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