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

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

doi:10.1093/brain/awu178

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

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

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Abstract

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.

Original language	English
Pages (from-to)	2600-2610
Number of pages	11
Journal	Brain
Volume	137
Issue number	9
Early online date	27 Jul 2014
DOIs	https://doi.org/10.1093/brain/awu178
Publication status	Published - 1 Sept 2014

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Response inhibition and serotonin_DALY_Acc23 May2014_GOLD VoR(CC BY NC)Final published version, 874 KBLicence: CC BY-NC

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Daly, E., Ecker, C., Hallahan, B., Deeley, Q., Craig, M., Murphy, C., Johnston, P., Spain, D., Gillan, N., Gudbrandsen, M., Brammer, M., Giampietro, V., Lamar, M., Page, L., Toal, F., Schmitz, N., Cleare, A., Robertson, D., Rubia, K., & Murphy, D. G. M. (2014). Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion. Brain, 137(9), 2600-2610. https://doi.org/10.1093/brain/awu178

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title = "Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion",

abstract = "It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.",

author = "Eileen Daly and Christine Ecker and Brian Hallahan and Quinton Deeley and Michael Craig and Clodagh Murphy and Patrick Johnston and Debbie Spain and Nicola Gillan and Maria Gudbrandsen and Michael Brammer and Vincent Giampietro and Melissa Lamar and Lisa Page and Fiona Toal and Nicole Schmitz and Anthony Cleare and Dene Robertson and Katya Rubia and Murphy, {Declan G M}",

year = "2014",

month = sep,

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doi = "10.1093/brain/awu178",

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Daly, E , Ecker, C, Hallahan, B, Deeley, Q , Craig, M , Murphy, C , Johnston, P , Spain, D , Gillan, N , Gudbrandsen, M , Brammer, M , Giampietro, V, Lamar, M, Page, L, Toal, F, Schmitz, N, Cleare, A, Robertson, D, Rubia, K & Murphy, DGM 2014, 'Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion', Brain, vol. 137, no. 9, pp. 2600-2610. https://doi.org/10.1093/brain/awu178

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T2 - a functional MRI study using acute tryptophan depletion

AU - Daly, Eileen

AU - Ecker, Christine

AU - Hallahan, Brian

AU - Deeley, Quinton

AU - Craig, Michael

AU - Murphy, Clodagh

AU - Johnston, Patrick

AU - Spain, Debbie

AU - Gillan, Nicola

AU - Gudbrandsen, Maria

AU - Brammer, Michael

AU - Giampietro, Vincent

AU - Lamar, Melissa

AU - Page, Lisa

AU - Toal, Fiona

AU - Schmitz, Nicole

AU - Cleare, Anthony

AU - Robertson, Dene

AU - Rubia, Katya

AU - Murphy, Declan G M

PY - 2014/9/1

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N2 - It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.

AB - It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.

U2 - 10.1093/brain/awu178

DO - 10.1093/brain/awu178

M3 - Article

C2 - 25070512

SN - 0006-8950

VL - 137

SP - 2600

EP - 2610

JO - Brain

JF - Brain

IS - 9

ER -

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

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