Thursday 14 July 2011

light on autism

Siblings of individuals with autism
A novel functional brain imaging endophenotype

of autism: the neural response to facial expression of

emotion

MD Spencer1, RJ Holt1, LR Chura1, J Suckling2, AJ Calder3, ET Bullmore2 and S Baron-Cohen1

Siblings of individuals with autism have over 20 times the population risk of autism. Evidence of comparable, but less marked,

cognitive and social communication deficits in siblings suggests a role for these traits in the search for biomarkers of familial

risk. However, no neuroimaging biomarkers of familial risk have been identified to date. Here we show, for the first time, that the

neural response to facial expression of emotion differs between unaffected siblings and healthy controls with no family history of

autism. Strikingly, the functional magnetic resonance imaging (fMRI) response to happy versus neutral faces was significantly

reduced in unaffected siblings compared with controls within a number of brain areas implicated in empathy and face

processing. The response in unaffected siblings did not differ significantly from the response in autism. Furthermore,

investigation of the response to faces versus fixation crosses suggested that, within the context of this study, an atypical

response specifically to happy faces, rather than to faces in general, accounts for the observed sibling versus controls

difference and is a clear biomarker of familial risk. Our findings suggest that an atypical implicit response to facial expression of

emotion may form the basis of impaired emotional reactivity in autism and in the broader autism phenotype in relatives. These

results demonstrate that the fMRI response to facial expression of emotion is a candidate neuroimaging endophenotype for

autism, and may offer far-reaching insights into the etiology of autism.

Translational Psychiatry (2011) 1, e19; doi:10.1038/tp.2011.18; published online 12 July 2011

Introduction

Siblings of individuals with autism have a greatly enhanced

risk of developing autism—estimated to be in excess of a 20-

fold increase compared with the general population.1–3

Furthermore, it is increasingly understood that many apparently

unaffected siblings (and their parents, as another

example of first-degree relatives) display subtle impairments

in the cognitive domains characteristically affected by

autism.4–7 Siblings of individuals with autism have however

been the subject of relatively little neuroimaging research.8–10

The concept of an endophenotype—a marker of familial risk

for a condition—has in recent years become the focus of

considerable attention in neuropsychiatric research. Although

the term was first used in the 1960s in the field of insect

biology,11 within a few years it was applied within psychiatry.12

An endophenotype is a heritable feature associated with a

condition, present in affected individuals regardless of

whether their condition is manifested, which co-segregates

with the condition in families and which is present in

unaffected family members at a higher rate than in the

general population.13 In such family members, endophenotypes

represent instances in which genes associated with a

particular condition exert measurable effects in individuals in

whom they are insufficient to cause the condition itself to

become manifest. The promise of characterizing endophenotypes

lies in their hypothesized intermediate position between

genotype and phenotype. Syndromes such as autism,

schizophrenia and bipolar disorder are complex constellations

of clinical signs and symptoms. Considerable phenotypic

heterogeneity exists within clinical populations and it is

likely that the etiologies of these conditions contain heterogeneity

too. In the case of autism, it has been recognized that

a unitary cause is unlikely.14 Attempts to characterize the

genetics of these conditions therefore will ultimately be

hampered by a reliance on traditional classificatory systems

that coalesce this heterogeneity into a unitary diagnosis.

As a smaller and simpler phenotypic unit than the condition

itself, the etiology of the endophenotype is likely to be

correspondingly simpler: it can be said to be ‘closer to the

level of gene action’.15

Difficulties in empathy and in the understanding of social

stimuli and situations form a central aspect of the autistic

phenotype.16 The neurophysiological response to faces, and

in particular facial emotional expressions, is atypical in autism.

This has been documented using electroencephalography,17

magnetoencephalography,18 positron emission tomography

19 and functional magnetic resonance imaging (fMRI)20

Received 21 April 2011; revised 2 June 2011; accepted 3 June 2011

1Department of Psychiatry, Autism Research Centre, University of Cambridge, Cambridge, UK; 2Department of Psychiatry, Herchel Smith Building for Brain and Mind

Sciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK and 3MRC Cognition and Brain Sciences Unit, Cambridge, UK

Correspondence: Dr MD Spencer, Department of Psychiatry, Autism Research Centre, University of Cambridge, Douglas House, 18b Trumpington Road, Cambridge

CB2 8AH, UK.

E-mail: mds1003@cam.ac.uk

Keywords: autism; endophenotype; fMRI; genetic; sibling

Citation: Transl Psychiatry (2011) 1, e19, doi:10.1038/tp.2011.18

www.nature.com/tp

studies. A considerable body of evidence reveals atypical

fMRI response to faces and other social stimuli within a

network of brain structures that has been termed the ‘social

brain’.21,22 This comprises the amygdala and its interconnections

with the superior temporal sulcus (STS), orbitofrontal

cortex, anterior cingulate cortex and fusiform face area (FFA),

among other regions. The STS is of particular importance not

only in being activated during a range of mentalizing tasks in

controls23 but also as a site within which brain structure and

function correlate with autistic traits in the general population.

24 Similarly, the FFA located within the fusiform gyrus of

the occipitotemporal cortex is particularly activated by facial

stimuli in controls25 and is greatly reduced in activation in

people with autism.20 Given reports of social deficits in

relatives of those with autism,26 the neural response to

emotional expressions in faces seems a promising area within

which to investigate possible endophenotypes of autism.

The aim of this study was to investigate the neural response

to facial expressions of emotion in adolescents with autism,

their unaffected siblings and controls with no family history of

autism, in order to enable the separation of neurobiological

markers associated with familial risk for autism from those

associated with the condition itself, and thus to suggest

candidate endophenotypes of autism.

Participants and methods

Participants. Participants comprised 40 adolescents (aged

12–18 years) with an autism spectrum disorder (ASD)

diagnosed as either autism or Asperger syndrome, 40

unaffected siblings and 40 typically developing controls. All

ASD participants met Diagnostic and Statistical Manual of

Mental Disorders, fourth edition criteria16 for autism or

Asperger syndrome, and were assessed as positive on

both the Autism Diagnostic Interview-Revised27 and the

Autism Diagnostic Observation Schedule-Generic.28

Participants with autism and their siblings were recruited by

approaching support groups for families with autism and

schools; controls were recruited through notices in schools

and community groups in similar neighborhoods to the

participants in the autism and sibling groups—in order to

minimize possible confounds relating to geography and

demographics. All siblings and controls scored below threshold

on a screening tool for ASD—the Social Communication

Questionnaire.29 Siblings were full biological siblings of the

participants with autism, based on parental report; controls

were defined as having no history of an ASD within any first- or

second-degree relative. General exclusion criteria were: fullscale

intelligence quotient (IQ) o70 as measured using the

Wechsler Abbreviated Scale of Intelligence,30 any psychiatric

diagnosis (other than ASD in the autism group), any current or

previous psychotropic medication, any history of seizures,

any history of head injury or intracranial surgery and any

history of drug abuse.

Participants with autism (35 males:5 females) had mean

age 14.56 years (range: 12.01–18.53; s.d.: 1.74) and mean IQ

106.5 (range: 73–146; s.d.: 16.6). Siblings (12 males:28

females) had mean age 14.83 years (range: 12.01–18.95;

s.d.: 2.14) and mean IQ 113.1 (range: 88–133; s.d.: 10.1).

Controls (20 males:20 females) had mean age 15.06 years

(range: 12.08–18.17; s.d.: 1.63) and mean IQ 112.4 (range:

83–136; s.d.: 11.1). Groups did not differ in terms of mean age

(P¼0.481; F¼0.737). The autism group had significantly

lower mean IQ than the sibling group (P¼0.033; F¼4.71) but

not the control group (P¼0.065; F¼3.50). Importantly, for

our investigation of markers of familial risk expressed as

differences between sibling and control groups, sibling and

control groups did not differ in terms of mean IQ (P¼0.753;

F¼0.100).

The protocol was approved by the Cambridgeshire 1

Research Ethics Committee. All participants and their parents

provided written informed consent.

Task protocol. Participants completed a task of implicit

facial emotion processing comprising eight blocks of happy

faces, eight blocks of fearful faces, eight blocks of neutral

faces and eight blocks of fixation crosses. Facial stimuli were

from an established battery of emotional faces,31 and

comprised eight different facial identities expressing happy,

fearful and neutral expressions (that is, 24 faces in total).

Stimuli were presented in a blocked design in one of two

pseudorandom orders (which were counterbalanced across

all participants in each study group) and were presented in

e-Prime version 2.0 Professional (Psychological Software

Tools, Pittsburgh, PA, USA). Each block lasted 20 s and

comprised four stimuli presented for 4 s each with an

interstimulus interval of 1 s. Blocks were separated by a 2 s

interblock interval. During task conditions (happy, fearful and

neutral faces) participants were required to press one of

two buttons to indicate the gender of the face using a

button box held in the right hand. During fixation blocks,

the participants were required to stare passively at a

fixation cross. As with the facial blocks, four fixation cross

stimuli were presented for 4 s each with an interstimulus

interval of 1 s.

Imaging protocol. All participants were scanned using

the same Siemens 3T Tim Trio scanner (Siemens Healthcare,

Erlangen, Germany) at the Medical Research Council Cognition

and Brain Sciences Unit, Cambridge, UK. Functional

images were acquired with a gradient echo planar

imaging sequence with the following parameters: repetition

time¼2000 ms, echo time¼30 ms, voxel size¼3 3 3mm,

field of view¼192 192mm, 64 64 acquisition matrix and a

781 flip angle. In all, 32 slices were acquired descending in the

transverse plane (slice thickness¼3mm, slice gap¼25%).

Each volume was acquired over 2 s and the first three volumes

were discarded to avoid equilibration effects.

Statistical analysis

Behavioral data. Behavioral data comprising accuracy and

reaction time of response on the sex discrimination task were

recorded in order to investigate whether any participant

performed at or below the level of chance and analyzed using

analysis of variance in PASW Statistics 18, Release Version

18.0.0 (SPSS, Chicago, IL, USA). The effect of group on

accuracy (P¼0.111; F¼2.241) and reaction time

(P¼0.191; F¼1.679) of response was not statistically

significant (analyses covarying for age and sex). Only two

A novel functional brain imaging endophenotype of autism

MD Spencer et al

Translational Psychiatry

participants (one participant with autism and one control)

performed at or below the level of chance on the sex

discrimination task. In case this was indicative of reduced

attention to the facial stimuli, all analyses were repeated

excluding these two participants to confirm that all

statistically significant results reported were robust to the

exclusion of the data from these two participants.

Imaging data. Preprocessing and first-level analyses were

performed in SPM8 (Wellcome Department of Cognitive

Neurology, London, UK) implemented using the automatic

analysis platform as previously described32 (Medical Research

Council Cognition and Brain Sciences Unit, Cambridge, UK)

according to the standard Medical Research Council Cognition

and Brain Sciences Unit pipeline comprising sinc

interpolation to correct for the acquisition of different brain

slices at different times, coregistration of echo planar imaging

and structural scans, normalization to Montreal Neurological

Institute (MNI) space33 and smoothing using a Gaussian

kernel of 10mm full width at half maximum. For each

subject, fMRI responses were modeled using a canonical

hemodynamic response function and the general linear model

was used to perform a first level, within-participants analysis

on the functional data from each subject individually for the

primary contrasts (happy minus neutral and fearful minus

neutral faces), with spatial realignment parameters entered as

covariates.

To characterize the patterns of activation within the brain in

the three participant groups, the first-level contrast images for

each study group were taken through to a second-level

analysis using a random-effects model, with age and sex

specified as covariates. Group-level activation maps were

generated with a global threshold set at Po0.05 following

correction for multiple comparisons on a whole-brain level

family-wise error (FWE) basis, and with a cluster extent (kE)

threshold set at 20 voxels. In the same way, all activation

results quoted (Table 1) are after the whole-brain level FWE

correction for multiple comparisons and kE threshold of

20 voxels.

To investigate possible biomarkers of familial risk as compared

with autism versus control differences, we examined

between-group differences in the fMRI response in autism,

sibling and control participants within the specific brain regions

identified as being significantly activated in the control group.We

therefore defined our regions of interest as the clusters of FWE

corrected Po0.05 significant activation within the control group

activation maps (Table 1), and used MarsBar34 to extract mean

activations for the primary contrast (happy minus neutral and

fearfulminus neutral) for each subject for each region of interest.

For illustration, we plotted these FWE corrected activation

maps onto the canonical Montreal Neuroimaging Institute

(MNI) 152 template brain image33 using SPM8, and onto a

three-dimensional-rendered template brain image using MRIcron

software (http://www.sph.sc.edu/comd/rorden/mricron/).35

Table 1 Main activations to happy and fearful versus neutral faces

MNI coordinates P-value

(FWE-corrected)

Z-score Cluster

size

Region

x y z kE (voxels)

Happy versus neutral faces

Control group

28 10 54 0.002 5.07 129 Left superior frontal gyrus

46 20 16 0.003 4.90 78 Right temporal pole

42 14 16 0.004 4.86 200 Left temporal pole

36 62 24 0.006 4.76 77 Left temporoparietal junction

54 64 10 0.009 4.66 115 Left posterior STS

44 52 28 0.010 4.65 60 Right FFA

4 26 54 0.012 4.60 64 Left dorsomedial prefrontal cortex

66 28 2 0.015 4.54 32 Right middle STS

28 92 8 0.018 4.51 26 Right cuneus

62 52 4 0.026 4.41 26 Left middle STS

24 94 8 0.031 4.37 20 Left cuneus

Sibling group

Nil

Autism group

Nil

Fearful versus neutral faces

Control group

44 48 22 0.006 4.78 38 Right FFA

Sibling group

40 42 16 0.005 4.80 33 Right FFA

Autism group

Nil

Abbreviations: FFA, fusiform face area; FWE, family-wise error; MNI, Montreal Neuroimaging Institute; STS, superior temporal sulcus.

Activated brain regions, corresponding MNI coordinates, cluster sizes, Z-scores and P-values. All analyses are corrected for multiple comparisons, and P-values are

expressed following whole brain level FWE correction at the threshold of Po0.05.

A novel functional brain imaging endophenotype of autism

MD Spencer et al

Translational Psychiatry

We conducted analyses of variance within PASW Statistics

18 to measure the overall effect of group on the primary

contrast activation data (happy minus neutral and fearful

minus neutral) for each region of interest. Age and sex were

modeled as covariates in all analyses. Similarly, we used

analyses of variance to investigate autism versus control,

control versus sibling and autism versus sibling differences,

again taking age and sex as covariates. We investigated

linear trend effects across the three groups using polynomial

regression, and where a statistically significant linear effect

was found, we examined the quadratic effect to confirm that

this was nonsignificant. We plotted the mean activation

contrast estimate (expressed in arbitrary units±standard

error of the mean) for the three study groups.

To investigate whether the atypical response to happy

versus neutral faces was driven by an atypical response to

happy or neutral faces, or to both, we examined the response

to faces versus fixation crosses. First-level analysis was as

above, taking the primary contrasts as happy and neutral

faces versus fixation crosses. Second-level statistical analysis

proceeded as described above for the emotional versus

neutral contrasts.

Results

Neural response to facial expressions of emotion: happy

versus neutral faces. We examined the differential

response within the brain to happy compared with neutral

faces. In controls, happy faces elicited increased activation

compared with neutral faces (Figure 1 and Table 1) within a

range of areas strongly implicated in face processing,

empathy and mentalizing: the right (P¼0.003) and left

(P¼0.004) temporal poles, left temporoparietal junction

(P¼0.006), left posterior STS (P¼0.009), right FFA

(P¼0.010), dorsomedial prefrontal cortex (P¼0.012) and

right (P¼0.015) and left (P¼0.026) middle STS. Increased

activation was also detected in the left superior frontal gyrus

(P¼0.002) and the right (P¼0.018) and left (P¼0.031)

cuneus. All P-values are expressed following correction for

multiple comparisons on a whole-brain level FWE basis. In

contrast, no activation differences were detected within

sibling and autism groups at the threshold of Po0.05 FWE

corrected.

To investigate biomarkers of familial risk compared with

autism versus control differences, we examined betweengroup

differences in the fMRI response in autism, sibling and

control participants within the specific brain regions identified

above as being significantly activated in controls to happy

versus neutral faces (listed in Table 1). For all 11 brain

regions, activation was significantly reduced in autism

compared with controls, with siblings demonstrating an

intermediate degree of impairment.

Activation in siblings was significantly reduced compared

with controls for 7 of the 11 brain regions: the left superior

frontal gyrus (P¼0.001; F¼11.664), the right (P¼0.002;

F¼9.986) and left (P¼0.005; F¼8.551) temporal poles, the

right middle (P¼0.004; F¼9.068) and left posterior

(P¼0.016; F¼6.064) STS, the left dorsomedial prefrontal

cortex (P¼0.005; F¼8.570) and the right FFA (P¼0.044;

F¼4.184) (univariate analyses of variance, covarying for age

and sex; Figures 1 and 2). Furthermore, for all 11 regions,

activation in the autism group was significantly reduced

compared with controls, the effect of group was significant

across all the three groups, and polynomial regression linear

contrast effects across all the three groups were significant

Middle

STS

Temporal

pole

FFA

-28 -16 +2

4.6

4.8

5.2

5.0

Superior DMPFC

frontal

Cuneus

Left Right

Posterior

STS

TPJ

P = 0.001 P = 0.002 P = 0.004

+10

0.2

0.1

0.0

0.3

-0.1

autism sibling control

autism sibling control autism sibling control

contrast estimate +/- SE

0.3

0.2

0.1

0.0

-0.1

0.4

-0.2

contrast estimate +/- SE

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0.1

0.0

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0.3

-0.2

contrast estimate +/- SE

0.3

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0.1

0.0

-0.1

contrast estimate +/- SE

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0.2

0.1

0.0

contrast estimate +/- SE

0.1

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0.0

contrast estimate +/- SE

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0.1

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0.0

contrast estimate +/- SE

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-0.1

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contrast estimate +/- SE

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contrast estimate +/- SE

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contrast estimate +/- SE

0.3

0.2

0.1

0.0

-0.1

-0.2

contrast estimate +/- SE

+24 +54

P < 0.001 P < 0.001 P < 0.001

Left superior

frontal gyrus

Right temporal pole Right middle STS

Left posterior

STS

Left DMPFC Left temporal pole

P = 0.005

P < 0.001

P = 0.016

P = 0.002

P = 0.005

P < 0.001

Right FFA Left middle STS

P = 0.044

P < 0.001

P = 0.003 P = 0.007

P < 0.001 P = 0.001

Left cuneus

Left TPJ Right cuneus

Figure 1 Neural response to happy versus neutral faces. Activation differences

(means±s.e.m.) between the functional magnetic resonance imaging response to

happy and neutral faces in adolescents with autism (n¼40), unaffected siblings

(n¼40) and controls (n¼40). Activation map indicates neural response to happy

versus neutral faces in controls, and shows activations to happy versus neutral

faces (Po0.05, FWE corrected) overlaid onto the canonical Montreal Neurological

Institute (MNI) 152 template brain image (axial section, z-coordinate indicated in

Montreal Neurological Institute space), with the colored bar indicating the T-value of

the plotted activation differences. DMPFC, dorsomedial prefrontal cortex; FFA,

fusiform face area; STS, superior temporal sulcus; TPJ, temporoparietal junction.

A novel functional brain imaging endophenotype of autism

MD Spencer et al

Translational Psychiatry

with no significant quadratic component. For all 11 regions,

activation in the autism group did not differ statistically

significantly from activation in siblings (Table 2).

Neural response to facial expression of emotion: fearful

versus neutral faces. In controls and in siblings, fearful

faces elicited increased activation compared with neutral

faces (Figure 3 and Table 1) within the right FFA (controls:

P¼0.006, siblings P¼0.005; FWE corrected). However, the

autism group did not display any significant activation

differences at the threshold Po0.05 FWE corrected.

As with the happy versus neutral analyses above, we

examined between-group differences in the fMRI response in

autism, sibling and control participants within the right FFA,

characterized above as the brain region significantly activated

in controls in fearful versus neutral faces. Activation in the

autism group was significantly reduced compared with

controls and a significant polynomial regression linear

contrast effect with no significant quadratic component was

detected across all the three groups (Figure 3 and Table 2).

However, activation in the sibling group did not differ

significantly from activation in controls or the autism group.

Neural response to faces versus fixation crosses. These

findings demonstrate a clear linear progression across

autism, sibling and control groups for atypical fMRI

activation to happy versus neutral faces. To address the

question as to whether the neural basis for this marker is an

atypical neural response to happy faces, neutral faces or to

both, we used the same brain regions defined by the

significant activations within controls to happy versus

neutral faces (comprising the 11 clusters listed in Table 1)

0.2

0.1

0.0

-0.1

0.3

-0.2

autism sibling

Middle STS Superior frontal

gyrus

Right Left

Temporal pole Temporal pole

control autism sibling control

autism sibling control autism sibling control

contrast estimate +/- SE

0.2

0.1

0.0

-0.1

0.3

-0.2

contrast estimate +/- SE

0.2

0.1

0.0

0.3

-0.1

contrast estimate +/- SE

0.2

0.1

0.0

0.3

-0.1

-0.2

contrast estimate +/- SE

P = 0.004 P = 0.001

P = 0.005

P < 0.001

P < 0.001 P < 0.001

P < 0.001

P = 0.002

Figure 2 Differences between ‘unaffected’ siblings and controls with no family history of autism in the neural response to happy versus neutral faces. Activation differences

(means±s.e.m.) between the functional magnetic resonance imaging response to happy and neutral faces in adolescents with autism (n¼40), unaffected siblings (n¼40)

and controls (n¼40). Activation map corrected for multiple comparisons at Po0.05 family-wise error corrected, and overlaid onto a three-dimensional-rendered template

brain within MRIcron. STS, superior temporal sulcus.

Table 2 Between-group differences in activations to emotional versus neutral faces

Region of significant activation

in controls

Between-group differences

P-value (F-statistic)

Effect of group

(across all three groups)

Polynomial regression

linear trend effect

Control versus

sibling

Control

versus

autism

Sibling versus

autism

P-value

(F statistic)

P-value

Happy versus neutral faces

Left superior frontal gyrus 0.001 (11.664) o0.001 (17.222) NS o0.001 (9.448) o0.001

Right temporal pole 0.002 (9.986) o0.001 (13.703) NS o0.001 (8.994) o0.001

Right middle STS 0.004 (9.068) o0.001 (18.608) NS o0.001 (11.073) o0.001

Left dorsomedial prefrontal cortex 0.005 (8.570) o0.001 (18.714) NS o0.001 (8.957) o0.001

Left temporal pole 0.005 (8.551) o0.001 (15.181) NS o0.001 (8.763) o0.001

Left posterior STS 0.016 (6.064) 0.002 (9.790) NS 0.002 (6.335) 0.001

Right FFA 0.044 (4.184) o0.001 (21.161) NS o0.001 (9.813) o0.001

Left middle STS NS o0.001 (13.595) NS 0.002 (6.711) o0.001

Left cuneus NS 0.001 (10.918) NS 0.004 (5.899) 0.001

Left temporoparietal junction NS 0.003 (9.769) NS 0.010 (4.802) 0.003

Right cuneus NS 0.007 (7.772) NS 0.014 (4.400) 0.004

Fearful versus neutral faces

Right FFA NS 0.025 (5.193) NS NS 0.017

Abbreviations: FFA, fusiform face area; NS, not significant; STS, superior temporal sulcus.

A novel functional brain imaging endophenotype of autism

MD Spencer et al

Translational Psychiatry

to extract activation contrast data for happy and neutral faces

versus fixation crosses. For happy faces versus fixation

crosses, we demonstrated a significant polynomial regression

linear contrast effect (with no significant quadratic

component) for all 11 regions: the right FFA (P¼0.001), left

dorsomedial prefrontal cortex (P¼0.001), left (P¼0.001) and

right (P¼0.013) temporal poles, left posterior STS

(P¼0.010), right (P¼0.002) and left (P¼0.016) middle

STS, right (P¼0.007) and left (P¼0.008) cuneus, left

temporoparietal junction (P¼0.007) and left superior frontal

gyrus (P¼0.026). In contrast, no statistically significant

polynomial regression linear contrast effects were

demonstrated for neutral faces versus fixation crosses. This

strongly suggests that, within the context of this study, an

atypical response specifically to happy faces accounts for the

atypical response to happy versus neutral faces in autism and

sibling groups. This therefore provides a clear biomarker of

familial risk for autism.

Discussion

Hypoactivation of the FFA and related ‘social brain’ areas in

response to facial stimuli is one of the most consistently

reported fMRI findings in autism.20 We have shown that

activation in a range of brain areas, including the FFA, is

significantly reduced in autism compared with controls in

response to emotional versus neutral faces, and furthermore

our findings indicate that the response within the FFA itself

differs significantly between siblings and controls. Moreover,

in siblings with no autism spectrum diagnosis and no manifest

severe behavioral features of autism, we have demonstrated

significant differences from controls in terms of the fMRI

response to happy versus neutral faces within a range of other

brain areas, particularly regions related to the STS and

temporal poles.

Importantly, the emotion and control conditions differed

only in terms of facial expression—with all other aspects of

these conditions, such as those related to the sex discrimination

task, being identical. This suggests that it is specifically

the implicit response to facial expression of emotion rather

than some other aspect of the task that is associated with the

significant sibling versus control differences observed.

The temporal poles, STS, temporoparietal junction and

medial prefrontal cortex form a network of brain areas strongly

implicated23,36–38 in empathy, mentalizing and theory of mind

(the ability to attribute mental states to others). On the basis of

the set of emotions tested here (happiness and fear), the

finding of an atypical neural response within these brain areas

in autism and sibling groups specifically to happy faces may

reflect the possibility that an implicit response to happy faces

is driven by empathy—impairments of which have a central

role within the phenotype of autism—whereas the response to

fearful stimuli (found in this study to be intact in siblings but not

individuals with autism) is likely driven by their role as

indicators of threat. Observed facial fear and anger may be

of sufficient evolutionary importance as danger cues that,

unlike facial happiness, they elicit an intact response in the

broader phenotype of autism. This is consistent with reports39

of an intact ‘anger superiority effect’ in autism, where angry

faces are salient and easier to spot within a collection of faces

than happy faces.

We did not select sibling pairs on the basis of gender and

hence, in keeping with known gender ratios in high-functioning

autism and Asperger syndrome, there is an over-representation

of males in the autism group. Gender is a very unlikely

explanation for our results, particularly as we have demonstrated

a strong fit to a linear trend across all three study

groups (autismosiblingsocontrols), whereas the gender

differences between autism versus sibling and sibling versus

control groups are in opposite directions. Furthermore, our

main findings of significant sibling versus control differences

(see Table 2) are most unlikely to be driven by gender as there

was no significant effect of gender in our analysis of variance

for happy versus neutral faces for these seven brain regions.

A potential statistical limitation of this study is that

participants with autism, their siblings and controls were

compared within the same analysis of variance models,

whereas the autism and sibling groups are not independent of

one another. However, our main findings of sibling versus

control differences are not affected by this potential limitation.

The heterogeneous phenotype and likely non-unitary

nature14 of autism require a dissection of the condition into

simpler building blocks with the goal of characterizing the

etiology of autism at the fine-resolution level of specific

components of neural structure or function and their genetic

associates. We propose that the fMRI response to happy

versus neutral faces within these brain areas is an endophenotype

of autism. As a biomarker of familial risk for autism, this

candidate endophenotype has the advantage of being a

quantitative measure, with greater statistical power than

categorical measures. These findings offer an attractive

autism

5.0

-48

4.8

4.6

sibling

Right FFA

control

P = 0.025

0.2

0.1

0.3

0.0

contrast estimate +/- SE

Figure 3 Neural response to fearful versus neutral faces. Activation differences

(means±s.e.m.) between the functional magnetic resonance imaging response to

fearful and neutral faces in the right FFA in adolescents with autism (n¼40),

unaffected siblings (n¼40) and controls (n¼40). Activation map indicates neural

response to fearful versus neutral faces in controls, corrected for multiple

comparisons at Po0.05 family-wise error corrected and overlaid onto the canonical

Montreal Neurological Institute (MNI) 152 template brain image (coronal section,

y-coordinate indicated in Montreal Neurological Institute space), with the colored bar

indicating the T-value of the plotted activation differences. Activation map overlaid

onto a three-dimensional-rendered template brain within MRIcron. FFA, fusiform

face area.

A novel functional brain imaging endophenotype of autism

MD Spencer et al

Translational Psychiatry

strategy to future genetic research, investigating the genetic

correlates of this candidate endophenotype.

Kanner’s original description of autism40 highlighted the role

of impaired ‘emotional reactivity’ in the phenotype of autism,

together with the observation of similar traits in family

members. Our findings suggest that an atypical implicit

response to facial expression of emotion may form the basis

of impaired emotional reactivity in autism and in the broader

autism phenotype26,41 in relatives. The identification of this

fMRI endophenotype of autism may serve as an important

step toward an understanding of the causal mechanisms that

underlie autism at a neural and genetic level.

Conflict of interest

ETB is employed half-time by the University of Cambridge and

half-time by GlaxoSmithKline plc. All the other authors declare

no conflict of interest.

Acknowledgements. We are grateful to all participants and their families

for their participation in our study and to all autism support organizations that helped

with recruitment. We are grateful for the technical assistance of Dr Cinly Ooi. This

research was funded by an MRC Clinician Scientist Fellowship to MDS from the UK

Medical Research Council (G0701919). LRC is supported by the Gates Cambridge

Scholarship Trust.

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published by Nature Publishing Group. This work is

licensed under the Creative Commons Attribution-Noncommercial-Share

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Whaling body passes reforms on 'cash for votes'

Richard Benyon: a "fantastic achievement" that will help the IWC to modernise

The International Whaling Commission (IWC) has approved measures designed to prevent past "cash for votes" scandals from happening again.

Countries will have to pay membership fees by bank transfer from government accounts, enabling traceability.
Previously, delegates have been able to turn up and pay in cash.
Observers were pleased the measures passed, though some were dismayed that plans to give non-governmental groups a bigger role were discarded.
Deliberations on the package - proposed by the UK - took an entire day out of the four scheduled for this meeting, and were eventually passed by consensus.
"This is a fantastic achievement that will modernise the IWC, bringing it in to line with other important international bodies, and give it real credibility," said UK Environment Minister Richard Benyon.
"We have been working on these proposals for a year and it is a credit to the UK that we have had them passed without needing a vote."
The measures should also improve communication, with meeting reports issued within two months rather than up to a year, as currently, and more information publicly available on the IWC's website.
Cash memory

We've seen how fanatical and irresponsible some NGOs can be”

End Quote Ole Samsing Danish IWC commissioner

But the most controversial element proved to be the money.

Several developing country delegations said their governments tended to provide money only a few days before meetings began, so bank transfer meant the money would arrive after the meeting had begun.
Delegations are unable to vote until fees have been paid.
A number argued for the use of bankers' drafts instead. This was received with some scepticism by some western observers, who believed some delegations were trying to maintain the capacity to pass on funds from a third party easily, as bankers' drafts are anonymous.
Eventually a compromise was found, enabling the IWC secretariat to accredit delegates if it is sure that payment has been initiated.

There were different views about what should replace the cash payments that some nations use

Daven Joseph, the IWC commissioner for St Kitts and Nevis, said he regretted the amount of time spent on these discussions but it had been necessary.
"We have been establishing the rules of procedure, and we have to be very careful in how those rules are established," he told BBC News.
"In some of our countries, whaling has never been given a top priority when it comes to accessing funds from the treasury."
Environmental groups said they were generally pleased that the measures had passed.
"This is a good day for whales and the commission established to protect them; everyone wins," said Patrick Ramage, director of the Global Whale Programme of the International Fund for Animal Welfare (Ifaw).
"These rule changes represent real progress as the IWC migrates into the 21st Century - a closed whalers' club is becoming a more credible commission, promoting whale conservation not commercial whaling."
Europe's split
However, Mr Ramage and many of his peers were disappointed that proposals to give non-governmental organisations (NGOs) more involvement in the IWC's formal discussions, as they have in many other international institutions, fell along the way.

Currently, six people from the NGO community - three from the pro-whaling side, and three of their opponents - are allowed to speak for five minutes each.

This component was jettisoned before the main negotiations began, a casualty of internal European Union discussions.
All EU members except Denmark supported greater NGO involvement.
But the European Commission wants to have the bloc act in unison where possible; and the UK agreed that having the proposal put forward as an EU document would give it more leverage.
But the only way to get the Danes on board was to abandon the section on NGOs. In the IWC, Denmark represents not itself, but Greenland, a whaling territory.
Earlier in the day, Danish whaling commissioner Ole Samsing had explained his opposition by referring to the Sea Shepherd Conservation Society, which is barred from the IWC meeting but which has been holding demonstrations outside.
"We've seen how fanatical and irresponsible some NGOs can be," he told delegates.
"I know they're not accredited to this organisation, but nevertheless they're representing some radical point of view so there is a reason for restricted treatment of NGOs here."
The great irony of this process was that in the end the proposal could not be admitted as an EU document on procedural grounds, as the EU is not a member of the commission.

Wednesday 13 July 2011

Help get medicines right, patients urged

Behind the Headlines
Brought to you by the NHS Knowledge Service

What is the problem?

The Royal Pharmaceutical Society warns that between 30% and 70% of patients have an error or unintended change to their medicines when their care is transferred from, say, a GP to a hospital or between hospitals.

Why is this a problem?

Getting the wrong medicine or the wrong dose of the right medicine can sometimes be harmful. The health regulator, the Care Quality Commission, says that about 4-5% of hospital admissions are due to avoidable mistakes with medicines. There are cases of people who have died as a result of being given the wrong doses of medicine after transferring between different care providers.

How can I, or my carer, can make sure I get the right medication?

If you have any doubts about your medicines ask a doctor or other healthcare professional for help, the Royal Pharmaceutical Society advises. If you do not understand what the doctor tells you, ask them to explain it more simply.

What can I do before I go into hospital?

Make sure you know what medicines you are taking and keep a complete, up-to-date list at home. You can list your medicines using this Royal Pharmaceutical Society medicines tracking form.

It’s also best to keep all medicines together in a safe place and make sure that you do not keep old out-of-date medicines.

How can I make sure that my medicines don’t change if I move between hospitals?

If you move from one place to another, make sure you take your list of medicines with you and if possible use a single container to keep all your packets or bottles of medicine together. In hospital, a doctor, nurse, or other healthcare professional should check your medicines within 24 hours of you arriving – ask someone for help if this doesn’t happen.

What happens when I leave hospital with new or different medicine?

Before you leave hospital, ask for your medicines to be explained to you, especially if there have been any changes to your medicine. You should ask for written or printed information so that you can remind yourself of the medicines or changes later.

Is there anything I should do after I have left hospital?

The next time you see your GP, check that they know about the changes to your medicines. You could also ask your local pharmacist for a “medicines use review” to help you better understand your medicines.

Ship sails in search of sustainable tuna

Sharks are among the species accidentally entangled in purse seine nets

Scientists are embarking on a two-month expedition in the Pacific aimed at finding ways to reduce the damaging accidental toll of tuna fishing.

They want to find techniques that help fishermen find the abundant skipjack tuna without also catching sharks, turtles, or threatened tuna species.
The scientists will sail on board a tuna purse-seine vessel from Ecuador.
Knowledge gained on the trip will be used to develop fishing techniques or new gear that are much more selective.
This could entail fishing at different times of day, at specific depths under the waves, or by more targeted use of fish aggregating devices (FADs).
"The overall objective is to explore some potential options for reducing the mortality of bigeye tunas and other 'undesirable' species while maximising catches of skipjack," said research leader Kurt Schaefer.
"We're looking for ways in which we can learn to harvest the skipjack without impacting other species such as bigeye and yellowfin - we're not yet testing what we consider to be practical solutions," he told BBC News.
Dr Schaefer has been a research scientist with the Inter-American Tropical Tuna Commission (IATTC) - one of the bodies charged with regulating tuna fishing in the open sea - for more than 30 years.
While the small, fecund skipjack (Katsuwonus pelamis) forms the basis of the canned tuna industry, the bigeye (Thunnus obesus) is an endangered species in the Pacific, primarily because of fishing.
The cruise departed from Ecuador on Tuesday, using the chartered commercial fishing vessel Yolanda L.
Modern FADs

New models of FAD could in future separate different species of tuna, and other fish

For reasons that are not entirely clear, fish and other marine creatures tend to congregate around floating objects such as logs.
Fishermen have learned to take advantage of this, deploying buoys - FADs - equipped with GPS and sonar.
When the sonar senses that fish have gathered, the buoy signals the parent vessel, which steams alongside to collect its haul.
Using a purse seine net, the boat can encircle and capture the entire shoal.
The scientists hope that understanding what makes various species move towards the FAD and then leave it again could open doors to fishing selectively.

“Start Quote

This combination of research, training and management is necessary if we want to make these fisheries more sustainable”

End Quote Victor Restrepo ISSF scientific advisor

"One of the things we're doing is behavioural studies using acoustic tags and telemetry," said Dr Schaefer.

"We'll be tagging these species, and trying to see whether there are times when you see separation eithed horizontally or vertically in the water, and whether you could use this to separate out catches.
"We'll also be looking for times of day at which the species might naturally separate - times when the skipjack, for example, might move away from the FAD."
Smaller species may be trying to shelter from predators, while bigger ones may see it as an easy source of food.
The various species may also be attracted away by different signals, such as water temperatures.
A remotely operated underwater vehicle (ROV) will be deployed to film fish behaviour around the FAD, and after entrapment in the purse seine net.
If different tuna species separate inside the net - some swimming high and others low, for example - that could also form the basis of a separation method.
Local knowledge
Having spent long periods at sea on fishing vessels, Kurt Schaefer believes experienced skippers may already know ways of targeting skipjack.
The scientists will analyse how well the Yolanda L's skipper is able to predict catches.

An underwater ROV (here being tested) will be deployed to film tuna in the nets

This research cruise is an initiative of the International Seafood Sustainability Foundation (ISSF), which brings scientists together with people from the seafood industry and from environmental groups.
It is the first of a number of cruises planned for different parts of the world's oceans.
Victor Restrepo, chairman of ISSF's scientific advisory committee, said the broader project aims to replicate what has already been achieved in some other fisheries by combining expertise held by fishermen with scientific findings.
"We are sharing what we learn with with skippers through workshops where scientists and fishers exchange ideas on these and other potential techniques," he said.
"And we are working with policymakers in the governments of countries with important purse seine fisheries so that they adopt regulations to implement these techniques.
"I believe that this combination of research, training and management is necessary if we want to make these fisheries more sustainable."
Whereas some environmental groups argue for the abandonment of FADs, the ISSF believes this is neither feasible nor desirable.
"It's the philosophy of ISSF and our partners that abandoning a fishery will not help to improve it," said ISSF president Susan Jackson, previously of food giants Del Monte and Heinz.
"We must help to improve practices that make fishing for tuna more sustainable."
The bluefin - the most talked about tuna species recently, and the most prized for sushi - is not a factor in this cruise.

Japan 'to continue' Antarctic whaling

Japan charges Sea Shepherd activists with launching incendiary devices onto the whaling ships

Japan intends to send its whaling fleet back to the Antarctic this year, a senior official has told BBC News.

There has been speculation that campaigns by activists, money problems and new rules at sea might persuade Tokyo to stop Antarctic whaling.

But at the International Whaling Commission (IWC) meeting, Japan's Joji Morishita said the plan was to return.

The Sea Shepherd Conservation Society, which forced the last hunt's early closure, says it will be back too.

Finding a way to deal with the organisation's vessels is the main obstacle Japan sees to continuing for the next season and beyond.

"We are now discussing how we can send our fleet back to the Antarctic Ocean," said Mr Morishita, Japan's deputy commissioner to the IWC and a senior official in the Fisheries Agency.

"Simply put, the attack from Sea Shepherd organisation is the one we have to consider how we prevent that to happen again."

During the IWC meeting, being held in Jersey, Japanese delegates showed pictures and videos that, they said, showed the campaigners attacking whaling vessels with projectiles including flares, which set netting alight, and glass bottles filled with foul-smelling butyric acid.

They also showed Sea Shepherd boats ramming the whalers, and said reinforced ropes had been put in the water to entangle propellers.

"The attack this past year became so severe that we didn't have any choice to try to prevent the worst from happening," said Mr Morishita.

Each successive year, Sea Shepherd has sent bigger fleets and faster vessels, while Japan has downscaled its forces; last season, for the first time, the activists had the upper hand.

Rather than catching 850-odd whales - the official target - the eventual haul was about 170.

It is not clear how Japan intends to protect its fleet in any future expedition - it was not just a matter of sending military patrols, Mr Morishita said, as that was a legal minefield.

Demonstrating force

A further obstacle Japan faces is that, from next year, new regulations on maritime pollution mean the Nisshin Maru, its factory ship, will not be permitted in Antarctic waters with tanks full of heavy fuel oil without a refit.

The Legalities of Whaling

Objection - A country formally objects to the International Whaling Commission (IWC) moratorium, declaring itself exempt. Example: Norway
Scientific - A nation issues unilateral "scientific permits"; any IWC member can do this. Example: Japan
Indigenous (aka Aboriginal subsistence) - IWC grants permits to indigenous groups for subsistence food. Example: Alaskan Inupiat

Guide to the Great Whales

Another is financial. Japan's national budget was in trouble even before the impact of the recent earthquake and tsunami; and with sales of whalemeat falling, the cost of the hunt is rising.

But Mr Morishita suggested all of these issues would be easier to overcome than Sea Shepherd's opposition.

Some observers have suggested that Japan sees blaming Sea Shepherd as a way to escape from Southern Ocean whaling without losing face.

Mr Morishita said this was not the case, and the basic policy remained unchanged.

Sea Shepherd activists have staged demonstrations outside the IWC meeting here - the organisation is barred from attending - and it is clear that it will send its fleet to the Southern Ocean again if Japan does return.

"Sea Shepherd will also return and will once again intercept and block their operations," the organisation's head Paul Watson wrote on his blog earlier this week.

"If they return, we will launch Operation Divine Wind, and our vessels the Bob Barker, the Steve Irwin, and the Brigitte Bardot will soon return to the remote and stormy seas of the Southern Ocean Whale Sanctuary to do what we do best - defend the whales!"

Animal experiments increase again

GM animals and "harmful mutant" animals largely account for the rise

The number of animal experiments carried out in the UK rose by 3% last year, according to government figures.

The rise was largely due to an increase in the use of genetically modified (GM) and mutant animals, a trend which shows no signs of abating.
The news comes as campaigners warn a new EU directive threatens standards of welfare for UK lab animals.
They argue that a number of the directive's regulations fall short of those already in place in the UK.
Just over 3.7 million scientific experiments on animals were started in Great Britain in 2010, an increase of 105,000 on the previous year.
The statistics show that breeding to produce genetically modified (GM) animals and harmful mutants (an animal with potentially harmful genetic defects) rose by 87,000 to 1.6 million procedures.
This rise, largely due to the increased breeding of mice and fish, represents an increase of 6%.
But when GM animals are excluded from the statistics, the total number of procedures rose by 18,000, from 2.09 million to 2.10 million.
Home Office minister Lynn Featherstone commented: "The figures released today once again show the important work being done in this country to regulate animal procedures and ensure the highest standards of animal protection are upheld.
"The UK has one of the most rigorous systems in the world to ensure that animal research and testing is strictly regulated."

Hungary destroys all GMO maize fields

//13 Jul 2011

Some 400 hectares of maize found to have been grown with genetically modified seeds have been destroyed throughout Hungary deputy state secretary of the Ministry of Rural Development Lajos Bognar said.

The GMO maize has been ploughed under, said Lajos Bognar, but pollen has not spread from the maize, he added. Unlike several EU members, GMO seeds are banned in Hungary.

Authorities have been checking for GMO crops since the beginning of this year as a new regulation came in force this March which stipulates GMO checks before seeds are introduced to the market.

The checks will continue despite the fact that seed traders are obliged to make sure that their products are GMO free, Bognar said.

Compensation unlikely

Controllers have found Pioneer and Monsanto products among the seeds planted. The free movement of goods within the EU means that authorities will not investigate how the seeds arrived in Hungary but they will check where the goods can be found, Bognar said.

Regional public radio reported that the two biggest international seed producing companies are affected in the matter and GMO seeds could have been sown on up to thousands of hectares in the country.

Local farmers complain that the use of GMO seeds has only been revealed now when it is too late to sow again and the entire year's harvest has been lost.

Another problem is that the company that distributed the seeds in Baranya county is under liquidation, therefore if any compensation is paid by the international seed producers, the money will be paid primarily to that company's creditors, rather than the farmers.

Southern Cross set to shut down and stop running homes

Care home operator Southern Cross is set to shut down after landlords owning all 752 of its care homes said they wanted to leave the group.

"It is currently envisaged that the existing group will cease to be an operator of homes," the firm said.

Southern Cross added that the landlords were still committed to providing continuity of care to its 31,000 residents.

Trading in the company's shares has been suspended.

The Darlington-based Southern Cross and its landlords and creditors are a month into a four-month restructuring period, which was agreed in crisis talks in June.

The statement said that the details of the restructuring were not yet settled and there was still a possibility of further changes.

It had been expected that some of the landlords would leave the group, leaving Southern Cross operating with between 250 and 400 homes, but now it appears that the group is to disappear altogether.

Analysis

Nick Triggle Health correspondent, BBC News

Ministers have been quick to promise that Southern Cross residents will not be turfed out on to the street.

But that does not mean that these vulnerable people are not facing a great deal of uncertainty and, potentially, upheaval.

The hope now is that the group will be broken up into chunks for other providers to take on.

If that happens the new owners may still want to close some of the homes - something that everyone agrees is both distressing and damaging for the health of those involved.

But the Southern Cross developments raise wider questions about the whole sector.

While the problems the group has faced have been linked to its business model, the situation has been further compounded by cuts in fees paid by councils.

Last year alone fees paid by local authorities for state-funded care home residents were cut by about 2.5% once inflation was taken account.

Suffice to say, the squeeze has been felt across the industry - not just by Southern Cross. It is getting increasingly tough to keep services going.

'Regret'

The process began when the UK's biggest care home operator said it was unable to pay its rent bills to its landlords.

The statement said that little or no value would be left for the shareholders.

"We regret the loss of value which shareholders have experienced," Southern Cross chairman Christopher Fisher said.

About 250 of the homes will immediately begin to be transferred to other operators.

The owners of the rest of the homes are still finalising their plans, but they may end up using the existing Southern Cross back-office staff and some of its management.

'Worrying' time

"We anticipate that the period of uncertainty which we have been experiencing will now draw to a close," Mr Fisher added.

But Michelle Mitchell at Age UK, said that despite the promises about continuity of care, "this has been a really worrying few months for Southern Cross residents and their families, with these latest developments only adding to their concern".

Labour MP John Mann called on the government to intervene to make sure that care home residents were not forced to move.

"No resident should be forced to move out of their home and in the big sell-off there must be no cherry picking of the better properties," said Mr Mann, who has four Southern Cross homes in his constituency.

"Government intervention is needed now so that resident needs are put first and to prevent an even greater disaster from unfolding."

Fee question

Martin Green, chief executive of the English Community Care Association, said the collapse of Southern Cross showed there were serious problems with the funding of care in the independent sector.

"I think the Southern Cross issue which has come to a head today, is very much an issue that other providers are facing because of the levels of resource that they have to deliver care on," he told BBC Radio 4's You and Yours programme.

"Fees are a really big issue and we've had several years of nil increases, and of course we've had inflation rates running at 4-5%."

David Rogers, chairman of the Local Government Association's Community Wellbeing Board, said: "Councils take the welfare of care home residents extremely seriously and throughout this process that has always been their priority."

"It's greatly reassuring, and testament to the good work which has been going on behind the scenes and the resilience of the care home system, that a solution has been found which will hopefully avoid major upheaval for the vulnerable people involved."

mengele plus

Thursday 14 July 2011

light on autism

Whaling body passes reforms on 'cash for votes'

Whaling body passes reforms on 'cash for votes'

Wednesday 13 July 2011

Help get medicines right, patients urged

Help get medicines right, patients urged

Categories

What is the problem?

Why is this a problem?

How can I, or my carer, can make sure I get the right medication?

What can I do before I go into hospital?

How can I make sure that my medicines don’t change if I move between hospitals?

What happens when I leave hospital with new or different medicine?

Is there anything I should do after I have left hospital?

Further reading