Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion

Daly, Eileen; Ecker, Christine; Hallahan, Brian; Deeley, Quinton; Craig, Michael C.; Murphy, Clodagh; Johnston, Patrick G.; Spain, Debbie; Gillan, Nicola; Gudbrandsen, Maria; Brammer, Michael; Giampietro, Vincent; Lamar, Melissa; Page, Lisa; Toal, Fiona; Schmitz, Nicole; Cleare, Anthony J.; Robertson, Dene; Rubia, Katya; Murphy, Declan

doi:10.1093/brain/awu178

Cited by 57 publications

(66 citation statements)

References 59 publications

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“…The amounts used are standard for ATD studies (e.g. Evers et al ., ; Fusar‐Poli et al ., ; Bilderbeck et al ., ; Daly et al ., , ). The total protein of the TRP‐ drink was 82.1 g. The amount of each amino acid contained in the TRP‐ drink was l ‐Alanine, 4.4 g; l ‐Arginine 3.9 g; l ‐Cystine, 2.2 g; Glycine, 2.6 g; l ‐Histidine, 2.6 g; l ‐Isoleucine, 6.4 g; l ‐Leucine, 10.8 g; l ‐Lysine monohydrochloride, 8.8 g; l ‐Methionine, 2.4 g; l ‐Phenylalanine, 4.6 g; l ‐Proline, 9.8 g; l ‐Serine, 5.5 g; l ‐Threonine, 5.5 g; l ‐Tyrosine, 5.5 g; l ‐Valine, 7.1 g. The TRP+ drink was the same as the TRP‐ drink, with the addition of 1.8 g l ‐Tryptophan.…”

Section: Methodsmentioning

confidence: 99%

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

Trotter

McGlone

McKie

et al. 2016

Eur J of Neuroscience

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C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4 h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. In addition, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were similar across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function.

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Section: Methodsmentioning

confidence: 99%

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

Trotter

McGlone

McKie

et al. 2016

Eur J of Neuroscience

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“…Tryptophan depletion, which is expected to cause decreased synaptic 5-HT, leads to worsened repetitive behaviors and irritability in autism (McDougle et al, 1993, McDougle et al, 1996). Neuroimaging studies show differential effects of tryptophan depletion on brain region activity by fMRI in the ASD population in contrast to typical controls, particularly in response to presentation of emotional faces (Daly et al, 2012, Daly et al, 2014). Adult studies suggested that serotonin reuptake inhibitors relieve symptoms of irritability and rigid-compulsive behavior in autism (Gordon et al, 1993, Hollander et al, 2005, Hollander et al, 2012); however studies in children have been less supportive, perhaps because of greater adverse events in children or because of methodological difficulties (King et al, 2009, King et al, 2013).…”

Section: The Central Serotonin System In Autism Spectrum Disordermentioning

confidence: 99%

The serotonin system in autism spectrum disorder: From biomarker to animal models

2016

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Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker.

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“…7 Serotonin plays a substantial role in abnormal inhibitory networks in autism. 11 The plasma level of tryptophan, which is a precursor for serotonin synthesis, is decreased in autism. 12 Moreover, supplementation with tryptophan as a precursor of serotonin is supposed to be effective for autism prevention.…”

Section: Introductionmentioning

confidence: 99%

A Randomized Double-Blind Placebo-Controlled Clinical Trial of Adjuvant Buspirone for Irritability in Autism

Ghanizadeh

Ayoobzadehshirazi

2015

Pediatric Neurology

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Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion

Cited by 57 publications

References 59 publications

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

Effects of acute tryptophan depletion on central processing of CT‐targeted and discriminatory touch in humans

The serotonin system in autism spectrum disorder: From biomarker to animal models

A Randomized Double-Blind Placebo-Controlled Clinical Trial of Adjuvant Buspirone for Irritability in Autism

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