C] (+)McN-5652 distribution volume throughout the global brain in the autistic group compared with the control group (P < .05, corrected), with the reductions being most pronounced in the frontal, temporal, parietal, and occipital lobes; in the limbic and subcortical regions; and in the cerebellum (Table 2 and Figure 2A).
Correlates of serotonin transporter with clinical characteristics in autistic participants
The [11C](+)McN-5652 distribution volume in the anterior cingulate cortex, the cingulate cortex, and the posterior cingulate cortex extending to the precuneus had a significantly positive correlation with the scores of the Faux Pas Test (P < .05, corrected) (Table 2 and Figure 2B).
We also evaluated the degree of repetitive and/or obsessive behavior and interests, which are additional clinical features of autism, using the Y-BOCS. A higher Y-BOCS score signifies more severe symptoms. There was a significant negative correlation between the Y-BOCS scores and the distribution volume of [11C] (+)McN-5652 in the thalamus extending to the parahippocampal region (P < .05, corrected) (Table 2 and Figure 2C).
No significant correlation was found between the [11C] (+)McN-5652 distribution volume and the symptom profiles of the HAM-A, HAM-D, or AQ.
Comparison of dopamine transporter distribution between groups
The SPM analysis revealed a significant increase in [11C]WIN-35,428 binding in the medial frontal region covering the orbitofrontal cortex in the autistic group compared with the control group (P < .05, corrected in voxel-level analysis) (Table 2 and Figure 2D).
No significant correlation was found between [11C]WIN-35,428 binding and the symptom profiles of the Faux Pas Test, Y-BOCS, HAM-A, HAM-D, or AQ.
Correlation between serotonin and dopamine transporter bindings
In the ROI analysis of the orbitofrontal cortex, which showed disturbances in [11C](+)McN-5652 and [11C]WIN-35,428 binding in the autistic group (Figure 1C, D, G, and H), the [11C](+)McN-5652 distribution volumes were significantly negatively correlated with the [11C]WIN-35,428 binding potentials of the autistic group (Figure 3) (r = −0.61; P = .004, according to Pearson product moment correlation coefficient).
The autistic participants had a significantly decreased [11C] (+)McN-5652 distribution volume throughout the brain, whereas they had a significantly increased [11C]WIN-35,428 distribution volume in the medial region of the orbitofrontal cortex, compared with those of the controls. These results suggest the impairment of the function of the serotoninergic systems throughout the brain and the overfunctioning of the dopaminergic systems in the orbitofrontal cortex of the autistic adults. However, the autistic participants studied herein are not a representative or a typical sample of the population of autistic individuals. We opted for autistic individuals with an IQ of greater than 70 in this study (ie, high-functioning individuals), although about 65% of autistic individuals are known to have an IQ of less than 70.55 In addition, approximately 20% to 38% of autistic individuals are reported to have epilepsy.56,57 However, in the present study, our autistic participants had no comorbidity, including epilepsy. Furthermore, our autistic participants were all drug naive. Therefore, our findings cannot be generalized to the entire population of autistic adults.
In the anterior and posterior cingulate cortices, where reduced serotonin transporter binding was noted in the autistic group, the magnitude of reduction was correlated with poor performance on the Faux Pas Test, which assesses social cognition ability. Our finding is in line with those of previous PET studies, which showed that reduced metabolism or blood flow in the cingulate cortices is associated with impairment of social cognition in autistic individuals.58,59 Our finding is also supported by a study that used single-photon emission computed tomography and demonstrated that adults with Asperger syndrome, a clinical entity that is part of a spectrum of pervasive developmental disorders, exhibit a reduction in serotonin 2A receptor binding in the cingulate cortices and that this binding reduction is related to impaired social interaction.60
We also found that, in the autistic participants studied, the reduction in the serotonin transporter binding in the thalamus correlated with repetitive and/or obsessive behavior and interests as assessed by the Y-BOCS. This finding is compatible with previous studies that showed that the thalamus is the principal site for the accumulation of selective serotonin reuptake inhibitors,61 which in turn ameliorate repetitive behaviors in some but not all autistic individuals.15 In the present study, there was, however, no correlation in any of the other regions that have been implicated as responsible for repetitive behavior in individuals with obsessive-compulsive disorder (eg, the basal ganglia, frontal regions, and hippocampus). A prior hydrogen 1–labeled magnetic resonance spectroscopy study has shown that, in adults with Asperger syndrome, increased prefrontal N-acetylaspartate levels are positively correlated with obsessional behavior.62 Furthermore, MRI studies of autistic adults have demonstrated enlargement of the caudate and putamen volumes, which is positively correlated with repetitive behaviors.63 Repetitive behaviors have also been shown to be related to the hippocampus volume in obsessive-compulsive disorder.64 In addition, individuals with autistic spectrum disorders were reported to have significantly higher concentrations of glutamate/glutamine and creatine/phosphocreatine in the amygdale-hippocampal region.65 One possible explanation for the lack of correlations found in these regions (the basal ganglia, frontal regions, and hippocampus) is that impairments in the regions other than the thalamus, if any, could be accounted for by altered dysfunctions that are not related to disturbed serotonin transporter bindings per se. Nevertheless, further work is needed to determine whether the localized reduction in serotonin transporter binding in the thalamus is specific to repetitive and/or obsessive behavior and interests seen in adults with high-functioning autism.
Increases in peripheral serotonin levels have been the most consistent finding in autistic children.6-10 High levels of peripheral serotonin are known to cause a loss of serotonin terminals during development, when serotonin transporters are located,66-69 and this may happen in the brain as well. Therefore, we speculate that the reduction of serotonin transporter binding found in the brain of autistic adults in this study may stem from altered serotoninergic systems at the developmental stage. The SLC6A gene polymorphism has been associated with autism,17,18 although other reports have not replicated these findings.70,71 Because the gene polymorphism could modulate the neurodevelopment and function of the brain19,20 and influence SLC6A4 expression,72,73 it may be responsible for the reduction of serotonin transporter binding that we observed in the present study.
Several limitations of our study bear mention. We repeated the SMP analysis separately for each of 5 clinical behaviors within the autistic participants, which may have led to a type I error. However, we found that 2 of the 5 clinical behaviors were correlated with the serotonin transporter bindings in particular brain regions, and, as discussed in the preceding paragraphs, these regions are considered to be critical and biologically plausible areas for involvement in these behaviors. Therefore, our results may not be attributable merely to type I error. Serotoninergic activity of the prefrontal cortical regions has been shown to correlate with aggressive behavior in humans.74 Some autistic individuals were reported to have aggression.75 In this context, we anticipated that our sample of autistic adults would show the relationship between reduced serotonin transporter binding and the degree of aggression. However, SPM analysis did not reveal any brain regions in which the reduced binding correlated with aggression as assessed by the AQ. This negative finding in the present study may have been because we recruited adults with high-functioning autism who were cooperative with the imaging procedures. We showed correlates of alterations in the serotonin transporter binding with clinical features. Causative inference cannot be based merely on such correlations. Therefore, our findings cannot be considered conclusive. To elucidate the direct causal relationship between altered serotonin transporter binding and autism, further studies will be needed. Finally, the present study was limited by its small sample size and lack of female participants.
Dopamine transporter binding was significantly and locally increased in the medial region of the orbitofrontal cortex in our autistic participants. Our finding of overfunctioning in the dopaminergic system is compatible with previous PET studies, which showed increased striatal dopamine D2 receptor binding in autistic children32 and elevated dopamine synthesis and storage in the striatum and frontal cortex of adults with Asperger syndrome.76 The orbitofrontal cortex is a key structure in the network underlying emotional regulation; dysfunction in the orbitofrontal-limbic circuit may be associated with behaviors in autism,77 such as impulsive and aggressive behaviors.75,78 However, the increased dopamine transporter binding was not correlated with aggression as assessed by the AQ in the present study. As mentioned in the preceding paragraphs, this may have been due to a bias arising from the selection of individuals with high-functioning autism in the present study, who are more cooperative with the PET imaging procedures than are autistic individuals as a whole. Thus, more work is needed in this regard.
When the relationship between dopamine and serotonin transporter binding was examined in our autistic participants, the dopamine transporter binding was significantly negatively correlated with that of the serotonin transporter. The mechanism underlying the interaction between the 2 transporters in the orbitofrontal region in autism is still unknown. However, some animal studies have illustrated that the number of dopaminergic neuron fibers increases in response to disruption of the serotoninergic system by a lesion in the nucleus raphe79 and that the uptake of serotonin into dopamine neurons takes place by means of dopamine transporters.80
With respect to our use of [11C]WIN-35,428 to evaluate dopamine transporter binding in the orbitofrontal cortex, a methodological issue should be addressed. The capability of the tracer for measuring low levels of dopamine transporter binding in the extrastriatal region is disputable. In the present study, we conducted 2 types of analytic procedures (ie, ROI method and SPM analysis) to estimate quantitative values of the orbitofrontal binding and to detect brain regions with significant changes. The difference in the shape of the time-activity curve of the orbitofrontal cortex between the groups (Figure 1G and H) and a series of our previous studies that have reported significant changes in the extrastriatal dopamine transporter binding48,81-83 indicate the validity for the use of [11C]WIN-35,428 for the purpose of the present study. This contention is also supported by our findings that the level of the orbitofrontal binding potential is higher in autistic individuals (0.27, based on our present data) than in their normal counterparts (0.19)48 and that the magnitude of this increase (58%) is greater than the reported level of within-subject test-retest variability (9.3%).84 Despite these accounts, a PET tracer with a much higher affinity to the extrastriatal dopamine transporter may be desirable.
Correspondence: Norio Mori, MD, PhD, Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan (morin@hama-med.ac.jp).
Submitted for Publication: November 8, 2008; final revision received March 26, 2009; accepted April 27, 2009.
Financial Disclosure: None reported.
Funding/Support: This study was supported by Special Expenses for Educational Research to Osaka-Hamamatsu Joint Research Center for Child Mental Development (Osaka University and Hamamatsu University School of Medicine) and a Grant-in-Aid for Scientific Research (B) (Dr Nakamura) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Research on Brain Science Fund (Dr Mori) from the Ministry of Health, Labor, and Welfare, Japan; by Takeda Science Foundation (Dr Nakamura); and by the Kato Memorial Trust For Nambyo Research (Dr Nakamura).
Additional Contributions: Toshihiko Kanno, BS, Yutaka Naito, MS, Katsuhiko Nishimura, MD, PhD, Kiyokazu Takebayashi, MD, PhD, and Yoshifumi Takai, MA, provided excellent technical support. Masayoshi Kawai, MD, PhD, and Shigeyuki Yamamoto, PhD, recruited the participants. Kaori Matsumoto, MA, conducted clinical assessments, including the Autism Diagnostic Interview–Revised and Autism Diagnostic Observation Schedule.
1.American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000
2.Baird
GSimonoff
EPickles
AChandler
SLoucas
TMeldrum
DCharman
T Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP).
Lancet 2006;368
(9531)
210- 215
PubMedGoogle ScholarCrossref 3.Szatmari
PPaterson
ADZwaigenbaum
LRoberts
WBrian
JLiu
XQVincent
JBSkaug
JLThompson
APSenman
LFeuk
LQian
CBryson
SEJones
MBMarshall
CRScherer
SWVieland
VJBartlett
CMangin
LVGoedken
RSegre
APericak-Vance
MACuccaro
MLGilbert
JRWright
HHAbramson
RKBetancur
CBourgeron
TGillberg
CLeboyer
MBuxbaum
JDDavis
KLHollander
ESilverman
JMHallmayer
JLotspeich
LSutcliffe
JSHaines
JLFolstein
SEPiven
JWassink
THSheffield
VGeschwind
DHBucan
MBrown
WTCantor
RMConstantino
JNGilliam
TCHerbert
MLajonchere
CLedbetter
DHLese-Martin
CMiller
JNelson
SSamango-Sprouse
CASpence
SState
MTanzi
RECoon
HDawson
GDevlin
BEstes
AFlodman
PKlei
L McMahon
WMMinshew
NMunson
JKorvatska
ERodier
PMSchellenberg
GDSmith
MSpence
MAStodgell
CTepper
PGWijsman
EMYu
CERogé
BMantoulan
CWittemeyer
KPoustka
AFelder
BKlauck
SMSchuster
CPoustka
FBölte
SFeineis-Matthews
SHerbrecht
ESchmötzer
GTsiantis
JPapanikolaou
KMaestrini
EBacchelli
EBlasi
FCarone
SToma
CVan Engeland
Hde Jonge
MKemner
CKoop
FLangemeijer
MHijimans
CStaal
WGBaird
GBolton
PFRutter
MLWeisblatt
EGreen
JAldred
CWilkinson
JAPickles
ALe Couteur
ABerney
TMcConachie
HBailey
AJFrancis
KHoneyman
GHutchinson
AParr
JRWallace
SMonaco
APBarnby
GKobayashi
KLamb
JASousa
ISykes
NCook
EHGuter
SJLeventhal
BLSalt
JLord
CCorsello
CHus
VWeeks
DEVolkmar
FTauber
MFombonne
EShih
AMeyer
KJAutism Genome Project Consortium Mapping autism risk loci using genetic linkage and chromosomal rearrangements [published correction appears in
Nat Genet . 2007;39(10):1285].
Nat Genet2007393319328
PubMedGoogle Scholar 4.Sebat
JLakshmi
BMalhotra
DTroge
JLese-Martin
CWalsh
TYamrom
BYoon
SKrasnitz
AKendall
JLeotta
APai
DZhang
RLee
YHHicks
JSpence
SJLee
ATPuura
KLehtimäki
TLedbetter
DGregersen
PKBregman
JSutcliffe
JSJobanputra
VChung
WWarburton
DKing
MCSkuse
DGeschwind
DHGilliam
TCYe
KWigler
M Strong association of de novo copy number mutations with autism.
Science 2007;316
(5823)
445- 449
PubMedGoogle ScholarCrossref 5.Weiss
LAShen
YKorn
JMArking
DEMiller
DTFossdal
RSaemundsen
EStefansson
HFerreira
MAGreen
TPlatt
OSRuderfer
DMWalsh
CAAltshuler
DChakravarti
ATanzi
REStefansson
KSantangelo
SLGusella
JFSklar
PWu
BLDaly
MJAutism Consortium, Association between microdeletion and microduplication at 16p11.2 and autism.
N Engl J Med 2008;358
(7)
667- 675
PubMedGoogle ScholarCrossref 6.Schain
RJFreedman
DX Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children.
J Pediatr 1961;58315- 320
PubMedGoogle ScholarCrossref 7.Hanley
HGStahl
SMFreedman
DX Hyperserotonemia and amine metabolites in autistic and retarded children.
Arch Gen Psychiatry 1977;34
(5)
521- 531
PubMedGoogle ScholarCrossref 9.Anderson
GMFreedman
DXCohen
DJVolkmar
FRHoder
ELMcPhedran
PMinderaa
RBHansen
CRYoung
JG Whole blood serotonin in autistic and normal subjects.
J Child Psychol Psychiatry 1987;28
(6)
885- 900
PubMedGoogle ScholarCrossref 11.Abramson
RKWright
HHCarpenter
RBrennan
WLumpuy
OCole
EYoung
SR Elevated blood serotonin in autistic probands and their first-degree relatives.
J Autism Dev Disord 1989;19
(3)
397- 407
PubMedGoogle ScholarCrossref 12.Cook
EH
JrLeventhal
BLHeller
WMetz
JWainwright
MFreedman
DX Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence.
J Neuropsychiatry Clin Neurosci 1990;2
(3)
268- 274
PubMedGoogle Scholar 13.Cross
SKim
SJWeiss
LADelahanty
RJSutcliffe
JSLeventhal
BLCook
EH
JrVeenstra-Vanderweele
J Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism.
Neuropsychopharmacology 2008;33
(2)
353- 360
PubMedGoogle ScholarCrossref 14.McDougle
CJNaylor
STCohen
DJAghajanian
GKHeninger
GRPrice
LH Effects of tryptophan depletion in drug-free adults with autistic disorder.
Arch Gen Psychiatry 1996;53
(11)
993- 1000
PubMedGoogle ScholarCrossref 15.Kolevzon
AMathewson
KAHollander
E Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability.
J Clin Psychiatry 2006;67
(3)
407- 414
PubMedGoogle ScholarCrossref 16.Yonan
ALAlarcón
MCheng
RMagnusson
PKSpence
SJPalmer
AAGrunn
AJuo
SHTerwilliger
JDLiu
JCantor
RMGeschwind
DHGilliam
TC A genomewide screen of 345 families for autism-susceptibility loci.
Am J Hum Genet 2003;73
(4)
886- 897
PubMedGoogle ScholarCrossref 17.Cook
EH
JrCourchesne
RLord
CCox
NJYan
SLincoln
AHaas
RCourchesne
ELeventhal
BL Evidence of linkage between the serotonin transporter and autistic disorder.
Mol Psychiatry 1997;2
(3)
247- 250
PubMedGoogle ScholarCrossref 18.Klauck
SMPoustka
FBenner
ALesch
KPPoustka
A Serotonin transporter (5-HTT) gene variants associated with autism?
Hum Mol Genet 1997;6
(13)
2233- 2238
PubMedGoogle ScholarCrossref 19.Wassink
THHazlett
HCEpping
EAArndt
SDager
SRSchellenberg
GDDawson
GPiven
J Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism.
Arch Gen Psychiatry 2007;64
(6)
709- 717
PubMedGoogle ScholarCrossref 20.Surguladze
SAElkin
AEcker
CKalidindi
SCorsico
AGiampietro
VLawrence
NDeeley
QMurphy
DGKucharska-Pietura
KRussell
TAMcGuffin
PMurray
RPhillips
ML Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces.
Genes Brain Behav 2008;7
(5)
543- 551
PubMedGoogle ScholarCrossref 21.Chugani
DCMuzik
OBehen
MRothermel
RJanisse
JJLee
JChugani
HT Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children.
Ann Neurol 1999;45
(3)
287- 295
PubMedGoogle ScholarCrossref 22.Chandana
SRBehen
MEJuhász
CMuzik
ORothermel
RDMangner
TJChakraborty
PKChugani
HTChugani
DC Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism.
Int J Dev Neurosci 2005;23
(2-3)
171- 182
PubMedGoogle ScholarCrossref 23.Makkonen
IRiikonen
RKokki
HAiraksinen
MMKuikka
JT Serotonin and dopamine transporter binding in children with autism determined by SPECT.
Dev Med Child Neurol 2008;50
(8)
593- 597
PubMedGoogle ScholarCrossref 24.Anderson
LTCampbell
MGrega
DMPerry
RSmall
AMGreen
WH Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms.
Am J Psychiatry 1984;141
(10)
1195- 1202
PubMedGoogle Scholar 25.Anderson
LTCampbell
MAdams
PSmall
AMPerry
RShell
J The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children.
J Autism Dev Disord 1989;19
(2)
227- 239
PubMedGoogle ScholarCrossref 26.Gillberg
CSvennerholm
L CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood.
Br J Psychiatry 1987;15189- 94
PubMedGoogle ScholarCrossref 27.Narayan
MSrinath
SAnderson
GMMeundi
DB Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid in autism.
Biol Psychiatry 1993;33
(8-9)
630- 635
PubMedGoogle ScholarCrossref 28.Comings
DEComings
BGMuhleman
DDietz
GShahbahrami
BTast
DKnell
EKocsis
PBaumgarten
RKovacs
BWLevy
DLSmith
MBorison
RLEvans
DDKlein
DNMacMurray
JTosk
JMSverd
JGysin
RFlanagan
SD The dopamine D
2 receptor locus as a modifying gene in neuropsychiatric disorders.
JAMA 1991;266
(13)
1793- 1800
PubMedGoogle ScholarCrossref 29.Hettinger
JALiu
XSchwartz
CEMichaelis
RCHolden
JJA DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families.
Am J Med Genet B Neuropsychiatr Genet 2008;147B
(5)
628- 636
PubMedGoogle ScholarCrossref 30.Gadow
KDRoohi
JDeVincent
CJHatchwell
E Association of ADHD, tics, and anxiety with dopamine transporter (DAT1) genotype in autism spectrum disorder.
J Child Psychol Psychiatry 2008;49
(12)
1331- 1338
PubMedGoogle ScholarCrossref 31.Ernst
MZametkin
AJMatochik
JAPascualvaca
DCohen
RM Low medial prefrontal dopaminergic activity in autistic children [letter] [published correction appears in
Lancet. 1998;351(9100):454].
Lancet19973509078638
PubMedGoogle Scholar 32.Fernell
EWatanabe
YAdolfsson
ITani
YBergström
MHartvig
PLilja
Avon Knorring
ALGillberg
CLångström
B Possible effects of tetrahydrobiopterin treatment in six children with autism-clinical and positron emission tomography data: a pilot study.
Dev Med Child Neurol 1997;39
(5)
313- 318
PubMedGoogle ScholarCrossref 33.Lord
CRutter
MLe Couteur
A Autism Diagnostic Interview–Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
J Autism Dev Disord 1994;24
(5)
659- 685
PubMedGoogle ScholarCrossref 34.Lord
CRisi
SLambrecht
LCook
EH
JrLeventhal
BLDiLavore
PCPickles
ARutter
M The Autism Diagnostic Observation Schedule–Generic: a standard measure of social and communication deficits associated with the spectrum of autism.
J Autism Dev Disord 2000;30
(3)
205- 223
PubMedGoogle ScholarCrossref 35.American Psychiatric Association User's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders SCID-I: Clinician Version. Washington, DC: American Psychiatric Press; 1997
36.Andreasen
NCEndicott
JSpitzer
RLWinokur
G The family history method using diagnostic criteria: reliability and validity.
Arch Gen Psychiatry 1977;34
(10)
1229- 1235
PubMedGoogle ScholarCrossref 38.Baron-Cohen
SO’Riordan
MStone
VJones
RPlaisted
K Recognition of faux pas by normally developing children and children with Asperger syndrome or high-functioning autism.
J Autism Dev Disord 1999;29
(5)
407- 418
PubMedGoogle ScholarCrossref 39.Stone
VEBaron-Cohen
SCalder
AKeane
JYoung
A Acquired theory of mind impairments in individuals with bilateral amygdala lesions.
Neuropsychologia 2003;41
(2)
209- 220
PubMedGoogle ScholarCrossref 40.Goodman
WKPrice
LHRasmussen
SAMazure
CFleischmann
RLHill
CLHeninger
GRCharney
DS The Yale-Brown Obsessive Compulsive Scale, I: development, use, and reliability.
Arch Gen Psychiatry 1989;46
(11)
1006- 1011
PubMedGoogle ScholarCrossref 41.Goodman
WKPrice
LHRasmussen
SAMazure
CDelgado
PHeninger
GRCharney
DS The Yale-Brown Obsessive Compulsive Scale, II: validity.
Arch Gen Psychiatry 1989;46
(11)
1012- 1016
PubMedGoogle ScholarCrossref 42.Hamilton
M Diagnosis and rating of anxiety. In: Lader
MH, ed.
Studies of Anxiety: Papers Read at the World Psychiatric Association Symposium, “Aspects of Anxiety,” London, November, 1967. Ashford, England: Headley Brothers Ltd for Royal Medico-Psychological Association; 1969:76-79.
Third special publication of The British Journal of PsychiatryGoogle Scholar 45.Rousset
OGMa
YEvans
AC Correction for partial volume effects in PET: principle and validation.
J Nucl Med 1998;39
(5)
904- 911
PubMedGoogle Scholar 46.Aston
JACunningham
VJAsselin
MCHammers
AEvans
ACGunn
RN Positron emission tomography partial volume correction: estimation and algorithms.
J Cereb Blood Flow Metab 2002;22
(8)
1019- 1034
PubMedGoogle ScholarCrossref 47.Sekine
YIyo
MOuchi
YMatsunaga
TTsukada
HOkada
HYoshikawa
EFutatsubashi
MTakei
NMori
N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET.
Am J Psychiatry 2001;158
(8)
1206- 1214
PubMedGoogle ScholarCrossref 48.Ouchi
YYoshikawa
EOkada
HFutatsubashi
MSekine
YIyo
MSakamoto
M Alterations in binding site density of dopamine transporter in the striatum, orbitofrontal cortex, and amygdala in early Parkinson's disease: compartment analysis for β-CFT binding with positron emission tomography.
Ann Neurol 1999;45
(5)
601- 610
PubMedGoogle ScholarCrossref 49.Sekine
YOuchi
YTakei
NYoshikawa
ENakamura
KFutatsubashi
MOkada
HMinabe
YSuzuki
KIwata
YTsuchiya
KJTsukada
HIyo
MMori
N Brain serotonin transporter density and aggression in abstinent methamphetamine abusers.
Arch Gen Psychiatry 2006;63
(1)
90- 100
PubMedGoogle ScholarCrossref 50.Meyer
JHHoule
SSagrati
SCarella
AHussey
DFGinovart
NGoulding
VKennedy
JWilson
AA Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes.
Arch Gen Psychiatry 2004;61
(12)
1271- 1279
PubMedGoogle ScholarCrossref 51.Szabo
ZMcCann
UDWilson
AAScheffel
UOwonikoko
TMathews
WBRavert
HTHilton
JDannals
RFRicaurte
GA Comparison of (+)-
11C-McN5652 and
11C-DASB as serotonin transporter radioligands under various experimental conditions.
J Nucl Med 2002;43
(5)
678- 692
PubMedGoogle Scholar 52.Wong
DFYung
BDannals
RFShaya
EKRavert
HTChen
CAChan
BFolio
TScheffel
URicaurte
GA
et al. In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [
11C]WIN 35,428.
Synapse 1993;15
(2)
130- 142
PubMedGoogle ScholarCrossref 53.Ouchi
YKanno
TOkada
HYoshikawa
EFutatsubashi
MNobezawa
STorizuka
TTanaka
K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease.
Brain 2001;124
(pt 4)
784- 792
PubMedGoogle ScholarCrossref 54.Meyer
JHMcNeely
HESagrati
SBoovariwala
AMartin
KVerhoeff
NPWilson
AAHoule
S Elevated putamen D
2 receptor binding potential in major depression with motor retardation: an [
11C]raclopride positron emission tomography study.
Am J Psychiatry 2006;163
(9)
1594- 1602
PubMedGoogle ScholarCrossref 55.Ritvo
ERJorde
LBMason-Brothers
AFreeman
BJPingree
CJones
MBMcMahon
WMPetersen
PBJenson
WRMo
A The UCLA–University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling.
Am J Psychiatry 1989;146
(8)
1032- 1036
PubMedGoogle Scholar 56.Tsakanikos
ECostello
HHolt
GBouras
NSturmey
PNewton
T Psychopathology in adults with autism and intellectual disability.
J Autism Dev Disord 2006;36
(8)
1123- 1129
PubMedGoogle ScholarCrossref 57.Danielsson
SGillberg
ICBillstedt
EGillberg
COlsson
I Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood.
Epilepsia 2005;46
(6)
918- 923
PubMedGoogle ScholarCrossref 58.Haznedar
MMBuchsbaum
MSMetzger
MSolimando
ASpiegel-Cohen
JHollander
E Anterior cingulate gyrus volume and glucose metabolism in autistic disorder.
Am J Psychiatry 1997;154
(8)
1047- 1050
PubMedGoogle Scholar 59.Ohnishi
TMatsuda
HHashimoto
TKunihiro
TNishikawa
MUema
TSasaki
M Abnormal regional cerebral blood flow in childhood autism.
Brain 2000;123
(pt 9)
1838- 1844
PubMedGoogle ScholarCrossref 60.Murphy
DGDaly
ESchmitz
NToal
FMurphy
KCurran
SErlandsson
KEersels
JKerwin
REll
PTravis
M Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.
Am J Psychiatry 2006;163
(5)
934- 936
PubMedGoogle ScholarCrossref 61.Smith
DF Neuroimaging of serotonin uptake sites and antidepressant binding sites in the thalamus of humans and “higher” animals.
Eur Neuropsychopharmacol 1999;9
(6)
537- 544
PubMedGoogle ScholarCrossref 62.Murphy
DGCritchley
HDSchmitz
NMcAlonan
GVan Amelsvoort
TRobertson
DDaly
ERowe
ARussell
ASimmons
AMurphy
KCHowlin
P Asperger syndrome: a proton magnetic resonance spectroscopy study of brain.
Arch Gen Psychiatry 2002;59
(10)
885- 891
PubMedGoogle ScholarCrossref 63.Hollander
EAnagnostou
EChaplin
WEsposito
KHaznedar
MMLicalzi
EWasserman
SSoorya
LBuchsbaum
M Striatal volume on magnetic resonance imaging and repetitive behaviors in autism.
Biol Psychiatry 2005;58
(3)
226- 232
PubMedGoogle ScholarCrossref 64.Atmaca
MYildirim
HOzdemir
HOzler
SKara
BOzler
ZKanmaz
EMermi
OTezcan
E Hippocampus and amygdalar volumes in patients with refractory obsessive-compulsive disorder.
Prog Neuropsychopharmacol Biol Psychiatry 2008;32
(5)
1283- 1286
PubMedGoogle ScholarCrossref 65.Page
LADaly
ESchmitz
NSimmons
AToal
FDeeley
QAmbery
FMcAlonan
GMMurphy
KCMurphy
DG In vivo
1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism.
Am J Psychiatry 2006;163
(12)
2189- 2192
PubMedGoogle ScholarCrossref 67.Whitaker-Azmitia
PM Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?
Int J Dev Neurosci 2005;23
(1)
75- 83
PubMedGoogle ScholarCrossref 68.Janusonis
SAnderson
GMShifrovich
IRakic
P Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism.
J Neurochem 2006;99
(3)
1019- 1031
PubMedGoogle ScholarCrossref 69.McNamara
IMBorella
AWBialowas
LAWhitaker-Azmitia
PM Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes.
Brain Res 2008;1189203- 214
PubMedGoogle ScholarCrossref 70.Maestrini
ELai
CMarlow
AMatthews
NWallace
SBailey
ACook
EHWeeks
DEMonaco
APInternational Molecular Genetic Study of Autism Consortium, Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit β3 (
GABRB3) gene polymorphisms are not associated with autism in the IMGSA families.
Am J Med Genet 1999;88
(5)
492- 496
PubMedGoogle ScholarCrossref 71.Persico
AMMiliterni
RBravaccio
CSchneider
CMelmed
RConciatori
MDamiani
VBaldi
AKeller
F Lack of association between serotonin transporter gene promoter variants and autistic disorder in two ethnically distinct samples.
Am J Med Genet 2000;96
(1)
123- 127
PubMedGoogle ScholarCrossref 72.Lesch
KPBengel
DHeils
ASabol
SZGreenberg
BDPetri
SBenjamin
JMüller
CRHamer
DHMurphy
DL Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.
Science 1996;274
(5292)
1527- 1531
PubMedGoogle ScholarCrossref 73.Bradley
SLDodelzon
KSandhu
HKPhilibert
RA Relationship of serotonin transporter gene polymorphisms and haplotypes to mRNA transcription.
Am J Med Genet B Neuropsychiatr Genet 2005;136B
(1)
58- 61
PubMedGoogle ScholarCrossref 75.Matson
JLNebel-Schwalm
MS Comorbid psychopathology with autism spectrum disorder in children: an overview.
Res Dev Disabil 2007;28
(4)
341- 352
PubMedGoogle ScholarCrossref 76.Nieminen-von Wendt
TSMetsähonkala
LKulomaki
TAAalto
SAutti
THVanhala
REskola
OBergman
JHietala
JAvon Wendt
LO Increased presynaptic dopamine function in Asperger syndrome.
Neuroreport 2004;15
(5)
757- 760
PubMedGoogle ScholarCrossref 77.Bachevalier
JLoveland
KA The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism.
Neurosci Biobehav Rev 2006;30
(1)
97- 117
PubMedGoogle ScholarCrossref 78.Davidson
RJPutnam
KMLarson
CL Dysfunction in the neural circuitry of emotion regulation: a possible prelude to violence.
Science 2000;289
(5479)
591- 594
PubMedGoogle ScholarCrossref 79.Bolte Taylor
JCunningham
MCBenes
FM Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats.
Neuroreport 1998;9
(8)
1811- 1815
PubMedGoogle ScholarCrossref 80.Zhou
FCLesch
KPMurphy
DL Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative.
Brain Res 2002;942
(1-2)
109- 119
PubMedGoogle ScholarCrossref 81.Ouchi
YKanno
TOkada
HYoshikawa
EFutatsubashi
MNobezawa
STorizuka
TTanaka
K Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson's disease.
Brain 2001;124
(pt 4)
784- 792
PubMedGoogle ScholarCrossref 82.Sekine
YIyo
MOuchi
YMatsunaga
TTsukada
HOkada
HYoshikawa
EFutatsubashi
MTakei
NMori
N Methamphetamine-related psychiatric symptoms and reduced brain dopamine transporters studied with PET.
Am J Psychiatry 2001;158
(8)
1206- 1214
PubMedGoogle ScholarCrossref 83.Sekine
YMinabe
YOuchi
YTakei
NIyo
MNakamura
KSuzuki
KTsukada
HOkada
HYoshikawa
EFutatsubashi
MMori
N Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms.
Am J Psychiatry 2003;160
(9)
1699- 1701
PubMedGoogle ScholarCrossref 84.Villemagne
VYuan
JWong
DFDannals
RFHatzidimitriou
GMathews
WBRavert
HTMusachio
JMcCann
UDRicaurte
GA Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [
11C]WIN-35,428 position emission tomography studies and direct
in vitro determinations.
J Neurosci 1998;18
(1)
419- 427
PubMedGoogle Scholar