Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children

Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using alpha[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.     

Blood serotonin and free tryptophan concentration in autistic children

In 37 autistic children and 67 normal control subjects, determinations of plasma free and total tryptophan and blood serotonin levels were made simultaneously in order to establish a relationship between these parameters and the clinical rating scales: Children's Psychiatric Rating Scale (CPRS-1), Werry-Weiss-Peters Activity Scale (WWPAS), and Developmental Quotient (DQ). The plasma free tryptophan level was significantly higher in autistic children than in normal control subjects. There tended to be a significant positive correlation between the plasma free tryptophan level and CPRS-1 or WWPAS score and a negative correlation between the plasma free tryptophan level and DQ. The blood serotonin level was significantly higher in autistic children than in normal control subjects. No correlation was established, however, between the blood serotonin level and CPRS-1, WWPAS score or DQ, and hence the clinical symptoms. Nor was there a correlation between blood serotonin and free tryptophan levels in these children. These results suggest that autistic children have some defect in tryptophan-serotonin metabolism in the brain, which is responsible for the clinical manifestations and behavioral abnormalities of infantile autism.     

Altered pineal serotonin binding in some suicides

Serotonergic abnormalities have been regularly reported in the brains of suicide victims. Because of evidence that pineal function is altered in depressed subjects and that serotonin-releasing axons may innervate the pineal, we assayed tritiated serotonin binding in a series of control and suicide pineals. High affinity binding was present, and there were apparent differences between some suicides and controls.     

Altered serotonin uptake kinetics in multiple sclerosis

Summary Platelet serotonin uptake was studied in 20 patients with multiple sclerosis (MS) in acute relapse and in 20 age-and sex-matched controls. While there was no difference in the maximum velocity of the uptake, Michaelis constants were significantly higher and correlated positively with the Disability Status Scale score. The results suggest a competitive block of the serotonin uptake sites in platelets of MS patients.     

Elevated blood serotonin in autistic probands and their first-degree relatives

Whole blood serotonin levels and platelet counts were studied in 14 families, representing 57 family members and 15 probands who met DSM III criteria for infantile autism. High serotonin appeared to segregate in families. When two parents had high serotonin, the serotonin level in their offspring was twice the parental level. When one parent had high serotonin, the serotonin level in the offspring approximated the level of serotonin in either the high serotonin parent or the low serotonin parent. For the case where both parents had low serotonin, in one family the children had low serotonin and in a second family, high serotonin levels were present in the autistic proband, and a sibling with severe mental retardation. Mean serotonin levels were higher for both male and female, autistics and family members, in the four black families than in the 10 Caucasian families.The research was supported in part by NIH-BRSG 2507-RR-0585-01, the March of Dimes 8-85-49, 8-85-08, and the Health Resources Foundation.     

Low platelet-poor plasma levels of serotonin in adult autistic patients

BACKGROUND: Hyperserotonemia has been reported in about a third of autistic patients. However, most studies have examined whole blood levels of serotonin (5-HT), the vast majority of which is found in platelets. The aim of this study was to determine 5-HT levels in platelet-poor plasma (PPP) in a group of adult patients with autism. METHODS: Levels of PPP 5-HT were compared between 10 adult drug-free autistic patients and 12 healthy controls. The Ritvo-Freeman Real-Life Rating Scale and the Overt Aggression Scale (OAS) were administered to the autistic group as a measure of symptom severity. RESULTS: Significantly lower PPP 5-HT levels were observed in the autistic group as compared to the controls (p = 0.03). In addition, PPP 5-HT levels were inversely correlated with OAS scores among subjects with autism (r = -0.64, p < 0.05). CONCLUSION: PPP 5-HT ('free') levels appear to be low in autistic patients and may play a role in the pathophysiology and symptomatology of the disorder.     

Decreasing self-stimulatory behavior with physical exercise in a group of autistic boys

Five autistic boys were observed during 27 language training sessions. Each session followed one of three periods: (a) physical exercise, (b) TV watching, or (c) regular academic work. It was found that (a) the lowest levels of self-stimulation followed physical exercise, (b) there were no differences in the levels of self-stimulation following TV watching and following academics, and (c) the levels of correct question answering were not affected by the three different previous periods. We wish to thank Dora VanStrepen, Alison Lennox, John Rager, Bill Sharkey, and Sheila Connolly for their cooperation and assistance, and Gordon McClure, principal, for providing an environment nurturant to research as well as to children and teachers.     

Functioning of the brain-stem auditory pathway in non-retarded autistic individuals

Functioning of auditory brain-stem pathways was examined in non-retarded autistic individuals (14-28 years of age). Functioning was assessed by recording ERPs (event-related brain potentials) generated by these auditory pathways. These ERPs were evoked by click stimuli and occurred within the first 8 msec following the onset of the click. To assess the ability of these early auditory pathways to process sensory stimuli of varying characteristics, we systematically varied click intensity, rate of stimulation, ear of stimulation, and polarity of clicks. The results show that non-retarded autistic individuals have normal functioning of the brain-stem auditory pathways which generate these ERPs: every autistic subject had normal ERPs. So, disorder in auditory brain-stem pathways which generate these ERPs is not necessary for autism to occur. The dysfunctioning neural systems directly responsible for autism in non-retarded individuals must be sought elsewhere. Ten of the autistic subjects in this study, whom we found to have normal auditory brain-stem ERPs, had previously been found to have abnormalities in longer latency cognitive ERP components (Courchesne et al. 1984, 1985). We conclude, therefore, that those abnormalities in longer latency components are not the downstream consequences of abnormalities in the structures generating the auditory brain-stem ERPs recorded in the present study.     

Association of serotonin concentration to behavior and IQ in autistic children

Twenty-five boys meeting DSM-III criteria for infantile autism were evaluated for IQ, age, and behavior score on the Autism Behavior Checklist (ABC), in order to determine the ability to predic platelet-rich plasma (PRP) serotonin concentrations. Multiple regression techniques were used to adjust the PRP serotonin concentration for medication and whole blood platelet count to allow meaningful comparisons of serotonin concentrations among the autistic children. Though we found no significant correlation between the adjusted serotonin concentration and the IQ, or between the adjusted serotonin concentration and the various ABC scale scores, four individual items of the ABC did correlate with the adjusted serotonin concentration. Individuals with all of these items appear to be more severely affected with the disorder of autism and have a tendency to higher adjusted PRP serotonin concentration.     

Platelet serotonin concentrations in autistic children and members of their families

Children with early infantile autism have often high platelet serotonin (5 HT) levels. According to this fact, we wondered if a genetic abnormality of 5 HT metabolism could be detected in family members of autistic children. We has thus determined platelet 5 HT levels in these children's mothers, fathers and siblings. It is noteworthy to find out that: autistic children have a mean platelet 5 HT level significantly higher than their siblings' (p less than 0.01); fathers' levels are significantly lower (-29%; p less than 0.001) than those of other family members' and of control group. Furthermore, for future purposes, we studied platelet 5 HT levels at different times during pregnancy in controls and in a woman already mother of an autistic child. We observed a raise (+31%; p less than 0.01) in platelet 5 HT during the first trimester of the pregnancy with a lowering towards normal levels during the eight month, in the woman with an autistic child as well as in the controls.     

Altered inter‐ and intrahemispheric functional connectivity dynamics in autistic children

Emerging evidence has associated autism spectrum disorder (ASD) with static functional connectivity abnormalities between multiple brain regions. However, the temporal dynamics of intra‐ and interhemispheric functional connectivity patterns remain unknown in ASD. Resting‐state functional magnetic resonance imaging data were analyzed for 105 ASD and 102 demographically matched typically developing control (TC) children (age range: 7–12 years) available from the Autism Brain Imaging Data Exchange database. Whole‐brain functional connectivity was decomposed into ipsilateral and contralateral functional connectivity, and sliding‐window analysis was utilized to capture the intra‐ and interhemispheric dynamic functional connectivity density (dFCD) patterns. The temporal variability of the functional connectivity dynamics was further quantified using the standard deviation (SD) of intra‐ and interhemispheric dFCD across time. Finally, a support vector regression model was constructed to assess the relationship between abnormal dFCD variance and autism symptom severity. Both intra‐ and interhemispheric comparisons showed increased dFCD variability in the anterior cingulate cortex/medial prefrontal cortex and decreased variability in the fusiform gyrus/inferior temporal gyrus in autistic children compared with TC children. Autistic children additionally showed lower intrahemispheric dFCD variability in sensorimotor regions including the precentral/postcentral gyrus. Moreover, aberrant temporal variability of the contralateral dFCD predicted the severity of social communication impairments in autistic children. These findings demonstrate altered temporal dynamics of the intra‐ and interhemispheric functional connectivity in brain regions incorporating social brain network of ASD, and highlight the potential role of abnormal interhemispheric communication dynamics in neural substrates underlying impaired social processing in ASD.     

Selective serotonin reuptake inhibitor-related extrapyramidal symptoms in autistic children: a case series

Abnormal movements occur rarely with selective serotonin reuptake inhibitors (SSRIs). This report describes four consecutive autistic children who developed extrapyramidal side effects (EPS) following SSRI exposure. Videotapes, physician notes, and parental interviews were used retrospectively to rate symptoms on the Extrapyramidal Symptom Rating Scale. Findings suggest that EPS is a potential complication of SSRI treatment in autistic children.     

Altered motor network recruitment during finger tapping in boys with Tourette syndrome

In Tourette syndrome (TS), not only the tics but also the findings on deficits in motor performance indicate motor system alterations. But our knowledge about the pathophysiology of the motor system in TS is still limited. To better understand the neuronal correlates of motor performance in TS, 19 treatment‐naïve boys [age 12.5 (SD 1.4) years] with TS without comorbid symptomatology were compared to an age‐matched healthy control group [n = 16; age 12.9 (SD 1.6) years] in regard to brain activation during right‐hand index finger tapping by means of functional magnetic resonance imaging. Group differences were found mainly in the left (contralateral) precentral gyrus, which was less activated in boys suffering from TS and in caudate nucleus as well as in medial prefrontal cortex, which was more activated compared to healthy boys. These results show that even in the first years after the onset of the disorder, an altered brain network of motor performance is recruited. These alterations in brain regions frequently associated with TS are probably based on functional changes, which are discussed in terms of early compensatory mechanisms of the motor execution network. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Social information processing in boys with autistic spectrum disorder and mild to borderline intellectual disabilities

Background   Children with autistic spectrum disorders (ASD) and mild to borderline intellectual disability (ID) have less adaptive behaviour and more behaviour problems than children with mild to borderline ID. Social information processing appears to be an important mechanism in the explanation of the socially inadequate behaviour of children with mild to borderline ID; however, little is known about the social information processing skills of children with ASD and mild to borderline ID.
Method   In the present study, a total of 136 boys in the age of 10–14 years participated; 26 with ASD (specifically Pervasive Developmental Disorder – Not Otherwise Specified) and mild to borderline ID, 54 with mild to borderline ID without ASD and 56 typically developing boys. They completed the Social Problem Solving Test to measure their social information processing.
Results   The research results show boys with PDD-NOS and mild to borderline ID to differ from typically developing boys in their encoding of information; they focus on negative and emotional information in the social situation. They differ from boys with mild to borderline ID in response generation, evaluation of inadequate solutions (aggressive and submissive responses) and assertive response decision.
Conclusions   The present study extends our knowledge regarding social information processing of children with ASD (PDD-NOS) and mild to borderline ID. This knowledge may be helpful in designing and adapting programmes (e.g. social skills training, self-management training) for the management of behaviour problems and development of adaptive behaviour of children with ASD and mild to borderline ID.     

Altered chemical metabolites in the amygdala-hippocampus region contribute to autistic symptoms of autism spectrum disorders.

BACKGROUND: Although several previous studies have been conducted, the neural basis of autism spectrum disorder (ASD) is poorly understood. The objective of the present study was to determine whether individuals with ASD have altered brain chemical metabolites and whether such alterations are related to their autistic symptoms. METHODS: N-acetylaspartate (NAA)/creatine (Cr) and choline/Cr ratios in the right medial temporal lobe (MTL), medial prefrontal cortex, and cerebellar vermis were measured in 38 individuals with ASD (mean age = 12.9 years), including 12 with autism, 15 with Asperger's Disorder, and 11 with pervasive developmental disorder not otherwise specified (PDD-NOS), and 16 matched healthy control subjects (mean age = 11.5 years) with proton magnetic resonance spectroscopy. Autistic symptoms were assessed by the Childhood Autistic Rating Scale-Tokyo Version. RESULTS: There was a significant group difference for NAA/Cr ratio in the right MTL between the autism, Asperger's Disorder, PDD-NOS, and control groups (p < .001), and the autism group had a significantly lower NAA/Cr ratio compared with the PDD-NOS (p < .001) and control (p < .001) groups. In the ASD group, there was a significant negative correlation between NAA/Cr ratio in the right MTL and their Childhood Autistic Rating Scale-Tokyo Version total scores (r = -.44, p = .01) and subscales of emotional response (r = -.38, p = .02) and listening response (r = -.54, p = .001). CONCLUSIONS: The results of the present study suggest that subjects with ASD have abnormalities of neural integrity in the amygdala-hippocampus region that are related to their severity and social impairments.     

Examination of circadian rhythmicity of blood serotonin and platelets in autistic and non-autistic children

A study was designed to determine whether circadian rhythmicity existed for blood serotonin concentrations and platelet counts in autistic and non-autistic children. Blood samples were drawn from hospitalized children, outpatients, and normal adults at varying times throughout the day and over prolonged periods. Circadian rhythmicity was not observed. The possibility remains that there existed very brief or prolonged rhythms which were not detectable by the methods used. The implications of these results in relation to previous findings on blood serotonin concentrations and platelet counts in autistic and non-autistic children are discussed.This research was supported by Public Health Service Grant HD 94612 to the UCLA Mental Retardation Center and the California Department of Mental Hygiene. The authors are indebted to Mrs. Rose Weisler, Miss Selma Plotkin, Miss Juli Wasserman and Mr. Joseph DeLee for administrative assistance and to Dr. J. Raymond and Miss Gwen McAfee of the UCLA Clinical Laboratory for help with platelet counts.     

Altered rapid eye movement sleep timing in serotonin transporter knockout mice

The monoamine neurotransmitter serotonin has long been implicated in development and maintenance of sleep patterns, yet the role of the serotonin transporter (SERT) in these processes has not been evaluated in detail. We report that genetically engineered SERT knockout mice exhibit more REM sleep (REMS) than wild type littermates (11 vs 7% of recording time under baseline conditions) and display more frequent REMS bouts that last longer. This phenotype resembles the previously reported long-term effect of repeated treatment with SERT inhibitor compounds rather than the acute REMS suppressing effect of treatment with such compounds, and is thus likely to reflect neuroadaptations to the absence of SERT, rather than an acute effect of its absence in the adult. While electroencephalographic (EEG) spectra did not differ between SERT knockout and wild type mice during non-REM sleep (NREMS) or REMS, the dynamics of the EEG during the transition from NREMS to REMS differed between the genotypes. The surge in EEG power in both the 6-9 Hz and 10-16 Hz ranges that occurs just prior to the onset of REMS (pre-REMS power surge) is of greater magnitude in SERT knockout mice than in wild type littermate controls. This observation contrasts with the reduced magnitude pre-REMS power surge observed in rats subjected to REMS deprivation relative to yoked controls. These results indicate that the pre-REMS power surge is influenced by REMS history and by monoaminergic transmission. Genetic differences in serotonin systems and developmental exposure to SERT blockers are likely to exert effects on REMS.