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Asperger Syndrome
A Proton Magnetic Resonance Spectroscopy Study of Brain
Declan G. M. Murphy, MBBS, MD, MRCPsych;
Hugo D. Critchley, MB ChB, DPhil, MRCPsych;
Nicole Schmitz, MSc, DipPsych;
Grainne McAlonan, MBBS, PhD;
Therese van Amelsvoort, MD, MRCPsych;
Dene Robertson, MBBS, MRCGP, MRCPsych;
Eileen Daly, BSc;
Andrea Rowe, MSc;
Ailsa Russell, MSc;
Andrew Simmons, PhD;
Kieran C. Murphy, MD, PhD;
Patricia Howlin, PhD
Arch Gen Psychiatry. 2002;59:885-891.
ABSTRACT
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Background Asperger syndrome (AS; an autistic disorder) is associated with impaired
social skills and obsessional/repetitive behavior. Patients with autism have
significant abnormalities in the frontal lobe and frontoparietal connectivity.
Nobody has examined the relationship between abnormalities in the frontal
and parietal lobes and clinical symptoms in people with AS.
Methods We used in vivo proton magnetic resonance spectroscopy to examine neuronal
integrity of the medial prefrontal and parietal lobes in 14 non–learning-disabled
adults with AS and 18 control subjects (of similar sex, age, and IQ). We obtained
measures of the prefrontal lobe in 11, the parietal lobe in 13, and both lobes
in 10 subjects with AS. We measured concentrations and ratios of N-acetylaspartate (NAA), creatine and phosphocreatine (Cr + PCr), and
choline (Cho). Levels of NAA, Cr + PCr, and Cho are indicators of neuronal
density and mitochondrial metabolism, phosphate metabolism, and membrane turnover.
Frontal metabolite levels were correlated with scores on the Yale-Brown Obsessive
Compulsive Scale and the Autism Diagnostic Interview.
Results Subjects with AS had a significantly higher prefrontal lobe concentration
of NAA (z = –3.1; P
= .002), Cr + PCr (z = –2.2; P = .03), and Cho (z = –2.9; P = .003). Increased prefrontal NAA concentration was significantly
correlated with obsessional behavior ( = 0.67; P
= .005); increased prefrontal concentration of Cho, with social function (
= 0.72; P = .02). We found no significant differences
in parietal lobe metabolite concentrations.
Conclusion Subjects with AS have abnormalities in neuronal integrity of the prefrontal
lobe, which is related to severity of clinical symptoms.
INTRODUCTION
PEOPLE WITH high-functioning autistic disorder (autism and Asperger
syndrome [AS]) are not learning disabled (mentally retarded), but they exhibit
characteristic impairments in social skills and obsessional/repetitive behavior.1 A consensus exists that the clinical features of autistic
disorder are strongly genetic2-4
and associated with brain dysfunction,5 but
the neurobiological basis of autistic symptoms is unknown. The frontal lobe
may be critically involved because, in nonautistic populations, damage to
or dysfunction of the prefrontal cortex is associated with autistic-like social
deficits and obsessional/repetitive behavior.6
Also, people with autism are reported to have significant differences in frontal
lobe metabolic maturation,7 anatomy,8 function,9 and connectivity
to parietal lobe.10 However, the relationship
between abnormalities in the frontal and parietal lobes and clinical symptoms
in people with autistic disorder is poorly understood.
One technique for addressing this question is in vivo magnetic resonance
spectroscopy (MRS), because it can be used to quantify neuronal integrity.
Phosphate 31–labeled MRS quantifies phosphate-containing compounds that
reflect high-energy phosphate and membrane phospholipid metabolism. In contrast,
proton (1H)–MRS provides spectra that can be used to measure N-acetylaspartate (NAA)-, creatine and phosphocreatine
(Cr + PCr)–, and choline (Cho)- containing substances. N-acetylaspartate is present in high concentration in gray matter and
neurons, and its synthesis is closely correlated with mitochondrial energy
metabolism. Therefore, NAA is often used as a measure of neuronal density
and/or mitochondrial function.11 In contrast,
Cr + PCr and Cho concentrations are used as measures of phosphate metabolism
and membrane turnover, respectively.11-18
A 31 P-MRS study19 reported that
young people with autism had a hypermetabolic energy state in the frontal
lobe and that frontal hypermetabolism and undersynthesis of neuronal membranes
were related to performance of verbal and executive function tasks. In contrast, 1H-MRS studies detected no abnormalities in neuronal integrity of the
parietal20 or the frontal lobe in people with
autism,21 but they reported lower levels of
NAA in the cerebellum.21 These MRS studies
were important first steps; however, to our knowledge, nobody has examined
subjects with AS using 1H-MRS or has related clinical symptoms
to neuronal integrity.
Obsessional/repetitive behavior is recognized as a core clinical symptom
in people with autistic disorder.22 For example,
(1) obsessional interests are a major diagnostic feature of autistic spectrum
conditions in DSM-IV.23
(2) Repetitive behaviors have been considered an integral part of the syndrome
since the classic description by Kanner.24
(3) Rutter25 stated that "ritualistic and compulsive
phenomena are very common in autism. . . . . It is not uncommon for them to
develop into frankly obsessional symptoms," and Baron-Cohen and Wheelwright26 reported that up to 92% of children with autism display
obsessional behaviors. Damage to or dysfunction of the prefrontal lobe is
associated with stereotyped, obsessional, and ritualistic behavior in the
general population, and abnormalities in frontal lobe development may account
for these symptoms in people with autism.6
However, this issue has never been investigated in people with AS. Therefore,
we used 1H-MRS to study the frontal and parietal lobes in subjects
with AS who were otherwise healthy, and we related frontal metabolic measures
to obsessional/repetitive behavior. Also, we performed a post hoc analysis
relating frontal metabolic measures to global clinical symptoms as measured
by the Autism Diagnostic Interview–Revised (ADI-R).27
PARTICIPANTS AND METHODS
PARTICIPANTS
Subjects with AS were recruited through local support groups and our
clinical research program in autism. We studied 14 high-functioning men with
AS, with a mean (SD) age of 30 (9) years and a mean (SD) Full-Scale IQ (FSIQ)
of 97 (14). Ten subjects were right-handed and 4, left-handed. A diagnosis
of AS was made using the criteria of the International Classification
of Diseases, 10th Revision28 by a team
consisting of 3 psychiatrists (H.D.C., D.G.M.M., and G.M.) and a psychologist
(P.H.). We included subjects with no reported language delay and who met autistic
criteria for social and obsessional behavior. It was also possible to apply
the ADI-R27 in 12 subjects with parental informants.
Control subjects were recruited locally by means of advertisement and
included 18 men with a mean (SD) age of 32 (8) years and a mean (SD) FSIQ
of 102 (8). Fourteen were right-handed and 4, left-handed. No control had
past or present mental health problems or physical disorders that affected
brain function.
All participants in the study underwent structured physical and psychiatric
examination29-30 (for the presence
of a DSM-IV Axis I or II disorder23),
and clinical magnetic resonance imaging. Participants were excluded if they
had a history of psychiatric disorder (other than AS), head injury, toxic
exposure, diabetes, hypertension, cardiovascular disease, abnormal results
of routine blood tests, alcohol or other drug abuse, a clinically abnormal
finding on routine magnetic resonance imaging, or a medical disorder associated
with autistic symptoms (eg, epilepsy). We measured the FSIQ using the Wechsler
Adult Intelligence Scale–Revised31; obsessional/repetitive
behavior, the Yale-Brown Obsessive Compulsive Scale32;
and handedness, the Annett Questionnaire.33
No participants were taking medication at the time of the study, although
2 subjects with AS had previously received psychotropic medication for obsessional
behavior and symptoms of anxiety (a selective serotonin reuptake inhibitor
in one, and a benzodiazepine in the other). We found no significant differences
between subjects with AS and controls in age, FSIQ, handedness, or education.
Research was approved by the local research ethics committee, and all participants
provided informed written consent.
SCANNING PROTOCOL
Subjects with AS and controls underwent scanning using a 1.5-T system
(GE Signa; General Electric, Milwaukee, Wis). An 8.5-mL voxel of interest
(VOI) was positioned in the right medial prefrontal lobe and incorporated
white and gray matter from the superior and medial prefrontal gyri, and a
portion of the anterior cingulate (placed at one third of the distance between
the anterior commissure and frontal pole and one half of the distance between
the dorsal and orbital margins of the prefrontal lobe, located medially) (Figure 1). An additional 8.5-mL VOI was located
in the right medial parietal lobe, including the precuneus, and contained
gray and white matter (placed at one half of the distance from the posterior
commissure to the back of the brain, and one third of the vertical distance
from the anterior commissure–posterior commissure line to the vertex).
An 8.5-mL point resolved selective spectroscopy (point-resolved selective
spectroscopy [PRESS] spectrum (echo time, 136 ms; repetition time, 2000 ms;
256 averages) was obtained from each voxel after chemical shift selective
[CHESS] water suppression. The MRS data were analyzed using SAGE/IDL software
(General Electric). Concentrations of metabolites were determined using derived
metabolite peak areas and documented relaxation characteristics of these neurochemicals
at 1.5 T with the total water signal of the VOI.34
Data of sufficient quality to be analyzed were obtained from the prefrontal
voxel in 11 subjects with AS and 18 controls, and from the parietal voxel
in 13 subjects with AS and 14 controls. Of those we studied, 10 subjects with
AS and 7 controls underwent frontal and parietal spectroscopy. We were unable
to obtain data from both regions in all participants owing to technical difficulties
(eg, problems "shimming" or participants wanting to withdraw).
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Location of voxels of interest (VOIs) in a proton magnetic resonance
spectroscopy (1H-MRS) study of metabolite concentrations and ratios.
A, An 8.5-mL VOI was positioned in the right medial prefrontal lobe and placed
one third of the distance between the anterior commissure and frontal pole
and one half of the distance between the dorsal and orbital margins of the
prefrontal lobe, located medially. B, An additional 8.5-mL VOI was located
in the right medial parietal lobe and was placed at one half of the distance
from the posterior commissure to the back of the brain and one third of the
vertical distance from the anterior commissure–posterior commissure
line to the vertex. R indicates right; L, left. C, Relationship between prefrontal N-acetylaspartate (NAA) concentration and score on the Yale-Brown Obsessive
Compulsive Scale in patients with Asperger syndrome (n = 11).
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Differences in lobar brain volume and/or proportions of white and gray
matter and cerebrospinal fluid (CSF) in the MRS VOI may confound group differences
in metabolite concentrations. Thus, to ensure that differences in regional
brain volume or tissue composition did not account for metabolic differences
between subject groups, we acquired a 3-dimensional inversion-recovery prepared
spoiled-grass data set at the same time that we acquired spectroscopic data.
These data covered the whole head (124 slices; 1.5-mm slice thickness) and
were used for manual tracing of lobar brain matter volume using Measure software35 and previously described methods.29
Also, the position of the MRS VOI relative to the spoiled-grass volume was
determined automatically using in-house software, and we analyzed each MRS
VOI using SPM (statistical parametric mapping) software (available at: http://www.fil.ion.bpmf.ac.uk/spm) to determine the percentage of gray
and white matter and CSF composition.
STATISTICS
We analyzed the data masked to subject status using SPSS software (SPSS
Inc, Chicago, Ill). We compared between-group differences in handedness using  2 tests, and demographic variables, hand-traced volume of brain matter
in the frontal and parietal lobes, tissue proportions of the VOI, and metabolite
concentrations and ratios using the Mann-Whitney test. To further investigate
whether our findings were confounded by differences in tissue proportions
of the VOIs, we compared metabolite concentrations using analysis of covariance
(covarying for percentages of gray and white matter and CSF).
To determine whether our data were driven by participants for whom we
were not able to perform parental interviews or by sampling heterogeneity,
we performed a further between-group analysis after restricting the inclusion
criteria to include only those subjects with AS for whom ADI-R scores were
available (n = 11) and participants who had data available from the prefrontal
and parietal lobes (10 subjects with AS vs 7 controls).
Finally, we related the concentrations of metabolites that were significantly
different in subjects with AS (ie, frontal NAA, Cr + PCr, and Cho) to obsessional/repetitive
behavior using the Kendall . Also, we performed a post hoc exploratory
analysis on the relation between abnormalities in frontal neuronal integrity
and global severity of clinical symptoms by correlating scores on the ADI-R
to frontal metabolite concentrations. Results are reported as significant
when P<.05 (2-tailed).
RESULTS
Compared with controls, subjects with AS had a significantly higher
prefrontal concentration of NAA, Cr + PCr, and Cho (Table 1); but we found no significant between-group differences
in the ratios of NAA/Cr + PCr, NAA/Cho, and Cho/Cr + PCr. These results were
unchanged when we included only those people for whom ADI-R scores were obtainable.
When the analysis was restricted to subjects who underwent prefrontal and
parietal spectroscopy, the difference in Cho concentration did not remain
significant (z = -0.98; P = .90).
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1H-MRS in Subjects With Asperger Syndrome and Control Subjects*
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We found no significant differences between subjects with AS and controls
in concentrations or ratios of NAA, Cho, or Cr + PCr within the parietal lobe.
This finding also remained true for the restricted analyses.
We found no significant between-group difference in the volume of the
frontal and parietal lobes or in the percentage of gray or white matter or
CSF content of the MRS VOIs. Our results remained significant in the frontal
lobe and nonsignificant in the parietal lobe when we corrected for tissue
proportion of the VOI using analysis of covariance.
Subjects with AS had significantly higher scores on the Yale-Brown Obsessive
Compulsive Scale. Within this group, prefrontal NAA concentration was significantly
positively correlated with the severity of obsessive/repetitive behavior (
= 0.67; P = .005) (Figure 1). The result remained significant when we excluded the
2 subjects with the lowest and the highest NAA concentrations and Yale-Brown
Obsessive Compulsive Scale scores ( = 0.55; P<.04).
Post hoc analysis demonstrated a significant correlation between social impairment
(the communication domain of the ADI-R and frontal Cho concentration (
= 0.72; P = .02).
COMMENT
In this relatively small study, we did not obtain spectra from both
brain regions in all participants, and we did not include subjects with classic
autism (ie, abnormalities in language development and learning disability).
Moreover, although our correlation of prefrontal measures and obsessional/repetitive
behavior was planned a priori, our correlation with ADI-R scores was not (and
so this latter result may be spurious). However, we used nonparametric statistical
tests, and our results remained significant when we dropped potential outliers;
also, we found no significant between-group differences in any demographic
variable we measured. Nonetheless, we need to repeat our study in a larger
group, to acquire data from multiple brain regions within the same subject
and to determine whether our findings generalize across the whole spectrum
of autistic disorders.
Obsessional/repetitive behavior is recognized as a core clinical symptom
in patients with autistic disorder.22-26
However, the relation between obsessional behavior in autistic disorder and
obsessive-compulsive disorder (OCD) in the general population is poorly understood.
Bolton et al4 argued that OCD might index an
underlying liability to autism because a significantly higher prevalence of
OCD is found in the relatives of subjects with autism, and individuals with
OCD are more likely to exhibit autistic-like social impairments than controls.
Also, in subjects with autism, treatment with selective serotonin reuptake
inhibitors significantly reduces obsessive/compulsive symptoms36
and repetitive thoughts and behavior37 (similar
to OCD in the general population). Nonetheless, others reported that obsessions
and compulsions in patients with autism have different characteristics from
those displayed by patients with OCD.38-39
For example, obsessions in people with OCD are usually seen as ego-dystonic
(typically involving thoughts of harm and contamination), whereas people with
autistic disorder are significantly more likely to hoard and order39 and to have obsessions about how things work.26 To our best knowledge, nobody has directly compared
the neurobiological associates of obsessional/repetitive behavior in people
with AS and those with OCD in the general population. However, studies of
OCD in non-AS populations using positron emission tomography and single-photon
emission computed tomography described significantly increased glucose metabolism
and/or blood flow in the prefrontal cortex. Moreover, some researchers reported
that in patients with OCD, increased absolute glucose metabolism correlated
with the severity of OCD.40-41
We also found evidence that increased NAA concentrations are associated with
obsessional behavior in subjects with AS. One potential explanation for this
increase in NAA concentration involves differences in mitochondrial, and hence
glucose, metabolism. Thus, similar to patients with OCD, obsessional symptoms
in people with AS may be related to metabolic differences in the prefrontal
lobe. However, we also found that our subjects with AS had a significantly
higher frontal lobe concentration of NAA that was significantly positively
correlated with more severe obsessional/repetitive behavior, whereas other
researchers reported that patients with OCD had a decreased NAA concentration
that negatively correlated with symptom severity.42
Thus, it is unclear whether the neurobiological basis of obsessional behavior
in subjects with AS differs from that in OCD, and further studies are required
to address this issue directly.
We do not suggest that neurobiological differences occur only in the
frontal lobe of patients with AS. Damasio and Maurer6
proposed that autism is due to dysfunction of the mesolimbic brain areas (ventromedial
prefrontal cortex, medial temporal lobe, striatum, and limbic thalamus), and
patients with autism exhibit impairments in higher cognitive functions subserved
by these brain regions.43-45
Neuropathological studies of patients with autism reported neuronal abnormalities
in the cerebral cortex, cerebellum, and limbic system.46-47
In vivo studies of brain anatomy described widespread abnormalities in brain
morphometry and cerebral gyrification,48-49
but increasingly point to the pathoaeotiogical importance of mesolimbic and
subcortical structures.50-53
Studies of brain metabolism and blood flow in autistic disorder using positron
emission tomography reported delayed metabolic maturation of the prefrontal
cortex7 and reduced functional associations
between the frontal and parietal regions at rest,10
reduced prefrontal and anterior cingulate metabolism during attentional and
verbal learning tasks,51, 54 and
reduced medial prefrontal blood flow during theory-of-mind tasks.9 Recent functional magnetic resonance imaging studies
of patients with autism reported reduced activation in the amygdala when making
emotional judgments of eyes55; in the amygdala
and cerebellar, mesolimbic, and temporal lobe cortical brain regions when
processing facial emotion56; and in the temporal
lobe during facial recognition tasks.57 Our
findings further support the position that the frontal lobe is implicated
in autistic disorder and suggest that previous reports of differences in frontal
metabolism and function are associated with differences in neuronal integrity.
We found that frontal, but not parietal, metabolite concentrations were
significantly increased in adults with AS. Thus, the frontal lobe may be more
affected than the parietal lobe in AS, and/or our findings may result from
regional differences in brain maturation because human brain development continues
into adult life and occurs at different times in different brain areas.58-59 For example, the frontal lobe matures
relatively late compared with the rest of the brain in synaptic pruning,60 myelination,61 and
acquisition of adult patterns of glucose metabolism.62
Also, postadolescent brain development is associated with a significant reduction
in gray matter volume of the frontal cortex, with relatively little change
in other brain regions (including the parietal lobe).58
Thus, maturation of the frontal lobe is normally delayed relative to other
brain areas, and so may continue to display a pathologic process in adulthood
that was more generalized in earlier life.
Previous MRS studies of neuronal integrity in subjects with autism are
in disagreement. A 31P-MRS study of high-functioning autistic adolescent
boys and young men that used surface coils reported that young patients with
autism had a hypermetabolic energy state in the frontal lobe when measures
from the right and left hemispheres were combined.19
In contrast a 1H-MRS study of the frontal lobe in 9 children with
autism and 5 of their siblings21 reported no
significant difference in NAA concentrations, but reported preliminary evidence
of lower levels of NAA in the cerebellum. A 1H-MRS study of 28
learning-disabled children with autism (9 with epilepsy) detected no abnormalities
in the neuronal integrity of the parietal lobe.20
We found significant differences in the frontal, but not the parietal, lobe
concentration of NAA, Cr + PCr, and Cho in non–learning-disabled adults
who were otherwise healthy and who had no significant differences in the volume
or gray-white matter composition of the VOIs we assessed. Thus, the results
of our study and those of other MRS studies most likely disagree owing to
differences in the technique used for data acquisition and, thus, the amount
and/or type of tissue sampled (eg, the use of surface coils does not allow
visualization of the tissues studied) and the age, intelligence, and physical
health of the study subjects.
We found that concentrations of all frontal metabolites were increased
in the subjects with AS. This finding may result from differences in regional
brain volume and brain tissue composition of the VOIs we studied, because
brain tissue composition changes after adolescence,58
and the relative concentrations of NAA, Cho, and Cr may differ in gray and
white matter.63 For example, autopsy studies
reported that the gray-white matter ratio varies from 2.26 to 2.3864-65 at 3 years of age to about 1.3 at
20 years of age.66 Moreover, some researchers
have reported a higher NAA and Cho signal intensity in gray than in white
matter, whereas others report the opposite. The Cr signal intensity is typically
higher in gray than in white matter.63 However,
the regional brain volumes and gray-white matter ratio in the people we studied
were similar to those in previous reports.29, 66-67
Also, we found no significant between-group differences in age, in regional
brain volume, or in the proportion of gray and white matter and CSF contained
in the MRS VOIs. Thus, our measures of regional brain volume and VOI tissue
proportion are most likely reliable, and our results cannot be fully explained
by these potential confounders.
Our results may be explained by differences in tissue density and/or
metabolism. For example, the increased NAA and Cr + PCr concentrations we
found in our subjects with AS suggest an increased density of metabolically
active neurons in the prefrontal lobe or a hypermetabolic state.11
If the increase in NAA concentration reflects an increase in neuronal density,
it should be unaffected by treatment, whereas if it reflects a metabolic abnormality,
this may reverse with treatment (as severity of obsessive/repetitive behavior
was related to NAA concentration). We suggest that abnormalities in neuronal
density/metabolism most likely result from differences in frontal maturation,
because NAA concentration rapidly increases as the brain develops and decreases
in adulthood,11 and neuropathological studies
of patients with autism reported abnormalities in neuronal development.47 The Cho-related compounds are components of neuronal
cell membranes and are found in highest concentration in neuroglia and myelin
sheaths.68 Thus, differences in the Cho concentration
may indicate differences in neuroglial number or neuronal membrane turnover
and/or may be linked to hypermetabolism involving phosphatidylcholine via
the action of phospholipase A2. In humans, membrane turnover is
increased by abnormal patterns of neuronal activation,69
and a significant elevation in CSF ganglioside concentration (an important
component of neuronal membranes) has been reported in patients with autism.70 Thus, differences in neuronal membrane turnover and
signal transduction provide the most parsimonious explanation for the increased
Cho concentration that we found in subjects with AS.
CONCLUSIONS
We found that subjects with AS have a significant increase in the concentrations
of NAA, Cho, and Cr + PCr. In healthy human brain development, postnatal neuronal
membrane turnover is high, and childhood is associated with increasing brain
concentrations of NAA and Cr + PCr, which then reduce to adult levels by the
late teenage years.71-72 Thus,
our findings imply that in AS, these developmental increases in metabolite
concentrations fail to down-regulate, and this failure is related to some
clinical symptoms in adulthood. Further studies are needed of brain development
and aging across the spectrum of people with autistic disorder.
AUTHOR INFORMATION
Submitted for publication October 10, 2000; final revision received
November 14, 2001; accepted December 7, 2001.
Corresponding author and reprints: Declan G. M. Murphy, MBBS, MD,
MRCPsych, P050 Institute of Psychiatry, De Crespigny Park, Camberwell, London
SE5 8AF, England (e-mail: sphadgm{at}iop.kcl.ac.uk).
From the Department of Psychological Medicine (Drs D. G. M. Murphy,
Critchley, McAlonan, van Amelsvoort, Robertson, and K. C. Murphy and Mss Schmitz,
Daly, Rowe, and Russell), the Neuroimaging Research Group, Institute of Psychiatry
(Dr Simmons), and the Department of Psychology (Dr Howlin), St George's Hospital
Medical School, London, England.
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