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Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder

  • Joaquim Radua (a1) and David Mataix-Cols (a2)
Abstract
Background

Specific cortico-striato-thalamic circuits are hypothesised to mediate the symptoms of obsessive–compulsive disorder (OCD), but structural neuroimaging studies have been inconsistent.

Aims

To conduct a meta-analysis of published and unpublished voxel-based morphometry studies in OCD.

Method

Twelve data-sets comprising 401 people with OCD and 376 healthy controls met inclusion criteria. A new improved voxel-based meta-analytic method, signed differential mapping (SDM), was developed to examine regions of increased and decreased grey matter volume in the OCD group v. control group.

Results

No between-group differences were found in global grey matter volumes. People with OCD had increased regional grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, as well as decreased volumes in bilateral dorsal medial frontal/anterior cingulate gyri. A descriptive analysis of quartiles, a sensitivity analysis as well as analyses of subgroups further confirmed these findings. Meta-regression analyses showed that studies that included individuals with more severe OCD were significantly more likely to report increased grey matter volumes in the basal ganglia. No effect of current antidepressant treatment was observed.

Conclusions

The results support a dorsal prefrontal–striatal model of the disorder and raise the question of whether functional alterations in other brain regions commonly associated with OCD, such as the orbitofrontal cortex, may reflect secondary compensatory strategies. Whether the reported differences between participants with OCD and controls precede the onset of the symptoms and whether they are specific to OCD remains to be established.

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Corresponding author
Joaquim Radua, Division of Psychological Medicine, Institute of Psychiatry, PO 69, King's College London, London SE5 8AF. Email: Joaquim.Radua@iop.kcl.ac.uk
Footnotes
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Declaration of interest

None.

Footnotes
References
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Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder

  • Joaquim Radua (a1) and David Mataix-Cols (a2)
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eLetters

Re: Heterogeneity of coordinate-based meta-analyses of neuroimaging data: an example from studies in OCD

Joaquim Radua, PhD student
22 March 2010

Ferreira and Busatto highlight the important issue of methodological differences across existing voxel-based meta-analytical methods. They urgeauthors of future meta-analyses to clearly justify their choice of methodological parameters. In this reply, we further address these methodological issues in order to provide guidance for future meta-analyses.

As pointed out by Ferreira and Busatto, one parameter critically influencing the results of a coordinate-based meta-analysis is the full-width at half maximum (FWHM) of the kernel. The optimal FWHM has been found to depend on the meta-analytic method [1]. In Signed Differential Mapping (SDM), a 25mm FWHM shows a good compromise between sensitivity andcontrol of false positives [2]. This FWHM may account for different sources of spatial error such as registration mismatch, the size of original clusters or the location of the peak coordinates within the clusters. Much smaller FWHMs are common in Activation/Anatomical Likelihood Estimation (ALE), usually 10-15mm [3]. However, the use of these small FWHMs has not been clearly justified and it might lead to a dramatic reduction in sensitivity. Salimi-Khorshidi et al. [1] found that the sensitivity of the ALE method with a standard deviation of 5mm (corresponding to 10-15mm FWHM) was approximately 50% of the sensitivity achieved with a standard deviation of 15mm (corresponding to 35mm FWHM).

Other limitations of ALE may be more serious [2;4] and have motivatedthe development of other methods such as SDM [2]. For example, coordinatesof increased and decreased activation (or, in this case, grey matter volume) are computed separately. This means that when calculating the meta-analytic increase in a voxel, the (negative) values of those studies reporting decreases in the same voxel are artificially replaced by zeros, leading to an inflation of the meta-analytic increase. Similarly, when computing the meta-analytic decrease, the (positive) values of those studies reporting increases in the same voxel are artificially replaced byzeros, leading to an inflation of the meta-analytic decrease. Therefore, brain regions with higher variability are more likely to be detected as significant in the meta-analysis, to the extent that some brain regions may appear to have both increases and decreases at the same time [for example, see 5]. This is both mathematically and physiologically implausible. Another advantage of SDM is the strict inclusion of coordinates that are statistically significant at the whole-brain level and using the same threshold throughout the brain [2]. This is of utmost importance given that it is not uncommon in neuroimaging studies that someregions (e.g. a priori regions of interest) are more liberally thresholdedthan the rest of the brain, thus potentially leading to false positives.

Unfortunately, psychiatric neuroimaging is plagued with methodological problems such as small sample sizes and overly liberal statistical methods, often making findings hard to replicate. Meta-analytical methods have the potential to overcome some of these limitations by helping researchers ‘see the forest before the trees’. However, if the methods or its parameters are not chosen rigorously, meta-analyses may suffer from the same problems that motivated their development in the first place.

References

1. Salimi-Khorshidi, G., Smith, S. M., Keltner, J. R., et al (2009) Meta-analysis of neuroimaging data: A comparison of image-based and coordinate-based Pooling of studies. Neuroimage, 45, 810-823.

2. Radua, J. and Mataix-Cols, D. (2009) Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry, 195, 391-400.

3. Rotge, J. Y., Langbour, N., Guehl, D., et al (2010) Gray matter alterations in obsessive-compulsive disorder: an anatomic likelihood estimation meta-analysis. Neuropsychopharmacology, 35, 686-691.

4. Laird, A. R., Fox, P. M., Price, C. J., et al (2005) ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Hum Brain Mapp, 25, 155-164.

5. Menzies, L., Chamberlain, S. R., Laird, A. R., et al (2008) Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev, 32, 525-549.

Declaration of interest

The authors have no competing interests to declare.

Authors

Joaquim Radua and David Mataix-Cols. Division of Psychological Medicine, Institute of Psychiatry, King's College London, PO 69, London, United Kingdom
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Conflict of interest: None Declared

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Heterogeneity of coordinate-based meta-analyses of neuroimaging data: an example from studies in OCD

Luiz K. Ferreira, Research Fellow
26 February 2010

Heterogeneity of coordinate-based meta-analyses of neuroimaging data:an example from studies in OCD

Two automated, coordinate-based meta-analyses of voxel-based morphometry (VBM) studies comparing obsessive-compulsive disorder (OCD) subjects and healthy controls have been recently published, respectively in the British Journal of Psychiatry1 and Neuropsychopharmacology.2 Surprisingly, their results are less concordant than one would have expected. We believe this is largely due to methodological differences across the studies.

In coordinate-based meta-analysis, three-dimensional brain maps are built based on the reported coordinates of voxels of peak statistical difference between groups, with higher values being assigned to voxels closer to these coordinates. The full-width at half maximum (FWHM) value of a Gaussian kernel determines the width of spatial distribution,1,3,4 thus critically influencing the results. Radua and Mataix-Cols1 used a 25mm FWHM kernel, while Rotge et al2 set this parameter at 12mm. Such distinction may explain two differences between their results. First, onlyRadua and Mataix-Cols reported gray matter (GM) increases in the right superior parietal cortex and precuneus, although both studies took exactlythe same parietal cortical coordinates (n=4) from the individual VBM investigations. However, these parietal coordinates were not in close proximity to each other, possibly reflecting the spatial uncertainty of OCD-related abnormalities in this area. Since the width of the distribution of voxel values reflects the spatial uncertainty of significant findings,3 the greater FWHM kernel used by Radua and Mataix-Cols possibly afforded greater sensitivity to detect parietal clusters of GM difference. Second, though both studies detected striatal foci of increased GM, Rotge et al’s findings were confined to the putamen while inthe study by Radua and Mataix-Cols these foci spread also to the globus pallidus and caudate nucleus. The greater FWHM value used by Radua and Mataix-Cols probably explains the lower spatial resolution of the striatalfoci in their meta-analysis.

Moreover, Rotge et al used the Activation Likelihood Estimation method,4 in which coordinates regarding increased and decreased GM are separately computed in independent maps. Conversely, Radua and Mataix-Colsused the signed differential mapping method,1 in which coordinates for findings of either increased or decreased GM are reconstructed in the samemap, thus influencing each other. Since VBM studies of OCD have identifiedfoci of both increased and decreased GM in the orbitofrontal cortex, this may explain why Radua and Mataix-Cols did not reproduce Rotge et al’s finding of GM increase in this region of critical relevance to the pathophysiology of OCD.5

An additional source of discrepancy relates to the criteria for coordinate selection. Rotge et al included all coordinates reported in theselected studies, regardless of statistical thresholds and correction for multiple comparisons. Conversely, Radua and Mataix-Cols employed stricter criteria, thus leading to the inclusion of fewer coordinates (as detailed in their article1).

In conclusion, these papers are an example of how methodological differences may critically influence the results of coordinate-based meta-analyses. Therefore, when performing such investigations, one should clearly justify the criteria used for coordinate selection and the choice of other methodological parameters. Future studies using such novel techniques should focus on how to foster greater methodological comparability and reproducibility of results.

References

1.Radua J, Mataix-Cols D. Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry 2009; 195: 393-402.

2.Rotge JY, Langbour N, Guehl D, Bioulac B, Jaafari N, Allard M, et al. Gray matter alterations in obsessive-compulsive disorder: an anatomic likelihood estimation meta-analysis. Neuropsychopharmacology 2010; 35: 686-91.

3.Eickhoff SB, Laird AR, Grefkes C, Wang LE, Zilles K, Fox PT. Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Hum Brain Mapp 2009; 30: 2907-26.

4.Turkeltaub PE, Eden GF, Jones KM, Zeffiro TA. Meta-analysis of thefunctional neuroanatomy of single-word reading: method and validation. Neuroimage 2002; 16: 765-80.

5.Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N, et al. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 2008; 321: 421-2.

Declaration of interest

The authors have no competing interests to declare.

Authors

Luiz Kobuti Ferreira, research fellow of the Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry,Faculty of Medicine, University of São Paulo, SP, Brazil.e-mail: kobuti@yahoo.comTel.: +55 11 30698132; fax: +55 11 30821015Address: Centro de Medicina Nuclear, 3◦ andar, LIM- 21Rua Dr. Ovídio Pires de Campos, s/nPostal Code 05403-010, São Paulo, SP, Brazil

Geraldo F. Busatto, Coordinator, Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, SP, Brazil.Address: Centro de Medicina Nuclear, 3◦ andar, LIM- 21Rua Dr. Ovídio Pires de Campos, s/nPostal Code 05403-010, São Paulo, SP, Brazil
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Conflict of interest: None Declared

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