Symptom dimensions and subtypes of obsessive-compulsive disorder: a developmental perspective.

In the absence of definitive etiological markers for obsessive-compulsive disorder (OCD% obsessive-compulsive (OC) symptom dimensions may offer a fruitful point of orientation. These dimensions can be understood as defining potentially overlapping clinical features that may be continuous with "normal" worries first evident in childhood. Although the understanding of the dimensional structure of OC symptoms is still imperfect, a recent large-scale meta-analysis has confirmed the presence of at least four separa ble symptom dimensions in children, as well as adults, with OCD. A dimensional approach does not exclude other methods to parse OCD. Thus far, a pediatric age of onset, the presence of other family members with OCD, and the individual's "tic-related" status appear to be potentially useful categorical distinctions. Although the OC symptom dimensions appear to be valid for all ages, it is unlikely that the underlying genetic vulnerability factors and neurobiological substrates for each of these symptom dimensions are the same across the course of development.

Obsessive-compulsive disorder (OCD) is a chronic and potentially disabling condition affecting from 1 % to 3% of the general adult population.[1,2] Similar rates have also been reported for children and adolescents.[3-5] Frequently, patients with OCD describe the sudden intrusion into consciousness of unwanted thoughts or unpleasant images. These obsessions are often accompanied by a profound sense of dread and the urge to complete specific compulsions. Compulsions are repetitive acts, typically performed a certain number of times or according to certain private rules, that, the individual is driven to complete, even though these acts are perceived as excessive.

The Diagnostic and Statistical Manual of Menial Disorders Fourth Edition, Text revision (DSM-IV-TR) [6] and other standard diagnostic classifications, such as the International Classification of Diseases, Tenth Edition (ICD-10),[ categorize OCD as a unitary nosological entity. While this parsimony has a certain formal appeal, it is misleading. The symptoms used to define OCD are heterogeneous and include various intrusive thoughts and preoccupations, rituals, and compulsions. Two individuals with OCD may have totally different and nonoverlapping symptom patterns.

From as far back as the earliest, descriptions of OCD, investigators have attempted to dissect, the phenotype into homogeneous subtypes. For example, Falret[8] made the distinction between “folie du doute” (madness of doubt) and “délire du toucher” (delirium of touch) in 1869. Most commonly, investigators have distinguished “washers” from “checkers.”[9-12] With a few notable exceptions, these attempts had limited success in relating the identified subtypes to biological markers, genetic factors, or treatment response, in part because pure subtypes of patients are rare, and the recruitment of sufficient sample sizes of each subtype is difficult and impractical.

The following review considers an alternative approach to obsessive-compulsive (OC) symptoms.[13,14] It begins with an examination of the potential value of a dimensional approach and then considers various potential subtypes of OCD, particularly among early-onset cases.

Obsessive-compulsive symptom dimensions

The first study to factor-analyze the Yale -Brown Obsessive-Compulsive Scale-Symptom Checklist (YBOCS-SC)[15] was that of Baer.[16] He factor-analyzed the 13 major categories of the Y-BOCS-SC in a sample of 107 patients and identified three factors, accounting for 48% of the variance; these were named “symmetry/ hoarding,” “contamination/cleaning,” and “pure obsessions.” .Following Baer's seminal work, Leckman and colleagues[17] evaluated the same 13 a priori categories used to group types of obsessions and compulsions in the YBOCS-SC in two large groups of OCD patients totaling over 300 cases.[18,19] In an effort, to identify valid “traits,” they included any OCD symptoms that patients “ever” experienced over the course of their lifetimes, as opposed to limiting these analyses to current symptoms. Remarkably, both data sets yielded nearly identical results. Four factors were identified that in total accounted for >60% of the variance in each data set.[17] Subsequently, Summerfeldt and colleagues[20] evaluated existing models of OCD symptom structure in 203 individuals. Using confirmatory factor analyses, they deter mined that, there was an “adequate fit” solely for a fourfactor model. A recent meta-analysis examined the data from 21 studies involving 5124 participants and confirmed the validity of the same four factors.[21] Studies were examined if they involved subjects with OCD and included an exploratory factor analysis of the 13 YBOCS-SC categories and the items therein.[14] Stratified meta-analysis was conducted to determine the factor structure of OCD in studies involving children and adults separately. The four factors generated were: (Factor I) Forbidden thoughts - aggression, sexual, religious, and somatic obsessions and checking compulsions; (Factor II) Symmetry - symmetry obsessions and repeating, ordering, and counting compulsions; (Factor III) Cleaning - cleaning and contamination; and (Factor IV) Hoarding - hoarding obsessions and compulsions. Factor analysis of studies including adults yielded an identical factor structure compared with the overall meta-analysis. The only differences between the factor structures involving adults and children were: (i) checking compulsions loaded highest on the Forbidden thoughts factor in adults and with the Symmetry factor in children; and (ii) somatic obsessions loaded highest on the Forbidden thoughts factor in adults and with the Cleaning factor in children. The shifting of checking symptoms from one factor to another is likely attributable to the inherent ambiguity of checking symptoms in the Y-BOCS-SC. This ambiguity in the checking category of the Y-BOCSSC has been addressed in the newly developed dimensional OCD scales such as the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS), which associates specific checking and avoidance OC symptoms with each OC symptom dimension/ factor.[22]

Although the understanding of the dimensional structure of OC symptoms is still imperfect, this quantitative approach to phenotypic traits has the potential to advance our understanding of OCD, and may aid in the identification of more robust endophenotypes. As reviewed below, preliminary data suggest that these dimensional phenotypes may be useful in our efforts to understand the natural history, genetics, neurobiology, treatment response, and outcomes of OCD.[13,14]

A developmental perspective

Typically, developing children engage in a significant amount of ritualistic, repetitive, and compulsive-like activity. This phenomenon reaches a peak at about 24 months of age.[23] Remarkably, the content of these behaviors closely resembles the OC symptom dimensions.[24] .For example, parents reported that their children arranged objects or performed certain behaviors until they seemed “just, right.” on average, beginning at 22 to 25 months of age (Factor II). Similarly, behaviors resembling those associated with the contamination/washing dimension were identified with such checklist items as, “Seemed very concerned with dirt, or cleanliness,” were found to have a mean age of onset from 22 to 24 months of age (Factor III). Finally, parents reported that their children on average began to “collect or store objects” (resembling the hoarding dimension) from 25 to 27 months of age (Factor IV). Although direct evidence linking the emergence of these behaviors to the later development of OCD is lacking, investigators have found that aspects of these ritualistic and compulsive-like behaviors are correlated with children's fears and phobias.[24-26] Further exploration of the factors that underlie the emergence and resolution of these behaviors in typically developing children may provide valuable insights into neurobiological substrates of OCD, as well as setting the stage for understanding subclinical forms of OCD.

Pediatric onset OCD

A dimensional approach docs not exclude other methods to parse OCD. Thus far, a pediatric age of onset, the presence of other family members with OCD, and the individual's “tic-related” status appear to be potentially useful categorical distinctions ( [21] Epidemiological studies indicate that OCD affecting children and adolescents is a highly prevalent, condition, with 2% to 4% of children being affected.[3-5]

Some of the strongest evidence for early-onset being a distinctive subtype of OCD comes from family-genetic studies that have consistently shown that the familial aggregation in OCD is largely concentrated among families with early-onset OCD probands.[19,28,29] .For example, in the Nestadt et al[29] study, the age at onset of OC symptoms in the 80 case probands ranged from 5 to 41 years. The median age at onset of symptoms was approximately 11 years; more than 75% of the probands had onset by age 14 years, and 90% by age 17 years. They then dichotomized their OCD cases into early-onset (5 to 1 7 years) and late-onset (18 to 41 years) groups. The prevalence of OCD in the relatives of probands with early- vs late-onset was 13.8% vs 0% (P=.006).The Pauls et al[19] study also documented the fact that there was a clear increase in the rate of subclinical OCD as well as OCD in the first-degree relatives of the early-onset probands. Family-genetic studies also provide the most compelling evidence that pediatric-onset OCD is etiologically heterogeneous. Specifically, there appears to be: a tic-related subtype; a familial, non-tic-rclatcd subtype; as well as a class of sporadic cases where no family history is evident.(

Tic-related OCD

The tic-related subtype may account, for as many as 10% to 40% of the pediatric-onset OCD cases.[19,30-33] Even in family genetics studies where probands with Tourcttc syndrome (TS) were actively excluded, at least 10% of the early-onset OC cases were tic-related.[29,30] Consequently, we define “tic-related OCD” as being a condition in which tics arc observed either in the proband or in one or more first-degree family members. Early-onset cases with a personal history of tics typically show a male predominance, and prominent OC symptoms in the Symmetry, Forbidden thoughts, and Hoarding dimensions, but fewer OC symptoms in the Cleaning dimension.[16-18] They are also much more likely to report, the presence of sensory phenomena.[18,34,35] Another marker of the distinctive nature of early-onset OCD is a differing pattern of psychiatric comorbidity. Children with tic-related OCD typically have higher rates of disruptive behavior disorders (attention deficit-hyperactivity disorder [ADHD] and oppositional defiant, disorder), and trichotillomania, as well as other specific and pervasive developmental disorders.[36-39]

Thus far, with the possible exception of Slit and Trk-like 1 (SLITRK1), no specific genes have been associated with tic-related OCD.[40] Neuroimaging studies have suggested that caudate volumes in childhood are predictive of future OCD severity in early adulthood as well as future tic severity.[41]

Although pediatric-onset OCD tends to respond well to behavioral interventions, particularly when combined with selective serotonin reuptake inhibitors (SSRIs),[27,42] it appears that the presence of tics reduces the beneficial effects of SSRI treatment but not cognitive-behavioral therapy (CBT) in children and adults.[43-45] In addition, individuals with tic-related OCD respond better to neuroleptic augmentation than do OCD patients without a personal history of a tic disorder.[46] The course and outcome of tic-related OCD may also be distinctive; characterized by an early peak in OC symptom severity at 12.5 years and followed by an increased likelihood of remission.[27,47]

Familial, non-tic-related early-onset OCD

This OCD subtype has been less fully characterized. First-degree family members are known to be at high risk for developing OCD and subclinical OCD, with approximately 25% being affected.[19] Many of these children are likely to be afflicted with obsessional concerns about the safety of close family members as well as contamination and compulsive washing. Higher than expected rates of anxiety and affective disorders are seen in early-onset cases and their first-degree family members. Generalized anxiety disorder (GAD), panic disorder, agoraphobia, separation anxiety disorder (SAD) and recurrent, major depression are frequently encountered, especially if a first-degree relative was diagnosed with OCD.[48,49] It also appears that some portion of these early-onset cases will remit before adulthood.[50-53]

A number of small neuroimaging studies have been conducted in pediatric-onset OCD.[54] To a large extent, their findings are consistent with the prevailing frontal-striatalthalamo-cortical model of the neural substrates of OCD. These studies have also provided evidence to support, the role of glutamate in the pathology of OCD. As noted above, these individuals are more likely than the ticrelated cases to respond to SSRI treatment.[27,42] They may also benefit from the use of glutamate modulating agents.[55]

Pediatric autoimmune neuropsychiatrie disorders associated with streptococcal infections

It has been hypothesized that some susceptible individuals develop OC symptoms and tics as a result of postinfectious autoimmune processes. Infections with group A P-hemolytic streptococci (GABHS) have been hypothesized to be responsible. Swedo and colleagues have proposed that this subgroup, identified by the acronym PANDAS (pediatric autoimmune neuropsychiatrie disorders associated with streptococcal infections), follows a unique “sawtooth” waxing and waning clinical course that is closely temporally linked to GABHS infections.[56] These sudden fluctuations complicate clinical management as well as the interpretation of efficacy and effectiveness of treatment studies.

The strongest, evidence that GABHS may be involved in the onset, of Tourette syndrome (TS) and OCD comes from a recent report by Mell et al.[57] TTiis is a case-control study of 144 children 4 to 13 years old who received their first, diagnosis of OCD, TS, or tic disorder between January 1992 and December 1999. Cases were matched to controls by birth date, sex, primary physician, and propensity to seek health care. Patients with OCD,TS, or tic disorder were more likely than controls to have had streptococcal infection in the 3 months before onset date. The risk was higher among children with multiple streptococcal infections within 12 months. Indeed, having multiple infections with group A P-hemolytic streptococcus within a 12-month period was associated with an increased risk of TS with an odds ratio of 13.6 (95% confidence interval 1.93-51.0). In addition to OCD,TS, and tic disorders, a specific link between ADHD and GABHS has been hypothesized,[58,59] and there is at least one case report and one epidemiological study where a link between GABHS and major depressive disorder (MDD) was also suggested.[58,60]

Brain imaging studies of PANDAS cases have consistently implicated the basal ganglia. Specific findings include the transient enlargement of the striatum and the basal ganglia as a whole.[59,61,62]

Although it has been postulated that GABHS infection must, be the initial autoimmune response-inciting event but that subsequent, symptom exacerbations can be triggered by other infectious agents,[63] a number of other précipitants have been identified, including the common cold and Mycoplasma pneumoniae infections.[64-66] Future prospective longitudinal studies are needed to confirm these findings and to clarify whether there is a common underlying immunological response that triggers symptom worsening.

In clinical longitudinal studies the results have been mixed. One study, which followed unselected OCD andTS cases longitudinally for 1 year, indicated no more than a chance association between newly acquired GABHS infections and tic symptom exacerbations.[67] Similarly, a case -control study found little evidence of increased tic or OC symptoms in the aftermath of well-documented (and treated) GABHS infections, casting some doubt on the hypothesis.[68] Kurlan et al also recently reported equivocal findings from a 2-year prospective longitudinal study.[69] Of note however, this study did report a significantly higher rate of GABHS infections in the PANDAS cases.

Finally, a report based on a more complete data set from the earlier study by Luo et al[67] has recently been published that describes a study in which consecutive monthly ratings of OC, tic, and depressive symptom severity were obtained for 45 cases and 41 matched healthy control subjects over a 2-year period.[70] Cases and controls were prospectively monitored for the onset of new GABHS infections and the level of psychosocial stress. Structural equation modeling for unbalanced repeated measures was used to assess the temporal sequence of newly recognized GABHS infections and psychosocial stress with the severity of tic, OC, and depressive symptoms. Using this state-of-the-art modeling technique for longitudinal data, stringently defined new GABHS infections were predictive of future tic and OC symptom severity, but did not predict future depressive symptom severity. Inclusion of newly recognized GABHS infections in the model enhanced the power of psychosocial stress in predicting future tic severity.

Promising areas of research with the potential to advance the field

Refinement of available instruments and advancing the therapeutics of pediatric OCD

Additional work is needed to examine the factor structure of the next generation rating instrument. - the Dimensional Yale-Brown Obsessive-Compulsive Scales (DY-BOCS).[22] An item level factor analysis of the DYBOCS is now under way involving >1000 individuals with OCD from Brazil, Spain, the USA, the UK, and Japan. These results will be of interest, in resolving how best to understand the somatic symptoms, superstitions, and miscellaneous OC symptoms, as well as other dysfunctional repetitive behaviors including tics, trichotillomania, skin picking, body dysmorphic disorder, and eating disorders. Instruments like the DY-BOCS also have the potential to advance therapeutics by focusing the clinician's attention on specific symptom dimensions. In many respects, CBT for OCD is based on a dimensional perspective.[71] The efficacy of CBT for OCD has been demonstrated in numerous controlled and meta-analytic studies. However, a significant number of patients still remain unimproved, or simply refuse or drop out. from this treatment. As reviewed elsewhere, adult patients with hoarding symptoms have been described as having poor compliance with and response to CBT. [13,14] For example, using a dimensional approach, Mataix-Cols and colleagues[72] examined 153 OCD outpatients who participated in a randomized controlled trial of CBT. Results showed that high scorers on the hoarding dimension were more likely to drop out prematurely from the trial and also tended to improve less than nonhoarding OCD patients. In addition, high scorers on the sexual/religious dimension responded less well to CBT. In a meta-analysis, patients with primary obsessive thoughts without rituals tended to improve less with CBT than those who had overt motor rituals.[73] In a study by Alonso and colleagues,[74] the presence of sexual and/or religious obsessions predicted poorer long-term outcome, but, because most patients received both SSRIs and CBT, it was not clear from this study whether these symptoms predicted poorer outcome with SSRIs, CBT, or both. Similar studies need to be undertaken in pediatric populations.

In adult studies, controlled trials with SSRIs have demonstrated a selective efficacy in OCD. However, up to 40% to 60% of patients do not have a satisfactory outcome.[75,76] Nonresponse to treatment in OCD is associated with serious social disability. These differences in treatment outcome emphasize the heterogeneity of OCD and the need for identifying predictors of treatment response. While definitive studies have not been undertaken, recent studies have suggested that, a symptom-based dimensional approach may prove to be valuable for identifying significant predictors of treatment, outcome. For example, at least five studies have shown that patients with high scores on the hoarding dimension respond more poorly to SSRIs.[13,14] In another study, high scores on the sexual/religious obsessions factor identified by Matrix-Cols and colleagues were associated with poorer long-term outcome with SSRIs and behavior therapy in 66 adult outpatients who were followed up for 1 to 5 years.[77] Two other groups have recently reported that the presence of sexual obsessions was a predictor of nonresponse to SSRIs.[74,78] In future studies, if individuals with sexual obsessions and related compulsions are shown to be less likely to respond to SSRIs than individuals with obsessions about, harm and related compulsions, this may argue for retaining sexual obsessions and related compulsions as a separate dimension as first, proposed by Mataix-Cols et al.[77] .Finally, preliminary studies from adult subjects indicate that patients with worries about harm (aggressive obsessions and compulsions) respond better to SSRIs than the remaining OCD patients.[79] Again, these studies need to be extended to adolescents with OCD and care needs to be taken to ensure the safety of these agents in prepubertal children.[80]

The importance of subclinical OCD

Obsessions and compulsions are frequently encountered in children and adults without OCD. The rate in children may be as high as 8%.[81] Tlic rate in adults without, a mental disorder may be as high as 13% to 15%, based on recent, data.[81] Subclinical OCD can cause significant interference. For individuals with anxiety and mood disorders, the presence of fears of doing harm (Forbidden thoughts) is frequently associated with help-seeking behavior.[81] These obsessional thoughts are distressing and prompt avoidance and many of the compulsive rituals including touching, counting, checking doors and windows, and washing. Based on the recent Fullanna et al[81] data, it is clear that these individuals are at increased risk of developing OCD. Early interventions may be especially beneficial for these high-risk individuals.

Longitudinal studies

Variation between individuals at particular points in time can mask detection of potentially important, developmental shifts. Longitudinal studies examining changes in risk exposure, OC symptoms, comorbid disorders, particularly when linked to performance on neuropsychological tests, brain processes, and immunological function.

Looking at these changes over a developmental time frame is likely to be a fruitful approach, particularly when linked with the ability to explore potential genetic determinants.[82] They have already proven their worth in studies of the temporal stability of OC symptom dimensions and psychosocial stress.[70,81,83] It is increasingly clear that obsessions and compulsions are common in the adult population, have their roots in childhood, and are associated with interference, risk for comorbid disorders, and help-seeking.[81] Longitudinal analyses could also have important implications in refining therapeutic decisions. Longitudinal studies of high-risk individuals who do not develop psychopathology may be especially valuable in elucidating protective factors, and serve as the basis for developing novel therapeutics.

Genetic studies

A dimensional approach may be particularly valuable for genetic studies, where it increasingly seems that, some vulnerability genes may be shared by more than a single disorder, and that subthreshold cases are likely to be found in family members. An initial confirmation of this approach comes from the recent study by Hasler and colleagues,[84] which collected data from 418 sibling pairs with OCD. Among potentially relevant comorbid conditions for genetic studies, they found that bipolar I/II and major depressive disorder were strongly associated with the Forbidden thoughts factor, whereas ADHD, alcohol dependence, and bulimia were associated with the Symmetry factor.

Twin and family studies suggest that genetic factors play a role in the expression of OCD.[85] Recent, advances in molecular genetics have greatly increased the capacity to localize disease genes on the human genome. These methods are now being applied to complex disorders, including OCD. Although earlier studies have indicated that the vertical transmission of OCD in families is consistent with the effects of a single major autosomal gene, it is likely that there are a number of vulnerability genes involved. One of the major difficulties in the application of these approaches is the likely etiologic heterogeneity of OCD and related phenotypes. Heterogeneity reduces the power of gene-localization methods, such as linkage analysis.[86-88] Etiologic heterogeneity may be reflected in phenotypic variability, making it highly desirable to dissect the syndrome, at the level of the phenotype, into valid quantitative heritable components van Grootheest et al[89] recently reviewed the twin literature and concluded that in pediatric onset OCD, OC symptoms are heritable, with genetic influences in the range of 45% to 65%. In adult onset, the evidence indicates a somewhat, lower estimate, ranging from 27% to 47%. OC symptom dimensions have rarely been evaluated in the context of twin studies, with the one exception being a recent study by van Grootheest. et al[90] In this study, data from a population sample of 1383 female twins from the Virginia Twin Registry was examined OC symptoms were measured by a self-report questionnaire with 20 items from the Padua Inventory. Investigators found that each of the OC symptom dimensions shared variation with a latent common factor. Variation in this common factor was explained by both genes (36%) and environmental factors (64%). In their data only the Contamination dimension appeared to be influenced by specific genes.

Like many other psychiatric disorders, family and affected sibling studies also suggest, that genetic factors play a role in the expression of OCD. Alsobrook and colleagues[91] were the first to use OC symptom dimensions in a familygenetic study. They found that, the relatives of OCD probands who had high scores on the obsessions/checking and symmetry/ordering factors were at greater risk for OCD than were relatives of probands who had low scores on those factors. The finding that relatives of OCD probands who had high scores on symmetry/ordering were at greater risk for OCD than were relatives of probands who had low scores has been replicated in a second independent family study.[92]

Using data collected by the Tourette Syndrome Association International Consortium for Genetics Affected Sibling Pair Study, Leckman and colleagues[93] selected all available affected TS pairs and their parents for which these OC symptom dimensions (factor scores) could be generated using the four-factor algorithm. Remarkably, 50% of the siblings with TS were found to have comorbid tic-related OCD and >30% of mothers and 10% of fathers also had a diagnosis of OCD. The scores for both Factor I (aggressive, sexual, and religious obsessions and checking compulsions) and Factor II (symmetry and ordering) were significantly correlated in sibling pairs concordant, for TS. In addition, the motherchild correlations, but. not father-child correlations, were significant for these two factors. Based on the results of the complex segregation analyses, significant evidence for genetic transmission was obtained for all factors.

A recent, study of 418 sibling pairs with OCD[94] found robust sibling-sibling intraclass correlations (after controlling for sex, age, and age of onset) for Factor IV (hoarding obsessions and compulsions) and Factor I (aggressive, sexual, and religious obsessions and checking compulsions). A smaller, but still significant, sib-sib intraclass correlation was found for Factor III (contamination/cleaning; P=.02) and Factor II (symmetry/ordering/arranging). Limiting the sample to female subjects more than doubled the sib-sib intraclass correlations for Factor II. Another much smaller study of 40 sibling pairs from Brazil found significant, sib-sib intraclass correlations when both siblings were female for Factor IV (hoarding).[94] When both siblings were male, they also reported a significant sib-sib intraclass correlation for Factor III (contamination/washing).

Future efforts to define the genetically determined host, factors that may predispose someone to develop PANDAS is also clearly needed. Thus far, the only hint, has been that patients with rheumatic fever typically have positive family histories of OCD, and that PANDAS cases have a higher rate of rheumatic fever in their familes.[69,95]

In sum, the use of quantitative traits that are familial may provide a powerful approach for detecting the genetic susceptibility loci that contribute to OCD. Our prediction is that some genes will be specific to certain OC symptom dimensions, while others will be “generalist” genes that influence the expression of OCD and closely related disorders including tic disorders, trichotillomania, body dysmorphic disorder, and various eating disorders. These generalist genes may exist within modules of coexpressed genes that are functionally related. Using this framework, it will be worthwhile to determine whether overlapping transcriptional networks underlie the expression of the OC spectrum of normal phenomena as they are regulated by specific evolutionarily conserved neural networks. Then when these networks become dysregulated, for whatever reason, OCD and related disorders emerge as disorders of mind, brain, and behavior.

Nongenetic risk factors

Despite our enthusiasm for the identification of dimension specific and subtype specific OCD vulnerability genes, it should also be noted that environmental factors doubtless play an important, role in the transmission of these traits across generations. Indeed, the bulk of the evidence concerning familial risk has come from affected sibling-pair studies and genetic family studies. In contrast to twin and adoption studies, the design of these studies simply tests for familial transmission; they do not exclude the likely role of nongenetic familial transmission, in which family members can serve as models for dysfunctional behaviors. More work is needed to identify the environmental factors that foster the onset and course of these symptoms. To date, the strongest evidence points to maternal adverse perinatal events,[96-98] and early psychosocial adversities as being associated with the future development of OCD.[99-103] Psychosocial stress is also a powerful determinant of future OCD severity, which in turn is predictive of the severity of future depressive symptoms.[70,83] Finally, sorting out the complexities of the interface between the central nervous system and the developing innate and adaptive immune systems is another major challenge for the field.[104]

Imaging studies

Functional neuroimaging studies have the potential to provide further validation of a dimensional approach to OCD and its various subtypes. Taken as a whole, these studies strongly link OC symptoms with altered activation of the orbito-frontal cortex, with less consistent involvement of anterior cingulatc gyrus, lateral frontal and temporal cortices, caudate nucleus, thalamus, amygdala, and insula.[54,105-117] A growing number of imaging studies are now incorporating ratings of OC symptom dimensions. In the first such study, using positron emission tomography, Rauch et al[108] found that checking symptoms correlated with increased, and symmetry/ ordering with reduced, regional cerebral blood flow in the striatum, while washing symptoms correlated with increased regional cerebral blood flow in the bilateral anterior cingulate and left orbitofrontal cortex. Phillips et al,[109] using functional magnetic resonance imagine (fMRI) compared OCD patients with mainly washing (n=7) or checking (n=7) symptoms, while they viewed pictures of either normally disgusting scenes or washerrelevant pictures. When viewing washing-related pictures, only washers demonstrated activations in regions implicated in emotion and disgust perception (ie, visual regions and insular cortex), whereas checkers demonstrated activations in frontostriatal regions and the thalamus. In a similar study, eight OCD patients with predominantly washing symptoms demonstrated greater activation than controls in the right, insula, ventrolateral prefrontal cortex, and parahippocampal gyrus when viewing disgust-inducing pictures.[110] Another study[111] found increased amygdala activation in a group of 11 washers during the presentation of contaminationrelated pictures. Saxena et al[112] found that 12 patients with predominantly hoarding symptoms showed reduced glucose metabolism in the posterior cingulate gyrus (vs controls) and the dorsal anterior cingulate cortex (vs nonhoarding OCD patients) and that severity of hoarding in the whole patient group (n=45) correlated negatively with metabolism in the latter region.

One elegant fMRI study[113] used a symptom provocation paradigm to examine, within the same patients, the neural correlates of washing, checking, and hoarding symptom dimensions of OCD. Each of these dimensions was mediated by distinct but partially overlapping neural systems. While patients and controls activated similar brain regions in response to symptom provocation, patients showed greater activations in the bilateral ventromedial prefrontal regions (washing experiment), putamen/globus pallidus, thalamus, and dorsal cortical areas (checking experiment), left prcccntral gyrus, and right orbitofrontal cortex (hoarding experiment). These results were further supported by correlation analyses within the patient group, which revealed highly specific positive associations between subjective anxiety, questionnaire scores, and neural response in each experiment. Another recent, study[114] demonstrated that eight patients with predominant washing symptoms showed increased neural responses to disgusting (but not fearful) faces, compared with nonwashing OCD patients (n=8) and healthy controls (n=19). Specifically, washers showed greater activation in the left ventrolateral prefrontal cortex (Brodmann area 47) compared with the other two groups. Finally, a study by Rauch and colleagues[115] tested for associations between OCD symptom factors and regional brain activation during an implicit learning task. They found that activation within the right, caudate was inversely correlated with the symmetry/arranging (Factor IT) and contamination/washing (Factor III) symptom dimensions; left orbitofrontal activation was directly correlated with the scxual/rcligious/aggressive/counting factor (Factor I) symptom severity.

Many of the most recent imaging studies have not included dimensional measures, or alternatively they have excluded OCD cases with prominent hoarding symptoms as a means of studying a more homogeneous subgroup of cases.[116,117] The variability in these studies raises the question of whether the inconsistencies in previous imaging studies of OCD could be accounted for by phenotypic variations among their subjects. If these preliminary findings are confirmed, and a consistent pattern of results can be documented by symptom factor, this would suggest that, discrete neural systems are activated in association with the evocation of specific OCS. We would predict that if a dimensional approach is useful, then a significant portion of the individual variation seen in these studies may be accounted for by the unique mix of symptom dimensions seen in any given patient. Initial studies generally support this conclusion.

The pursuit of endophenotypes

Neuropsychological testing in adults with OCD has demonstrated deficits in visuospatial skill, inhibitory control reversal learning, and less consistent deficits in cognitive set shifting and executive planning.[118-124] In adults with OCD, the most exciting findings to date are those recently reported by Chamberlain et al.[107] They have reported abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype. If this truly is a ”trait“ finding, then it will be critical to determine when these patterns first become evident, and whether or not they are associated with specific OC symptom dimensions or subtypes of disease.

Neuropsychological testing data on children with OCD is comparably sparse. On the other hand, measures of intelligence in children with OCD have been fairly well studied. Higher full-scale intelligence in childhood has been associated with the future development, of OCD in a population-based sample.[39] This finding was replicated in a longitudinal follow-up study of long-term outcome of children with tic-related OCD, in which a higher childhood 10 was associated with increased severity of OC symptoms in adulthood.[47] Recently, Bloch et al (unpublished data) reported that a greater verbal-performance IQ discrepancy was associated with pediatric onset OCD. This association of verbal-performance IQ discrepancy and OCD was still significant, after adjusting for full-scale IQ, age, and gender and excluding OCD subjects with comorbid ADHD or TS. Again, it will be crucial to determine if this is a ”trait“ marker. If it is, then it will be important to determine when this neurophysiological profile first becomes evident, and whether or not it is associated with specific OC symptom dimensions or subtypes of disease.

A final promising endophenotype concerns potential deficits in sensorimotor gating and the use of electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings to identify at-risk individuals. As in TS and schizophrenia, some individuals with OCD present, with deficits in sensorimotor gating typically defined through a reduction in prepulse inhibition.[125,126] These deficits may help us understand how normally occurring intrusive thoughts (eg, a thought about harm coming to one's own child) come to be regarded as highly meaningful (eg, “This thought means I am a terrible person and a potential danger to my child”); and how once they are established they can create a vicious cycle that to some degree is self rinforcing. We speculate that neurons within the frontal-striatal-thalamo-cortical circuits form behavior-dependent oscillating networks of various sizes and frequencies that bias input selection in favor of these normally occurring thoughts and their negative appraisal, and that at least in some cases this is due to a loss of striatal interneurons.[127-129] Coherent activity within these networks is likely to modulate sensorimotor gating as well as to lead to goal-directed motor actions. When these networks are dysrhythmic, there may be a loss of control of sensory and cognitive inputs and subsequent motor action. The known electrophysiological effects of medications, repetitive transcranial magnetic stimulation, and surgical interventions used to treat OCD are likely to have an ameliorative effect on these aberrant oscillations.[130,131] Similarly, a case can be made that successful behavioral treatments involve the willful training of regions of the prefrontal cortex not to make a motor response to these unwanted cognitive and sensory urges, so that these prefrontal regions can become effective modulators of aberrant thalamocortical rhythms.

Conclusions

In addition to the existence of subtypes of OCD, a strong case can be made to support the use of a dimensional approach to OC symptoms. A dimensional approach, combined with a developmental framework, should permit, the integration of new knowledge from a broad range of scientific disciplines from genetics and neurobiology to the development of safe and effective treatments, perhaps ones tailored to specific dimensions. The quantitative nature of these dimensions should also prove to be another important, asset, as it will add statistical power and readily allow the inclusion of subthreshold cases across a broad range of studies, including populationbased studies.[81]

As we are currently in the midst of revising our diagnostic manuals, it is worth noting that the available data strongly support, current dimensional views of psychopathology in general and OCD in particular and have implications for DSM-V. First, the specification of subtypes of OCD as well as the major symptom dimensions of OCD in the DSM-V would better capture the heterogeneity of the disorder and encourage further research in the field.[132] Second, it will be important to specify the presence of subsyndromal OCD, as it. is frequently associated with help-seeking behavior and a variety of comorbid conditions.[81]