Intra-individual cognitive imbalance in ASD between perceptual reasoning and ambiguity-solving related to tool use: Comparison among children exhibiting ASD, AD/HD, and typical development.

OBJECTIVE: Several studies have suggested that objective deficits in the processing of abstract information in conjunction with an enhanced ability to process concrete information is a definitive characteristic of autism spectrum disorder (ASD). However, this cognitive imbalance is not necessarily clear in high-functioning autistic individuals who do not display absolute differences relative to typically developing (TD) populations. Thus, the purpose of this study was to identify this cognitive tendency in high-functioning autistic individuals using intra-individual cognitive comparisons. METHODS: The reaction times (RTs) of TD children, children with ASD, and children with attention deficit hyperactivity disorder (AD/HD) (n=17 in each group, mean age=11.9years, age range=9.8-15.8years) were compared using the Which/How-to-Apply Tools (W/HAT) test, which consists of tasks requiring the adaptive use of novel tools and familiar tools in atypical and typical situations. Differences in RTs between the atypical and typical trials ([A-T]) were used to assess intra-individual cognitive imbalances. RESULTS: As predicted, the [A-T] scores of the ASD group were significantly higher than those of the TD group even though the RTs in the atypical and typical trials did not differ. Additionally, the [A-T] values were significantly higher in the ASD group than in the AD/HD group, which indicates that the cognitive imbalance was specific to ASD individuals. No significant interaction was detected between the trial and subject group. CONCLUSIONS: The findings of this study demonstrate that a cognitive imbalance in ASD individuals may enhance the current understanding of the pathophysiology of this disorder, which is found in a range of individuals, including those with obvious cortical dysfunction to those with only intra-individual imbalances.

Adaptive ability to cope with atypical or novel situations involving tool use: an fMRI approach.

We investigated the neural mechanisms underlying the ability to cope in atypical or novel situations using tools. We hypothesized that two cognitive components support this ability: adaptive coordination (for adapting to situational demands) and cognitive inhibition (for inhibiting the incongruent actions afforded by tools). We had subjects choose novel tools for a given task or choose among familiar tools in an atypical situation, during which we examined cortical activation in their brains using functional magnetic resonance imaging. Neural activation during adaptive coordination was observed in the left lateral orbitofrontal cortex, inferior frontal gyrus and sulcus, middle and medial frontal gyrus, intraparietal sulcus, precentral sulcus, inferior temporal gyrus, supramarginal gyrus, the bilateral insula, anterior cingulate cortex, and the right callosal sulcus. Activation indicating cognitive inhibition was observed in the right middle and inferior frontal gyrus. These findings demonstrate that the left parietal region shapes basic action, whereas the right frontal region inhibits stereotypical action. The left frontal regions are thought to be linked to the processing of ambiguous actions and play key roles in coordinating actions, whereas other regions are involved in processing situational contexts. Our results may be important for understanding the neural systems underlying adaptability to daily social situations.

Onset of clinical effects and plasma concentration of fluvoxamine in Japanese patients.

It is widely accepted that selective serotonin reuptake inhibitors (SSRIs) require 2 to 4 weeks of administration before improvements in emotional symptoms of depression are seen. We evaluated whether early monitoring of Hamilton Rating Scale for Depression (HAMD) scores in patients treated with the SSRI fluvoxamine could predict antidepressant response, and also assessed the relationship between the onset of clinical response following the start of fluvoxamine administration and its plasma concentration. Twelve depressed patients (baseline HAMD score ≥15) received an initial dose of fluvoxamine (50 mg/d) followed by an optimized maintenance dose according to their clinical symptoms after 7 d. HAMD scores and plasma drug concentrations were determined at 7 and 28 d after the first administration. There were 7 responders and 5 non-responders on day 28, as evaluated by HAMD scores. The HAMD score for the responders was significantly lower than that for the non-responders on day 7 (mean±S.D., 11.6±6.1 vs. 26.6±6.5, p=0.006). Thus, the reduction in HAMD score on day 7 was clearly divided between responders and non-responders. On day 28, the plasma concentration of fluvoxamine in responders was lower than that in non-responders (14.2±10.5 ng/ml vs. 44.2±28.1 ng/ml, p=0.051). Furthermore, receiver operating characteristic curve analysis conducted on day 28 revealed an upper concentration threshold of 28.2 ng/ml (p=0.042), with none in the responder group above that level. Our results suggest that HAMD score after the first week of treatment with fluvoxamine and the upper threshold of plasma drug concentration could predict whether a patient is a non-responder.

Further evidence for the role of MET in autism susceptibility.

MET receptor tyrosine kinase (MET)-mediated signaling has been implicated in multiple aspects of neocortical and cerebellar neuronal growth and maturation. A promoter functional SNP (rs1858830) that disrupts the transcription of MET has been reported to be strongly associated with autism spectrum disorders (ASD) in the Caucasian population. Here, we performed a trio association study of MET with ASD in Japanese subjects (n=126 trios). Based on the HapMap data on the Japanese population, 15 SNPs were chosen for the association study. One SNP located in intron 1, rs38841, showed a nominal association with autism (p=0.044; OR=1.61) when analyzed using the transmission disequilibrium test. To the best of our knowledge, this is the first replication study of the association of MET with autism, in any non-Caucasian population. Association of rs38841 with autism was further confirmed in 252 Caucasian trios from AGRE (p=0.0006). An interesting observation is that all three SNPs of MET (rs1858830, rs38845 and rs38841) shown to be associated with autism in three independent studies including the present one, are located towards the 5'end of the gene at a span of 9.4 kb. Our results provide further evidence for a possible role of MET in the pathogenesis of ASD.

Effects of cigarette smoking and cytochrome P450 2D6 genotype on fluvoxamine concentration in plasma of Japanese patients.

Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiatric diseases. The aim of this study was to assess the clinical impact of cigarette smoking on plasma fluvoxamine concentration in Japanese patients, and evaluate whether the cytochrome P450 (CYP) 1A2 and CYP2D6 genotypes have effects on that concentration. Thirty-two Japanese patients receiving fluvoxamine were enrolled. They were maintained on the same daily dose of fluvoxamine (mean + or - S.D., 109.4 + or - 66.2 mg/d) for at least 4 weeks to obtain the steady-state plasma concentration. The steady-state plasma concentration-to-dose (C/D) ratio of fluvoxamine in patients who smoked (n = 6, 11.8 + or - 6.5 ng/ml/dose) was significantly lower than that in non-smoker patients (n = 26, 22.8 + or - 11.2 ng/ml/dose). There was no significant difference for the C/D ratio of fluvoxamine in patients with CYP1A2 -3860G/G, -3860G/A, and -3860A/A between non-smokers and smokers. Among non-smoker patients, the C/D ratios of fluvoxamine in those with one and two mutated alleles of CYP2D6 were 1.6- and 1.4-fold higher, respectively, than those with no mutated alleles, though the differences among those three genotype groups were not significant. Furthermore, stepwise multiple regression analysis revealed that cigarette smoking and daily dose had significant positive correlations with the plasma concentration of fluvoxamine. Our findings suggest that cigarette smoking has a significant impact on the steady-state plasma concentration of fluvoxamine in Japanese patients.

An association study of monoamine oxidase A (MAOA) gene polymorphism in methamphetamine psychosis.

Methamphetamine continues to be the most widely abused drug in Japan. Chronic methamphetamine users show psychiatric signs, including methamphetamine psychosis. Monoamine oxidase A (MAOA) is one of the major enzymes responsible for the degradation of neurotransmitters. Abnormalities in MAO levels have been related to a wide range of psychiatric disorders. We examined whether or not the MAOA-u variable-number tandem repeat (VNTR) has a functional polymorphism in methamphetamine psychosis and whether or not such a polymorphism is related to the prolongation of psychosis. As expected, there was a significant difference in the MAOA-u VNTR between males with persistent versus transient methamphetamine psychosis (p=0.018, odds ratio (OR)=2.76, 95% CI: 1.18-6.46). Our results suggest that the high-activity allele class of MAOA-u VNTR in males may be involved in susceptibility to a persistent course of methamphetamine psychosis. We found no differences among females. The sample size of females with methamphetamine psychosis was too small to have significant analysis.

Genetic and expression analyses reveal elevated expression of syntaxin 1A ( STX1A) in high functioning autism.

Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (5-HTT), which modulates serotonin levels, is a major therapeutic target in autism. Therefore, factors that regulate 5-HTT expression might be implicated in autism. One candidate 5-HTT-regulatory protein is the presynaptic protein, syntaxin 1A (STX1A). We examined the association of STX1A with autism in a trio association study using DNA samples from 249 AGRE trios with autistic probands. Only male probands were selected, since autism is more prevalent among males. The probands of 102 trios had IQ>70, and were considered as high functioning autism (HFA). In transmission disequilibrium test (TDT) analysis, rs2293485 (p=0.034) and rs4717806 (p=0.033) showed nominal associations with HFA; modest haplotype association was also observed. The SNPs that showed associations were related to early developmental abnormalities (ADI-R_D). We further compared STX1A mRNA expression in the lymphocytes of drug-naive HFA patients (n=12) and age- and sex-matched controls (n=13). STX1A expression in the HFA group was significantly higher (p=0.001) than that of controls. Thus, we suggest a possible role of STX1A in the pathogenesis of HFA. During early childhood, there is a period of high brain serotonin synthesis that is disrupted in autistic children; STX1A might influence the serotonergic system during this stage of neurodevelopment, as implied by the association with ADI-R_D.

A novel scale including strabismus and 'cuspidal ear' for distinguishing schizophrenia patients from controls using minor physical anomalies.

The present study explored minor physical anomaly items relevant to schizophrenia in order to establish a scale that can distinguish schizophrenia from controls using newly identified items along with items from the refined Waldrop scale. Seven items were significantly more frequent among schizophrenia patients (N=218) than controls (N=226). Among these seven items, two novel features, strabismus and 'cuspidal ear' showed markedly different prevalence rates between schizophrenia and control groups. A six-item scale, including the newly identified strabismus and cuspidal ear, was selected for most accurately discriminating patients with schizophrenia from controls. This scale correctly classified 59.6% of patients and 78.9% of control subjects. This new scale is procedurally more exacting and quantitative, and more relevant to schizophrenia than the original Waldrop scale. The validity of this scale should be sound since it was tested on a larger number of cohorts than used in previous research. Our scale can be used as a biomarker for predicting risk for future development of schizophrenia. The scale may also facilitate the identification of schizophrenia susceptibility genetic/environmental factors by stratifying etiologically heterogeneous patients according to physical abnormalities.

Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts.

BACKGROUND: DISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts. METHODS: We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing. RESULTS: The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396T

A polydiagnostic and dimensional comparison of epileptic psychoses and schizophrenia spectrum disorders.

After establishing the validity of the Japanese version of the Operational Criteria Checklist for Psychotic Illness (OPCRIT), we applied it to 58 consecutive patients with epileptic psychoses (index group) and to age- and sex-matched controls with schizophrenia spectrum disorders (control group). Compared with the control group, the index group had a low family history of schizophrenia, high premorbid personality disorder and unemployment, abrupt or acute onset of psychosis, good recovery with single or multiple episodes, and low deterioration from a premorbid level of function. From 9% to 52% of the index group and 38% to 84% of the control group were diagnosed with schizophrenia according to the operational criteria used. The percentages of patients diagnosed with schizophrenia based on various diagnostic criteria in the two groups were similar. In the index group, a diagnosis of schizophrenia was more commonly made among patients with inter-ictal psychosis than among those with post-ictal psychosis. An exploratory factor analysis identified five factor solutions of manic, negative, depressive, vegetative, and positive symptoms. Although positive and negative factor values were lower in the index group than in the control group, the two groups shared a similar factor profile. These results indicate that the difference in symptomatology between the two groups was quantitative rather than qualitative.

Childhood-onset schizophrenia and tryptophan hydroxylase gene polymorphism.

We explored the relationship between the tryptophan hydroxylase gene polymorphism and susceptibility to childhood-onset schizophrenia in a Japanese sample. Subjects were 51 Japanese patients who met DSM-IV criteria for schizophrenia before age 16 and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was performed by PCR-RFLP using Nhe I. The frequency of the A allele was relatively higher in patients with childhood-onset schizophrenia than in controls (odds ratio, OR = 1.47, 95% CI = 0.97-2.37, P = 0.097). There was a nearly doubling of the risk for childhood-onset schizophrenia associated with the AA genotype compared to other genotype groups; OR = 1.97, 95% CI = 0.91-4.22, P = 0.058.

Obstetric adversity and age at first presentation with schizophrenia: evidence of a dose-response relationship.

OBJECTIVE: The purpose of the study was to determine if a dose-response relationship exists between obstetric adversity and age at first presentation with schizophrenia. METHOD: The Dublin Psychiatric Case Register was used to identify subjects with schizophrenia. Data on obstetric complications, social class of origin, and family history of psychiatric illness were obtained for those subjects. RESULTS: A total of 409 patients with ICD-9 schizophrenia were identified. Patients with a history of obstetric complications presented earlier to psychiatric services. As the number of complications increased, the mean age at first presentation decreased. This effect was independent of social class of origin and family history of psychiatric illness. CONCLUSIONS: Obstetric adversity exerts an independent influence on the age at first presentation with schizophrenia, in a dose-response manner. This finding supports the existence of a causal relationship between obstetric adversity and age at first presentation with schizophrenia.

Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B.

The increased incidence of minor physical anomalies (MPAs) in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. Ocular misalignment, or strabismus, falls into the category of MPAs, but this phenotype has not been assessed in schizophrenia. This study reveals that a subtype of strabismus, constant exotropia, displays marked association with schizophrenia (P=0.00000000906). To assess the genetic mechanisms, we examined the transcription factor genes ARIX (recently identified as a causative gene for syndromic strabismus) and its paralogue, PMX2B. We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia (P=0.029). The polymorphisms were also associated with overall schizophrenia (P=0.012) and more specifically with schizophrenia manifesting strabismus (P=0.004). These results suggest a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. This study also highlights the unique nature of the polyalanine length variations found in PMX2B. In contrast with other transcription factor genes, the variations in PMX2B show a high prevalence, with deletions being more common than insertions. Additionally, the polymorphisms are of ancient origin and stably transmitted, with mild phenotypic effects. In summary, our study lends further support to the disruption of neurodevelopment in the etiology of schizophrenia, by demonstrating the association of a specific MPA, in this case, constant exotropia with schizophrenia, along with molecular variations in a possible causative gene.