Elsevier

Cortex

Volume 62, January 2015, Pages 89-108
Cortex

Special issue: Review
Widespread structural brain changes in OCD: A systematic review of voxel-based morphometry studies

https://doi.org/10.1016/j.cortex.2013.01.016Get rights and content

Abstract

The most widely accepted model of obsessive–compulsive disorder (OCD) assumes brain abnormalities in the “affective circuit”, mainly consisting of volume reduction in the medial orbitofrontal, anterior cingulate and temporolimbic cortices, and tissue expansion in the striatum and thalamus. The advent of whole-brain, voxel-based morphometry (VBM) has provided increasing evidence that regions outside the “affective” orbitofronto-striatal circuit are involved in OCD. Nevertheless, potential confounds from the different image analysis methods, as well as other factors, such as patients' medication and comorbidity status, may limit generalization of results.

In the present paper, we systematically reviewed the whole-brain VBM literature on OCD by focussing specifically on degree of consistency between studies, extent to which findings have been replicated and interrelation between clinical variables and OCD anatomy, a potentially crucial factor that has been systematically examined only in a limited number of studies. The PubMed database was searched through February 2012. A total of 156 studies were identified; 18 of them fulfilled the inclusion/exclusion criteria and included 511 patients and 504 controls. Results support the notion that the brain alterations responsible for OCD are represented at the network level, and that widespread structural abnormalities may contribute to neurobiological vulnerability to OCD. Apart from defects in regions within the classic “affective” circuit, volume reduction of the cortical source of the dorsolateral (DL) prefronto-striatal “executive” circuit (dorsomedial, DL, ventrolateral and frontopolar prefrontal cortices), and of reciprocally connected regions (temporo-parieto-occipital associative areas) is consistently described in OCD patients. Moreover, increased volume of the internal capsule and reduced frontal and parietal white matter volumes may account for altered anatomical connectivity in fronto-subcortical circuitry. Morphometric changes in both “affective” and “executive” parallel the disease clinical course, being at the same time responsible for variation in symptom severity. Thus, OCD mechanisms involve a more widespread network of cerebral dysfunctions than previously thought, which may explain the heterogeneity in clinical manifestations and symptom severity.

Introduction

Obsessive–compulsive disorder (OCD) is still considered a unitary nosologial entity in standard nomenclatures (DSM-IV-TR and ICD-10) despite increasing recognition of its phenotypic heterogeneity. This disabling condition is typically characterized by the presence of recurrent, persistent, and intrusive ego-dystonic thoughts, impulses, or images (obsessions), and repetitive behaviours or mental acts (compulsions), which are executed to avoid anxiety or neutralize obsessions (American Psychiatric Association, 2000). However, OCD-affected patients vary widely with respect to symptom type (e.g., hoarding vs cleaning), symptom severity, age of symptom onset, and comorbidities (e.g., tic disorders, depression). This suggests that both general and specific etiological factors contribute to the observed phenomenological heterogeneity. Indeed, several studies conducted using a symptom dimensional approach (Mataix-Cols et al., 2005) demonstrated that different symptoms are mediated by distinct neural systems (Saxena et al., 2004; Lawrence et al., 2007; An et al., 2009; van den Heuvel et al., 2009) and characterized by specific neuropsychological deficits (Lawrence et al., 2006; Di Paola et al., 2012).

Generalist models of OCD propose that abnormalities of the cortico-striatal circuits that involve the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), thalamus and striatum play an important role in its pathophysiology (Graybiel and Rauch, 2000; Saxena and Rauch, 2000; Menzies et al., 2008). This biological model has been partially validated by direct investigations of circuits that might be involved in the pathogenesis of the disorder. Specifically, functional neuroimaging studies, which provide in vivo evidence of brain abnormalities in OCD patients, have reported congruent results such as hyperactivity in orbitofronto-striatal circuits both in a resting state (Baxter et al., 1988) and during periods of provoked OCD symptoms (Rauch et al., 1994). Conversely, results of morphometric studies are more contradictory. There are reports of increased grey matter (GM) volume in the OFC and other structures belonging to the orbitofronto-striatal circuit (Kim et al., 2001; Valente et al., 2005; Christian et al., 2008) and of reduced volume in the same regions (Pujol et al., 2004; van den Heuvel et al., 2009) or no volumetric changes (Jenike et al., 1996; Bartha et al., 1998). As a case in point, a meta-analytic study that searched for volumetric alterations in regions predicted to be involved in OCD a priori, reported reduced volume in the OFC and ACC, and increased volume in the thalamus, but no change in the basal ganglia (BG) (Rotge et al., 2009). On the other hand, a quantitative meta-analysis of whole-brain structural MRI studies using a new approach to avoid biases towards a priori brain regions (signed differential mapping – SDM, Radua and Mataix-Cols, 2009) showed increased bilateral regional GM volumes in the BG as well as decreased bilateral regional GM volumes in the dorsal mediofrontal/anterior cingulate gyri extending to the supplementary motor area and frontal eye fields, but no volumetric differences in the OFC (Radua and Mataix-Cols, 2009). Alternatively, decreased GM density in the OFC and increased GM density in the BG and ACC was reported in an anatomical likelihood estimation (ALE; Turkeltaub et al., 2002) meta-analysis (Rotge et al., 2010) performed on investigations using whole-brain voxel-based morphometry (VBM; Ashburner and Friston, 2000). The same study showed decreased GM density in several areas outside the orbitofronto-striatal regions, e.g., the frontal eye field, the dorsolateral (DL) prefrontal cortex (PFC), the supramarginal gyrus (SMG), and the anterior PFC. Such discrepancies may be partially accounted for the different methods used in the considered studies as typical region of interest (ROI)-based meta-analyses are affected by a limited and potentially biased inclusion of brain regions (Radua and Mataix-Cols, 2012) while the use of voxels rather than conventional divisions of the brain improves the correct localization of potential abnormalities, since is based on a whole-brain analysis of the differences between patients and controls (Borgwardt et al., 2012). On the other hand, meta-analytic methods used in voxel-based meta-analyses also have drawbacks as for instance, analyses are not weighted by sample size in the ALE method. However, a recent version of the SDM [Effect Size-SDM (ES-SDM), Radua and Mataix-Cols, 2012] using well-established statistics, seems to be a promising toll for optimizing the sensitivity of existing peak-probability methods, while protecting against the false positives.

Nevertheless, since investigators began using fully automated whole-brain VBM methods to assess structural changes in OCD patients, increased and consistent evidence has been reported that brain abnormalities are not limited exclusively to the “affective” orbitofronto-striatal circuit, but extend to the DL prefronto-striatal “executive” circuit and additional regions including the parietal, temporal and occipital lobes (Yoo et al., 2008; Kopřivová et al., 2009; Togao et al., 2010).

Whole-brain investigations of local changes in GM and white matter (WM) volumes of OCD patients demonstrated that morphometric abnormalities were not limited to GM, but also involved the primary WM tracts that connect the nodes of the orbitofronto-striatal circuit (Togao et al., 2010) and other WM areas in the parietal and occipital lobes (Lázaro et al., 2009, Lázaro et al., 2011; Riffkin et al., 2005).

The reported findings of extensive GM abnormalities in regions not anticipated by the orbitofronto-striatal model, and in WM connections outside the “affective” circuit provided the means for extending and revising the current neuroanatomical theory of OCD. Indeed, it has been suggested that the orbitofronto-striatal model may not be sufficient to explain the brain basis of the disorder and that abnormalities across several regions and dysfunction at the network level may account for the pathogenesis and clinical expression of OCD (Menzies et al., 2008). However, such insightful assumption is currently based on scattered evidence coming from functional (e.g., van den Heuvel et al., 2005; Schienle et al., 2005) and structural neuroimaging studies and basically grounded on the notable discrepancies between findings from cognitive studies, showing impairments in cognitive processes not regarded to rely so heavily on orbitofrontal function (e.g., van den Heuvel et al., 2005; Chamberlain et al., 2004), and the present theoretical model of OCD.

On the basis of these considerations, and to investigate the existence of additional structural alterations in the disorder, we thoroughly reviewed the existing whole-brain VBM literature on OCD. Evidence supporting the “orbitofronto-striatal circuit” hypothesis of OCD (Graybiel and Rauch, 2000; Aouizerate et al., 2004) is reported individually, and empirical support for the existence of widespread anatomical alterations in OCD is discussed separately. We focused specifically on the degree of consistency between studies and the extent to which findings have been replicated. Moreover, given that clinical variables such as symptom dimensions, medication status, comorbidity status, and symptom severity may be associated with differential structural abnormalities, we purposely considered the relationship between these variables and OCD anatomy, a potentially crucial factor that has been systematically examined only in a limited number of studies (e.g., Radua and Mataix-Cols, 2009).

Section snippets

Literature search and study selection

We used the Medline engine to search for neuroimaging articles that employed the whole-brain VBM technique in OCD patients. The PubMed database was searched through February 2012, without limits for year of publication and using the Key words obsessive-compulsive disorder and any of the following terms: structural neuroimaging, brain morphometry, voxel-based morphometry or whole-brain voxel-based morphometry.

The reference list of identified studies and review papers was also hand-searched to

Brain regions involved in the classic model of OCD: the orbitofronto-striatal “affective” circuit

Although not all studies agree on this issue, a remarkable amount of neuroimaging data on OCD has demonstrated the presence of structural abnormalities in BG and a number of frontal structures. Among these regions, some areas have been established as “key brain regions” in the pathophysiology of the disorder, including the OFC, ACC, striatum and thalamus, as well as the temporolimbic regions (Atmaca et al., 2008; Pujol et al., 2004; Radua and Mataix-Cols, 2009; Saxena and Rauch, 2000; van den

Comment on the classical model

The evidence reviewed is consistent with the notion that abnormalities in orbitofrontal, cingulate, thalamic, and temporolimbic regions play a central role in the pathophysiology of OCD.

Nevertheless, locations and directions of the changes in the OFC were heterogeneous across studies. In fact, four investigations (Kim et al., 2001; Valente et al., 2005; Christian et al., 2008; Szeszko et al., 2008) reported increased volume and five (Pujol et al., 2004; Yoo et al., 2008; Lázaro et al., 2009;

Conclusion

On the basis of our extensive review of brain morphometric studies in OCD patients, we suggest that the current orbitofronto-striatal model of the disorder may not be sufficient to entirely explain the cerebral basis of the clinical manifestations of OCD. Indeed, when the results are integrated with the pathophysiology of OCD, evidence shows that multiple circuits are involved in the disease.

First, the reported investigations confirm the saliency of the “affective” fronto-striatal loop

Limitations

Our systematic review has several limitations. First, although based on whole-brain analyses of differences between patients and controls, is grounded on the available published results, which often do not report null findings or discard as false positives or artifacts abnormalities not thought to be related to the disorder (Borgwardt et al., 2012). Second, results from the reviewed studies are necessarily “binarized” (significant vs non-significant or increased vs decreased) with a loss of

Funding

This work was supported by the Italian Ministry of Health RC 06-07-08-09-10 and RF 06-07-08 grants.

References (90)

  • A. den Braber et al.

    White matter differences in monozygotic twins discordant or concordant for obsessive–compulsive symptoms: A combined diffusion tensor imaging/voxel-based morphometry study

    Biological Psychiatry

    (2011)
  • F.L. Duran et al.

    Association between symptom severity and internal capsule volume in obsessive–compulsive disorder

    Neuroscience Letters

    (2009)
  • T. Endrass et al.

    Overactive performance monitoring in obsessive–compulsive disorder: ERP evidence from correct and erroneous reactions

    Neuropsychologia

    (2008)
  • A.R. Gilbert et al.

    Brain structure and symptom dimension relationships in obsessive–compulsive disorder: A voxel-based morphometry study

    Journal of Affective Disorders

    (2008)
  • A.R. Gilbert et al.

    Gray matter differences between pediatric obsessive–compulsive disorder patients and high-risk siblings: A preliminary voxel-based morphometry study

    Neuroscience Letters

    (2008)
  • A.M. Graybiel et al.

    Toward a neurobiology of obsessive–compulsive disorder

    Neuron

    (2000)
  • J. Kopřivová et al.

    Medial frontal and dorsal cortical morphometric abnormalities are related to obsessive–compulsive disorder

    Neuroscience Letters

    (2009)
  • M.L. Kringelbach et al.

    The functional neuroanatomy of the human orbitofrontal cortex: Evidence from neuroimaging and neuropsychology

    Progress in Neurobiology

    (2004)
  • S. Kühn et al.

    Reduced thickness of anterior cingulate cortex in obsessive–compulsive disorder

    Cortex

    (Sep. 17, 2013)
  • L. Lázaro et al.

    A voxel-based morphometric MRI study of stabilized obsessive–compulsive adolescent patients

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2011)
  • L. Lázaro et al.

    Brain changes in children and adolescents with obsessive–compulsive disorder before and after treatment: A voxel-based morphometric MRI study

    Psychiatry Research

    (2009)
  • A.D. Lawrence et al.

    Cognitive functions and corticostriatal circuits: Insights from Huntington's disease

    Trends in Cognitive Science

    (1998)
  • N.S. Lawrence et al.

    Neural responses to facial expressions of disgust but not fear are modulated by washing symptoms in OCD

    Biological Psychiatry

    (2007)
  • L. Menzies et al.

    Integrating evidence from neuroimaging and neuropsychological studies of obsessive–compulsive disorder: The orbitofronto-striatal model revisited

    Neuroscience & Biobehavioral Reviews

    (2008)
  • L. Nahum et al.

    Neural response to the behaviourally relevant absence of anticipated outcomes and the presentation of potentially harmful stimuli: A human fMRI study

    Cortex

    (2011)
  • S. Nishida et al.

    Anterior insular volume is larger in patients with obsessive–compulsive disorder

    Progress in Neuro-Psychopharmacology & Biological Psychiatry

    (2011)
  • M.L. Phillips et al.

    Neurobiology of emotion perception I: The neural basis of normal emotion perception

    Biological Psychiatry

    (2003)
  • J. Riffkin et al.

    A manual and automated MRI study of anterior cingulate and orbito-frontal cortices, and caudate nucleus in obsessive–compulsive disorder: Comparison with healthy controls and patients with schizophrenia

    Psychiatry Research: Neuroimaging

    (2005)
  • J.Y. Rotge et al.

    Meta-analysis of brain volume changes in obsessive–compulsive disorder

    Biological Psychiatry

    (2009)
  • M.F. Rushworth et al.

    Functional organization of the medial frontal cortex

    Current Opinion in Neurobiology

    (2007)
  • C. Savage et al.

    Organizational strategies mediate nonverbal memory impairment in obsessive–compulsive disorder

    Biological Psychiatry

    (1999)
  • S. Saxena et al.

    Functional neuroimaging and the neuroanatomy of obsessive compulsive disorder

    Psychiatric Clinics of North America

    (2000)
  • A. Schienle et al.

    Neural responses of OCD patients towards disorder-relevant, generally disgust-inducing and fear-inducing pictures

    International Journal of Psychophysiology

    (2005)
  • C. Soriano-Mas et al.

    Identifying patients with obsessive–compulsive disorder using whole-brain anatomy

    NeuroImage

    (2007)
  • P. Turkeltaub et al.

    Meta-analysis of the functional neuroanatomy of single-word reading: Method and validation

    NeuroImage

    (2002)
  • O. Togao et al.

    Regional gray and white matter volume abnormalities in obsessive–compulsive disorder: A voxel-based morphometry study

    Psychiatry Research

    (2010)
  • M. Ullsperger et al.

    Neuroimaging of performance monitoring: Error detection and beyond

    Cortex

    (2004)
  • A.A. Valente et al.

    Regional gray matter abnormalities in obsessive–compulsive disorder: A voxel-based morphometry study

    Biological Psychiatry

    (2005)
  • G. Zappalà et al.

    Traumatic brain injury and the frontal lobes: What can we gain with diffusion tensor imaging?

    Cortex

    (2012)
  • M. Zarei et al.

    Changes in gray matter volume and white matter microstructure in adolescents with obsessive–compulsive disorder

    Biological Psychiatry

    (2011)
  • G.E. Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annual Review of Neuroscience

    (1986)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (2000)
  • S.K. An et al.

    To discard or not to discard: The neural basis of hoarding symptoms in obsessive–compulsive disorder

    Molecular Psychiatry

    (2009)
  • A.R. Aron et al.

    Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans

    Nature Neuroscience

    (2003)
  • R. Bartha et al.

    A short echo 1H spectroscopy and volumetric MRI study of the corpus striatum in patients with obsessive–compulsive disorder and comparison subjects

    American Journal of Psychiatry

    (1998)
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