Abnormal brain size effect on the thalamus in autism

Psychiatry Research: Neuroimaging 147 (2006) 145 – 151 www.elsevier.com/locate/psychresns

Abnormal brain size effect on the thalamus in autism Antonio Y. Hardan a,⁎, Ragy R. Girgis a,b , Jason Adams a , Andrew R. Gilbert a , Matcheri S. Keshavan c , Nancy J. Minshew a a

Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA b Department of Psychiatry, College of Physicians and Surgeons, Columbia University, and New York State Psychiatric Institute, New York, NY, USA c Department of Psychiatry, Wayne State University, Detroit, MI, USA Received 4 August 2005; received in revised form 16 December 2005; accepted 31 December 2005

Abstract This study was conducted to examine the volume of the thalamus in autism and to investigate the effect of brain size on this structure in an attempt to replicate, in a larger sample, findings from a previous study reporting the existence of a relationship between brain volume and thalamus in healthy controls but not in individuals with autism. Additionally, the relationships between thalamic volumes and clinical features were examined. Volumetric measurements of the right and left thalamic nuclei were performed on MRI scans obtained from 40 high-functioning individuals with autism (age range: 8–45 years) and 41 healthy controls (age range: 9–43 years). No differences were observed between the two groups for unadjusted thalamic volumes. However, the expected linear relationship between TBV and thalamic volume was not observed in individuals with autism. Furthermore, no correlations were observed between thalamic volumes and clinical features. Findings from this larger study are consistent with the previous report of an abnormal brain size effect on the thalamus in autism and support the possibility of abnormal connections between cortical and subcortical structures in this disorder. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Thalamus; Autism; MRI; Brain volume; Structural neuroimaging

1. Introduction Autistic disorder (AD) is a pervasive developmental disorder characterized by impaired social interactions and communication, as well as restricted interests and activities (American Psychiatric Association, 1994). The etiology is now widely believed to be related to underdeveloped neural circuitry, although the precise mechanisms underlying this phenomenon remain unknown ⁎ Corresponding author. Department of Psychiatry, Western Psychiatric Institute and Clinic, 3811 O'Hara St., Pittsburgh, PA 15213, United States. Tel.: +1 412 246 6797; fax: +1 412 235 5446. E-mail address: [email protected] (A.Y. Hardan).

(Minshew, 2004). Morphometric neuroimaging studies have identified a number of structural abnormalities in autism, both when examining total brain volume (TBV) (Piven et al., 1995; Courchesne et al., 2001; Hardan et al., 2001a; Aylward et al., 2002) and when investigating several brain structures such as the hippocampus (Saitoh et al., 2001), amygdala (Abell et al., 1999), and cerebellum (Piven et al., 1997; Hardan et al., 2001b). These findings support that the underlying brain abnormality in autism is not localized, but rather involves disturbed connections of neural networks (Minshew, 1996b; Piven et al., 1997), such as the cerebello-thalamo-cortical circuit (Muller et al., 2003).

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Over the last decade, several cognitive functions and their underlying neural circuitry have been implicated in the pathophysiology of autism, including emotional processing (Hall et al., 2003), language (Chugani et al., 1997; Muller et al., 1998), and social cognition (Pelphrey et al., 2004; Waiter et al., 2004). The thalamus is consistently identified as a key component of many of these circuits, with several positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) investigations highlighting abnormalities of this structure in autism. Reduced metabolic correlations have been reported in a group of mostly high-functioning individuals with autism (HFA) involving the frontal and parietal cortices, as well as subcortical structures including the thalamus (Horowitz et al., 1988). In a recent PET study, unilateral alterations of serotonin synthesis were reported in the dentatothalamocortical pathway, with asymmetries of serotonin synthesis in frontal cortex, thalamus, and dentate nucleus of the cerebellum in seven boys with autism (Chugani et al., 1997). In a subsequent PET study by the same group, four autistic and five healthy men were examined while listening to, repeating, and generating sentences (Muller et al., 1998). Differences in activation were found in the autistic group compared with controls in the right dentate nucleus, the left frontal region, and the thalamus (Muller et al., 1998). More recently, a PET study of emotion recognition reported higher cerebral blood flow in several brain regions including the right thalamus in eight adult individuals with autism compared with healthy controls (Hall et al., 2003). Finally, data from fMRI studies have also suggested a role for the thalamus in the pathophysiology of autism, showing abnormal activation during visually paced finger movements (Muller et al., 2001), but not when performing a spatial working memory task (Luna et al., 2002). While multiple investigations have examined functional abnormalities of the thalamus in autism, limited structural information is available. An early computerized tomography study reported no anatomical alterations of this structure in autism (Creasey et al., 1986); however, recent studies applying novel methodologies have reported anomalies (Herbert et al., 2003; Tsatsanis et al., 2003; Waiter et al., 2004). In a voxel-based morphometric analysis of HFA, abnormalities in gray matter were observed in multiple brain regions, including the right thalamus (Waiter et al., 2004). In a recent morphometric study, increased size of the diencephalon, which includes the thalamus, was observed in highfunctioning boys with autism (Herbert et al., 2003). Interestingly, this difference was not found when total brain volume (TBV) was accounted for in the analysis

(Herbert et al., 2003). In another MRI-based volumetric study, no differences in the thalamus were observed between a sample of 12 HFA and 12 normal control subjects (Tsatsanis et al., 2003). However, different relationships were observed between brain size and thalamic volume in the two groups, with significant and positive correlations in controls but not in the patient group (Tsatsanis et al., 2003). The authors suggested possible underdevelopment of the connections between cortical and subcortical regions, and indicated the need for further examination of the thalamus in a larger sample size (Tsatsanis et al., 2003). In light of this emerging evidence, additional investigations are warranted to further examine the existence of any morphometric alterations of the thalamus in autism and more importantly to assess its relationship with brain size. The main objectives of this study are to examine the size of the thalamus and to replicate, in a larger sample, the recent finding of different relationships between thalamic volume and brain size in individuals with autism and healthy controls (Tsatsanis et al., 2003). An additional objective is to investigate the relationship of the thalamus to the clinical features of autism as measured by the Autism Diagnostic Interview-Revised (ADI-R) (Lord et al., 1994). 2. Methods 2.1. Participants Participants comprised HFA subjects between the ages of 8 and 45 years and 41 healthy controls between the ages of 9 and 43 years. Subjects were recruited through outpatient research clinics associated with a university-based medical center. Expert clinical evaluation in compliance with published clinical descriptions of HFA (Minshew, 1996a) and two structured research diagnostic instruments, the ADI-R and the Autism Diagnostic Observation Schedule (ADOS) (Lord et al., 1989), were used to establish the diagnosis of autism. Subjects who met ADI-R and ADOS criteria for autism but did not display delayed language development were considered to have Asperger's Disorder and were excluded from this study. Control subjects were children, adolescents, and adults recruited from the community through advertisements in areas socioeconomically similar to those of the families of origin of the autistic subjects. Questionnaires, telephone interviews, face-toface interviews, and observation during the administration of psychometric tests were used to screen potential control subjects. All subjects were medically healthy and had a full-scale IQ (FSIQ) of 70 or higher.

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Evidence of an associated infectious, genetic, or metabolic disorder, such as fragile-X syndrome or tuberous sclerosis, was used to exclude potential autistic subjects. In addition, evidence of birth asphyxia, head injury, or a seizure disorder was used to exclude potential autistic and control subjects. Exclusions were based on neurological history and examination, physical examination, and chromosomal analysis or metabolic testing if indicated. Potential control subjects were also screened to exclude those with a family history of autism, obsessive–compulsive disorder, developmental-cognitive disorder, affective disorder, learning disability, anxiety disorder, schizophrenia, or other neurological or psychiatric disorders thought to have a genetic component. The Hollingshead method (Hollingshead, 1975) was used to assess socioeconomic status of the family of origin. FSIQ, Performance IQ (PIQ), and Verbal IQ (VIQ) were measured with the age-appropriate version of the Wechsler Intelligence scale (WAIS-R or WISC-R). The Institutional Review Board approved the methodology of the study, including MRI scanning for minors. Procedures were fully explained to all subjects and, when applicable, to their parent or legal guardian. Written informed consent was obtained from subjects or their guardians. 2.2. MRI scans All scans were obtained on a General Electric (Milwaukee) 1.5 Tesla Signa scanner. The imaging protocol consisted of two T1-weighted (TR = 500, TE = 20) series: a sagittal series of 3-mm slice thickness parallel to the midline structure, and an axial series of 5-mm slice thickness. An additional 1.5-mm SPGR (spoiled gradient recalled echo in steady state) coronal sequence (TR = 35, TE = 5, NEX = 1, flip angle = 45°) was collected, and used for all of the measurements reported in this study. All images were transferred from the acquisition facility to the image analysis laboratory via file transfer protocol and archived on CD-ROM disks. 2.3. Neuroanatomic measures 2.3.1. Thalamus Anatomical measurements of the right and left thalamus were conducted on a Macintosh workstation using the semi-automated software; NIH Image (version 1.55) (Rasband, 1997). The thalamic nuclei were identified bilaterally in reference to standard atlases (Daniels et al., 1987; Talairach and Tournoux, 1988), and measurements were done according to procedures previously

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described (Gilbert et al., 2001). In the development of reliability, two raters (J.A. and A.G.) were used. The intra-class correlation coefficients (ICCs), established by tracing 10 training scans, for right and left thalamus were above 0.92 (J.A. and A.G.). After reliability was established, all thalamic tracings were performed manually in the coronal plane by one trained evaluator (J.A.), blind to group assignment and to the subjects' identities. The mamillary body was used as the anterior boundary; the internal capsule, the lateral boundary; the third ventricle, the medial boundary; the inferior border of the third ventricle, the inferior boundary. The posterior boundary was considered to be where the hemispheres of the thalamus merge under the crux fornix. The superior boundary was defined as the main body of the lateral ventricle (Portas et al., 1998). 2.3.2. Total brain volume The measurements were made on a Gateway 2000 graphics workstation (N. Sioux City, SD) using custom graphics software developed locally (Aylward et al., 1998). The cerebellum and brainstem were included in TBV measurements, but cerebrospinal fluid was not. In addition, the foramen magnum was identified as the lower boundary of the brainstem and consequently of TBV. Segmentation of brain from cerebrospinal fluid and extracerebral tissue was performed using a semiautomated thresholding procedure (Aylward et al., 1998). Measurements were performed blind to diagnosis. Intra-rater reliability testing yielded an ICC of 0.99 on 10 brains for obtaining brain volumes with this procedure. Since two different programs were used to conduct the morphometric studies (i.e., NIH Image for the thalamus and locally developed software for TBV), TBV measurements were obtained from 10 scans using both software and revealed high reliability between the two programs (R = 0.95) and acceptable ICC (R = 0.85). 2.4. Data analysis Between-group differences were analyzed with twotailed Student t-tests and were reported as means and standard deviations (M ± S.D.). Pearson's correlation coefficients were used to examine the association between TBV and thalamic volumes after determining the linear relationship between the two variables. Analysis of covariance (ANCOVA) was proposed to compare the two subject groups on structure volumes while controlling for confounding factors such as age, height, FSIQ, and TBV. However, this was not feasible for TBV since a linear relationship was observed

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between the TBV and thalamic volumes in controls (total thalamus: R = 0.13, F = 5.71, P = 0.02; left thalamus: R = 0.15, F = 6.62, P = 0.01; right thalamus: R = 0.10, F = 4.28, P b 0.05), but not in patients (total thalamus: R = 0.23, F = 2.34, P = 0.16; left thalamus: R = 0.04, F = 1.74, P = 0.20; right thalamus: R = 0.05, F = 2.09, P = 0.16). As a result, the application of ANCOVA to detect group differences after adjusting for TBV was not possible. Instead, we divided the sample with respect to TBV using the median split approach. T-tests were used to compare the autistic and control groups on thalamic volumes after stratifying by TBV. In addition, a two-way analysis of variance (ANOVA) was used to simultaneously examine the relationship of thalamic volume with subject and TBV groups. For analyses reaching significance, post hoc testing was performed (Tukey multiple comparison test: Cicchetti, 1994; Tsatsanis et al., 2003). Spearman's rho correlation coefficients were used to examine the relationship of the thalamic volumes and ADI-R summary scores. Spearman rho correlation was used because the continuous nature of the scores on the ADI-R items has not been established. Probability figures were considered significant if they achieved significance at conventional levels (i.e., P b 0.05). Laterality index was calculated based on the following formula: [(Left − Right) / (Left + Right)] × 100. 3. Results There were no significant differences between the autistic and control subjects for age (autistics: 19.3 ± 9.9 years; range 8.8–45.7; controls: 18.6 ± 8.6 years; range 9.2–43.9), FSIQ (autistics: 103.1 ± 14.6; range 75–135; controls: 104.2 ± 9.7; range 86–121), or height as a measure of body size (autistics: 65.02 ± 6.8 inches; range 50–77; controls: 65.42 ± 6.48 inches; range 50– 73). The complete demographic information has previously been published, and no differences were observed between the two groups on VIQ, PIQ, and socioeconomic status (Hardan et al., 2003). Of the 81 total participants, only four were female, two from each group. Table 1 summarizes the structure volumes of all subjects. No differences were observed in the right, left, or total unadjusted thalamic volumes between the autistic and control groups. A non-significant increase in TBV was observed in the autistic group compared with controls (autistic: 1350.45 ± 134.78 cc; control: 1315.06 ± 123.68 cc; t = 1.23, df = 79, P = 0.22). The level of significance of all of these comparisons remained the same after controlling for height and/or age. Similarly, no change in the level of significance occurred when females were

Table 1 Volumetric measurements (cc) of the thalamus in autistic and normal control subjects Autistic

All subjects Right thalamus Left thalamus Total thalamus Subjects with TBV b 1333 cc Right thalamus Left thalamus Total thalamus Subjects with TBV N 1333 cc Right thalamus Left thalamus Total thalamus

Control

t

df

P

Mean

S.D.

Mean

S.D.

n = 40 4.59 4.08 8.67 n = 17

1.45 1.22 2.59

n = 41 4.67 4.13 8.80 n = 23

1.36 1.30 2.58

−0.27 −0.19 −0.23

79 79 79

0.79 0.85 0.82

4.68 4.14 8.82 n = 23

1.39 1.21 2.49

4.18 3.64 7.82 n = 18

1.27 1.08 2.30

1.17 1.38 1.31

38 38 38

0.25 0.18 0.20

4.53 4.03 8.56

1.51 1.24 2.72

5.30 4.76 10.06

1.23 1.32 2.43

−1.77 −1.80 −1.84

39 39 39

0.09 0.08 0.07

TBV: total brain volume.

excluded. Furthermore, 19 subjects were taking different psychotropics, mostly serotonergic agents. No change in the level of significance occurred between the two groups after exclusion of these individuals. The examination of the relationship between thalamic volumes and TBV revealed the existence of a positive correlation in the control group (right thalamus: r = 0.31, P = 0.05; left thalamus: r = 0.38, P = 0.01; total thalamus: r = 0.36, P = 0.02). As stated above, a median split approach was applied to further investigate the differences in these relationships between the two groups. The median TBV was 1333 cc. No differences were found in any of the demographic data after stratifying for TBV, except for FSIQ, in individuals with a TBV b 1333 (autistic: 96.3 ± 11.9; control: 104.4 ± 10.0; t = −2.34, df = 38, P = 0.03). As expected, thalamic volumes were larger in subjects with high TBV compared with those with low TBV among controls (right thalamus: t = − 2.86, df = 39, P = 0.01; left thalamus: t = − 2.99, df = 39, P = 0.01; total thalamus: t = − 3.03, df = 39, P b 0.01) but, interestingly, not among autistic subjects (right thalamus: t = − 0.31, df = 38, P = 0.76; left thalamus: t = 0.27, df = 38, P = 0.79; total thalamus: t = 0.30, df = 38, P = 0.76). These differences remained unchanged when controlling for FSIQ and for body size as measured by height. Additionally, a two-way ANOVA was conducted with diagnostic group (controls, patients) and TBV (above and below the median) as independent variables and thalamic volumes as the dependent variables. No main effects were observed for TBV or diagnosis. However, there was a significant interaction effect for diagnosis and TBV (right

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thalamus: F = 4.33, df = 3, 77, P = 0.04; left thalamus: F = 5.09, df = 3, 77, P = 0.03; and total thalamus: F = 4.98, df = 3, 77, P = 0.03). Post hoc comparisons were performed using the Tukey multiple comparison tests and revealed that the interaction effect is related mostly to the differences between thalamic volumes in the control group, with subjects in the high TBV group showing significantly greater thalamic volumes than the low TBV group (right thalamus: P = 0.05; left thalamus: P = 0.02; and total thalamus: P = 0.03). The relationship between the sizes of the right and left thalamus was examined as differences in the level of association have been previously reported (Tsatsanis et al., 2003). A strong correlation was found not only in the control group (r = 0.89, P b 0.01), but also in the autistic group (r = 0.90, P b 0.01). No laterality was observed in the thalamic volumes as measured by the absolute value of left-minus-right thalamus (autistic: 0.65 ± 0.49; control: 0.68 ± 0.49, t = − 0.16, df = 79, P = 0.88) and the laterality index (autistic: − 5.60 ± 7.28; control: −6.33 ± 6.68, t = 0.47, df = 79, P = 0.64). Finally, no significant correlations were observed between right, left, or total thalamic volumes and any of the three summary scores from the ADI-R in the autistic subjects (social deficits, communication impairments, and stereotypic behaviors). 4. Discussion In this study, abnormal brain volume effects on the thalamus were observed in a large sample of HFA compared with controls. In particular, an absence of the expected linear relationship between thalamic volumes and TBV was observed in the patient group, indicating that the heterogeneity of total brain size in autism (Piven et al., 1995; Courchesne et al., 2001; Hardan et al., 2001a; Aylward et al., 2002) may be affecting subcortical structures. Results of the current investigation also support the reported underdeveloped connectivity between cortical and subcortical regions (Minshew, 1996b; Piven et al., 1997; Tsatsanis et al., 2003). These findings appear to be unrelated to height as a measure of body size. However, the possible effects of these variables on other structures should be examined since they may affect other brain regions in a distinct manner, especially in individuals with autism. Findings from this study are consistent with the only published report specifically examining the volume of the thalamus in autism using MRI scans (Tsatsanis et al., 2003). No differences were observed in thalamic volumes between the patient and control groups in both studies. However, brain size effects on

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these structures were found in the healthy group, but not in the patient group, and were manifested as greater volume of the thalamus in individuals with high TBV that in subjects with low TBV. Additionally, while thalamic volumes were significantly larger in the control group among high TBV subjects in Tsatsanis et al. (2003), this difference showed only a trend in the present investigation. Of note, several differences exist between the two studies. The mean thalamic volumes appear to be different between the two studies in the patient as well as the control groups (e.g., total thalamic volume in the autistic group was 8.67 ± 2.59 cc in this study and 13.57 ± 0.61 cc in the previous study) despite similar ages (mean age for autistic subjects = 19.3 years for this study and 21.0 years in Tsatsanis et al. (2003)). In addition, laterality was not found in the present investigation. These discrepancies could be accounted for by the differences in the number of autistic subjects (n = 40 in this study and n = 12 in the previous study) and volumetric measurement methodologies applied in the two studies, including the imaging software used and the boundary definitions (Tsatsanis et al., 2003). In the present investigation, an absence of the normal linear relationship of the thalamus to brain size was observed in a sample of HFA, which is different from the positive and linear correlation that was found for the orbitofrontal cortex and TBV in the same sample in both groups (Hardan et al., in press). Morphometric alteration of the thalamus in this pervasive developmental disorder is consistent with evidence from several investigations supporting the role of this structure in the pathophysiology of autism. The thalamus, through the corticothalamo-cortical pathways, is widely believed to play an important role in information processing in the human brain (Herrero et al., 2002; Sherman and Guillery, 2002), and many neuropsychological deficits characterizing individuals with autism have been suggested to involve abnormalities in information processing (Minshew et al., 1997). In fact, a recent fMRI study investigating a sentence-comprehension task in HFA pointed to the thalamus as a structure involved in collaborative networks implicated in such cognitive functions (Just et al., 2004). The examination of the relationship of thalamic volume and clinical features as assessed in the present investigation was overall negative. This is consistent with the limited associations that have so far been reported between brain size and clinical correlates (Piven et al., 1995), although investigators have described the existence of some relatively weak relationships between head circumference and symptoms of

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autism (Lainhart et al., 1997). Further studies are needed to shed light on these relationships. There are several limitations of this study. The autistic sample was restricted to high-functioning subjects with autism, which limits the generalizability of the results. The exclusion of very young children in this study further limits the significance of the results since abnormalities may be less pronounced in older individuals. The possible lack of sufficient referrals from minorities to the research clinic may have caused the study sample to be less characteristic of a community population. Methodologically, limitations include the dependence on arbitrary locations of landmarks to identify structural boundaries, and the use of two different morphometric programs to conduct the volumetric measurements. In summary, the results of this study replicate findings from a previous study reporting an abnormal brainsize effect on the thalamus in autism (Tsatsanis et al., 2003). Future investigations should examine the existence of any associations between neurobiological alterations, such as volumetric measurements or activation patterns, and brain size in an attempt to assess the interaction between these findings and any clinical correlates. These efforts may help to shed light on the pathophysiology of increased brain size and head circumference in autism. Acknowledgments This work was supported in part by NIMH grant MH 64027 (Hardan), and NICHD grant HD 35469 and NINDS grant NS 33355 (Minshew). We are grateful for the efforts and commitment of the participants and their families in this study. References Abell, F., Krams, M., Ashburner, J., Passingham, R., Friston, K., Frackowiak, R., Happe, F., Frith, C., Frith, U., 1999. The neuroanatomy of autism: a voxel-based whole brain analysis of structural scans. Neuroreport 10, 1647–1651. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). APA, Washington, DC. Aylward, E.H., Anderson, N.B., Bylsma, F.W., Wagster, M.V., Barta, P.E., Sherr, M., Feeney, J., Davis, A., Rosenblatt, A., Pearlson, G.D., Ross, C.A., 1998. Frontal lobe volume in patients with Huntington's disease. Neurology 50, 252–258. Aylward, E.H., Minshew, N.J., Field, K., Sparks, B.F., Singh, N., 2002. Effects of age on brain volume and head circumference in autism. Neurology 59, 175–183. Chugani, D.C., Muzik, O., Rothermel, R., Behen, M., Chakraborty, P., Mangner, T., da Silva, E.A., Chugani, H.T., 1997. Altered serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Annals of Neurology 42, 666–669.

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