Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Watanabe, Takamitsu; Yahata, Noriaki; Abe, Osamu; Kuwabara, Hitoshi; Inoue, Hirokazu; Takano, Yosuke; Iwashiro, Norichika; Natsubori, Tatsunobu; Aoki, Yuta; Takao, Hidemasa; Sasaki, Hiroki; Gonoi, Wataru; Murakami, Masaya; Katsura, Masaki; Kunimatsu, Akira; Kawakubo, Yuki; Matsuzaki, Hideo; Tsuchiya, Kenji J.; Kato, Nobuo; Kano, Yukiko; Miyashita, Yasushi; Kasai, Kiyoto; Yamasue, Hidenori

doi:10.1371/journal.pone.0039561

Cited by 69 publications

(74 citation statements)

References 56 publications

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“…The 40 participants with ASD included all 15 participants with ASD in our previous case-control fMRI study. 8 Seven of them were excluded because of technical problems (2 participants), current use of a psychotropic medication (2 participants), or frequent atypical responses to congruent stimuli (3 participants).…”

Section: Participantsmentioning

confidence: 99%

“…The task and stimuli in this study were the same as those used in our previous case-control 8 and healthy participant 37 studies. The stimuli consisted of 80 original monochrome movies with a length of 1.5 seconds (Video).…”

Section: Task and Stimulimentioning

confidence: 99%

“…This analysis was conducted as a region-of-interest (ROI) analysis for 7 brain regions (eTable 2 in Supplement) that were a priori selected on the basis of our previous case-control study. 8 The ROIs were defined as 4-mm-radius spheres. To validate the spatial specificity of oxytocin's neural effects, we also conducted a whole-brain analysis using a random-effects model (P < .05 corrected based on the family-wise error [FWE] rate).…”

Section: Fmri Analysismentioning

confidence: 99%

“…In our previous case-control fMRI study that compared behavioral and neural responses during the task between TD individuals and those with ASD, 8 the individuals with ASD showed significantly fewer NVJs with significantly longer response times (eFigure 2 in Supplement). During the judgments, they also showed significantly diminished brain activity in several brain regions, including medial prefrontal regions (eTable 2 in Supplement).…”

mentioning

confidence: 96%

“…4,[25][26][27]29 We devised a psychological task that requires participants to make judgments regarding the intentions of others based on sociocommunicational content in which the verbal and nonverbal information conflicts. This task is thought to be appropriate for examining oxytocin's effects on sociocommunicational deficits of ASD because, in our previous case-control study using functional magnetic resonance imaging (fMRI), 8 the same task enabled us to detect ASDspecific neural responses whose magnitudes significantly correlated with the severity of sociocommunicational deficits. Moreover, previous studies have also suggested that psychological tasks focusing on understanding others' intention, based on a process of verbal and nonverbal conflicts, can effectively detect sociocommunicational deficits in individuals with ASD.…”

mentioning

confidence: 99%

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Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity

et al. 2014

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IMPORTANCE Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocin's beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide.OBJECTIVE To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial.INTERVENTIONS Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURESUsing functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTSIntranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P Յ .01). CONCLUSIONS AND RELEVANCEThese findings provide the first neurobiological evidence for oxytocin's beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide.TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393

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Section: Participantsmentioning

confidence: 99%

Section: Task and Stimulimentioning

confidence: 99%

Section: Fmri Analysismentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity

et al. 2014

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Cortical and subcortical glutathione levels in adults with autism spectrum disorder

et al. 2015

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Increased oxidative stress has been postulated to contribute to the pathogenesis of autism spectrum disorder (ASD). However, reports of alterations in oxidation markers including glutathione (GSH), the major endogenous antioxidant, are indirect, coming from blood plasma level measurements and postmortem studies. Therefore we used in-vivo 3 Tesla proton magnetic resonance spectroscopy ([1H]MRS) to directly measure GSH concentrations in the basal ganglia (BG) and the dorsomedial prefrontal cortex of 21 normally intelligent adult males with ASD and 29 controls who did not differ in age or IQ. There was no difference in brain GSH between patients and controls in either brain area; neither did GSH levels correlate with measures of clinical severity in patients. Thus [1H]MRS measures of cortical and subcortical GSH are not a biomarker for ASD in intellectually able adult men. Autism Res 2016, 9: 429-435.

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Levodopa treatment and dendritic spine pathology

et al. 2017

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Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission. Recent studies using rodent models have reported dendritic spine head enlargement in the caudate-putamen, nucleus accumbens, primary motor cortex, and prefrontal cortex in cases where chronic levodopa treatment following dopaminergic denervation induced dyskinesia-like abnormal involuntary movement. Hypertrophy of spines results from insertion of alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptors into the postsynaptic membrane. Such spine enlargement indicates hypersensitivity of the synapse to excitatory inputs and is compatible with a lack of depotentiation, which is an electrophysiological hallmark of levodopa-induced dyskinesia found in the corticostriatal synapses of dyskinetic animals and the motor cortex of dyskinetic PD patients. This synaptic plasticity may be one of the mechanisms underlying the priming of levodopa-induced complications such as levodopa-induced dyskinesia and dopamine dysregulation syndrome. Drugs that could potentially prevent spine enlargement, such as calcium channel blockers, N-methyl-D-aspartate receptor antagonists, alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid receptor antagonists, and metabotropic glutamate receptor antagonists, are candidates for treatment of levodopa-induced complications in PD. © 2017 International Parkinson and Movement Disorder Society.

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Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Cited by 69 publications

References 56 publications

Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity

Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity

Cortical and subcortical glutathione levels in adults with autism spectrum disorder

Levodopa treatment and dendritic spine pathology

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