Elsevier

Biological Psychiatry

Volume 43, Issue 9, 1 May 1998, Pages 623-640
Biological Psychiatry

A.E. Bennett Research Award
Toward a Neurodevelopmental Model of Obsessive–Compulsive Disorder

https://doi.org/10.1016/S0006-3223(97)00443-5Get rights and content

Abstract

Background: Neurobiological models for obsessive–compulsive disorder (OCD) have consistently implicated ventral prefrontal cortical and striatal circuits in the pathophysiology of this disorder, but typically have not utilized a developmental framework for conceptualizing the illness.

Methods: We describe an integrated series of neurobiologic studies aimed at testing the hypothesis that neurodevelopmental abnormalities of ventral prefrontal–striatal circuits may be involved in and contribute to the etiology and presentation of the illness.

Results: Using studies of oculomotor physiology, we have identified a selective deficit in neurobehavioral response suppression in OCD that may be related to failures in the developmental maturation of frontostriatal circuitry. Magnetic resonance imaging studies showed that treatment-naive pediatric OCD patients had significant volumetric abnormalities in ventral prefrontal cortical and striatal regions but no abnormalities in dorsolateral prefrontal cortex. Severity of OCD symptoms but not illness duration was related to ventral prefrontal cortical and striatal volumes.

Conclusions: Critical neurodevelopmental changes in ventral prefrontal–striatal circuitry may be associated with the initial presentation of OCD, and a developmentally mediated network dysplasia may underlie OCD. Such dysplasia in ventral prefrontal cortical circuits could manifest clinically by disrupting brain functions that mediate ongoing purposive behaviors.

Introduction

Obsessive–compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and repetitive, ritualistic behaviors that are distressing and debilitating for patients. Pediatric OCD has been recognized as being more common than previously believed with a lifetime prevalence of 2–3% Flament et al 1988; Hanna 1995; Valleni-Basile et al 1994. Despite its high prevalence and the attendant morbidity, the pathophysiology of OCD remains unclear with a plethora of theories and a paucity of well-replicated findings. In this paper, we review a series of studies by our group on treatment-naive pediatric OCD patients seeking to address the following questions: 1) Is OCD a neurodevelopmental disorder? 2) Which neuroanatomical structures are involved in OCD? 3) What is the nature of the physiological abnormality in OCD? 4) Which neurochemical systems are involved in OCD? and 5) What is the risk period for development of OCD? Based on our findings, we propose an integrative developmental neurobiologic model for the pathophysiology of OCD.

Several clinical observations point to the possible neurodevelopmental origins of OCD. As many as 80% of all cases of OCD have their onset in childhood and adolescence Pauls et al 1995. Pierre Janet, who was instrumental in developing a modern description of OCD, described childhood OCD and its associated cognitive disturbances. Janet (1903) and Freud (1924) also commented on the premorbid constitutional impairment that may predispose to this disorder. This raises the possibility of OCD being a neurodevelopmental disorder, and underscores the importance of studying pediatric OCD patients near illness onset to better define the nature of neurodevelopmental abnormalities in the pathogenesis of the disorder. This can also help minimize the confounds of illness chronicity and treatment intervention.

The presentation of OCD in children is quite similar to its presentation in adulthood, suggesting that the risk for OCD emerges during early childhood development Bolton 1996. Previous studies have suggested a mainly developmental subtype of OCD characterized by a male preponderance, earlier age of onset, and more frequent neurological features, particularly basal ganglia dysfunction (for review see Blanes and McGuire 1997.

Another observation supporting the neurodevelopmental model of OCD is its well-known comorbidity with Tourette’s syndrome, a neurodevelopmental disorder. Familial OCD also appears to be increased in the younger-onset subgroup, suggesting that genetic factors may play an important role in this subtype Lenane et al 1990; Pauls et al 1995. The best evidence that genetic factors are important in the etiology of the disorder comes from findings of specific associations between tics and OCD Pauls et al 1995.

Significant impairment in neurologic function has been demonstrated in OCD patients as compared to healthy controls Behar et al 1984; Conde Lopez et al 1990; Hollander et al 1990. Our group Pierri et al 1996 compared 14 treatment-naive pediatric OCD patients to 15 age- and sex-matched healthy controls on a modified version of a standardized examination of neurological soft signs, the Neurological Evaluation Scale (NES) Buchanan and Heinrichs 1989. Pediatric OCD patients had significantly increased total NES scores relative to controls. OCD patients also performed significantly more poorly than controls on tasks of sensory integration and motor overflow, and also had significantly more left-sided sensorimotor abnormalities than did their age- and sex-matched healthy control counterparts. These neurological soft sign abnormalities were not associated with illness duration, supporting the hypothesized link between abnormalities in neuromotor development and the development of psychopathology. Thus, the frequent onset in childhood of the illness, the similarity between OCD and developmentally normal childhood rituals, the premorbid “constitutional” predisposition dating back to early childhood, and the presence of neurologic soft sign abnormalities observed at illness onset with absence of deterioration with illness progression lend support to the hypothesis that a neurodevelopmental deviation rather than an acquired degenerative process contributes to the pathogenesis of the disorder.

Abnormalities in basal ganglia–frontal cortex interaction have been widely held to be involved in causing obsessive and compulsive symptoms Insel 1992; Khanna 1988; Modell et al 1989. Indirect support for this hypothesis comes from observations of increased rates of obsessive and compulsive symptoms in basal ganglia disorders such as Tourette’s syndrome and Sydenham’s chorea Pitman et al 1987; Swedo et al 1989; von Economo 1931. The fact that psychosurgical lesions of ventral prefrontal cortical (VPFC) regions such as the anterior cingulum can markedly reduce obsessive and compulsive symptoms Jenike et al 1991 also implicates this brain area in OCD. More direct evidence comes from functional neuroimaging studies that have demonstrated increased metabolic rates in VPFC Baxter et al 1988; Swedo et al 1992. In studies of adult OCD patients with childhood onset, VPFC and striatal activity correlate with OCD symptom severity and response to treatment Baxter et al 1992; Benkelfat et al 1990; Hoehn-Saric et al 1991; Rauch et al 1994; Swedo et al 1992.

Alexander et al (1986) described four basal ganglia–thalamocortical circuits that center on different parts of the frontal cortex: 1) the “motor” circuit focused on precentral primary motor fields; 2) the “oculomotor circuit” on the frontal eye fields; 3) the “prefrontal” circuit on the dorsolateral prefrontal cortex (DLPFC); and 4) the “limbic” circuit on the anterior cingulate and medial orbital prefrontal cortex. Thus, the nonmotor output of the basal ganglia targets three cortical areas: DLPFC, orbital prefrontal cortex, and anterior cingulate cortex. These prefrontal-connected circuits appear to be relatively distinct. For example, VPFC projects to ventromedial caudate, whereas DLPFC projects to dorsal caudate Fuster 1989. Ablations of VPFC result in perseverative interference in behavioral set Iversen and Mishkin 1970, and similar deficits are observed following lesion of the ventromedial caudate Divac et al 1967; Rosvold 1968, Rosvold 1972; Rosvold and Szwarcbart 1964. OCD is characterized by an inability to control specific perseverative behavior reminiscent of the deficits observed in animals with lesions to these regions. OCD patients have demonstrated hypermetabolism of these regions Baxter et al 1988; Swedo et al 1992. Lesions of VPFC also appear to cause disruption of inhibitory emotional mechanisms, resulting in impulsive and socially inappropriate behavior Luria 1966; Stuss and Benson 1983. Based on observations of patients with large frontal lesions, Eslinger and Damasio (1985) have suggested that VPFC lesions cause deficits in “analysis and integration of stimuli pertaining to real-life situations” that can lead to behavioral, intellectual, and emotional dysregulation, characteristic of OCD.

VPFC is connected with limbic structures in the cingulate and anterior temporal lobes, and thus is particularly well situated to integrate motivational and emotional processes. This VPFC zone is referred to as paralimbic cortex Mesulam 1986. Improved understanding of frontolimbic functional systems is needed for psychobiological models of OCD. Flor-Henry et al (1979) have suggested that OCD reflects VPFC dysfunction, with loss of normal inhibitory processes in VPFC, and that this disturbance accounts for the obsessions, which may represent an inability to inhibit ongoing purposive behaviors. Gray (1982) has also suggested that interactions between VPFC and paralimbic cortex are important in OCD. Malloy (1987) hypothesized that a structural and functional disconnection may exist in OCD, and that VPFC dysfunction has direct effects on ongoing purposive behavior, which contributes to the emergence of OCD symptoms. VPFC lesions in animals result in difficulty inhibiting or unlearning previous response patterns when they are no longer appropriate Pitman et al 1987 and exaggerated emotional responses to previously nonthreatening cues Butter et al 1970. OCD patients have difficulty inhibiting senseless and absurd rituals and thoughts so that formerly benign situations become unpleasant Malloy 1987. Thus, there appears to be a possible parallel between the domain of deficits in OCD and some of the neurobehavioral deficits associated with VPFC dysfunction; integrated basic and clinical studies are needed to document a clear association.

A striking reorganization of human brain anatomy and function occurs during childhood and adolescence. The prefrontal cortex, in particular, is known to undergo substantial developmental changes during this period. Huttenlocher (1979) noted an initial increase and subsequent marked decline in synaptic density during adolescence in human postmortem prefrontal cortex. In vivo neuroimaging studies have also supported this finding. Thompsen et al (1985) observed significant decreases in gray matter/white matter ratios between 20 months and 16 years of age. Jernigan and Tallal (1990) subsequently observed a linear reduction in volume of cortex between 8 and 30 years of age. A marked reduction in cortical gray matter volume around the time of puberty was observed. Minshew et al (1992) conducted an in vivo 31-phosphorous magnetic resonance spectroscopy examination of dorsal prefrontal cortex of healthy controls during adolescence and observed a reduction in phosphomonoesters and an increase in phosphodiesters, suggesting a decreased rate of membrane phospholipid synthesis during adolescence. Chugani et al (1987) also found that regional metabolic rates in frontal lobes show a marked reduction in adolescence. These observations are consistent with the view that a substantial cortical synaptic pruning occurs during adolescence Feinberg 1982, Feinberg 1983; Purves and Lichtman 1980.

Given the implication of frontal cortex to higher cognitive function and its many projections to most cortical and subcortical brain regions Weinberger 1993, it is imperative to understand its normal development. Similar to in vivo neuroimaging studies, preliminary neurobehavioral assessment of frontal lobe functioning supports a developmental trajectory of cognitive functions subserved by this area Levin et al 1991; Welsh et al 1991. Crnic and Pennington (1987) discuss the benefits in integrating developmental psychology and systems neuroscience for the study of normal human development and developmental neuropsychiatric disorders. Two well-designed normative developmental studies of frontal lobe executive functioning Levin et al 1991; Welsh et al 1991 have helped to provide a window on prefrontal function in children. Their findings suggest that frontal lobe lesions and abnormalities in children older than 8 years of age are likely to disrupt cognition, inhibitory mechanisms of attention, and memory as reflected by concept formation, flexibility, and planning in problem solving and semantic organization. These abilities are incompletely developed in younger children. Since much of the development is before age 12 years, however, it is important to study younger children to evaluate developmental trends in frontal lobe functioning, which may be especially relevant to OCD.

In summary, although a good deal of knowledge has accumulated about the functional anatomy of the prefrontal cortex in recent years, we still do not know a great deal about the developmental progression of VPFC–striatal circuits and the acquisition of specific cognitive abilities believed to be subserved by this circuitry. Since VPFC–striatal circuitry has been implicated in the pathophysiology of OCD, correlations of performance on neurobehavioral and neuropsychologic tasks with quantitative morphometric measurement of brain anatomy are critical to guide the development of a mechanistic understanding of the neural circuitry implicated in the pathophysiology of OCD.

There have been relatively few structural brain imaging studies published in OCD, and the studies to date have not yielded consistent findings. Of the two computerized tomography studies that measured caudate volumes, one found significantly smaller caudate volumes in older adolescent and young adult male OCD patients compared to controls Luxenberg et al 1988, whereas another found no difference in caudate volumes Stein et al 1993. Of the five magnetic resonance imaging (MRI) studies in adult OCD patients that have been performed, three found no significant difference between OCD and control caudate sizes Aylward et al 1991, Aylward et al 1996; Kellner et al 1991, whereas two found abnormal caudate volumes in OCD Robinson et al 1995; Scarone et al 1992. Methodological variations between studies, illness chronicity, and prior psychotropic medication use may have contributed to these discrepancies.

We conducted an MRI study to examine striatal morphology in treatment-naive pediatric OCD patients, 7–17 years of age, and age- and sex-matched healthy controls near the onset of illness to study the possible role of abnormal developmental processes in the illness Rosenberg et al 1997a. OCD patients had significantly smaller striatal volumes than controls that correlated inversely with obsessive but not compulsive symptom severity, illness duration or severity of depression or anxiety. When we measured the putamen and caudate subcomponents of the striatum separately, significantly smaller putamen but not caudate volumes were observed in the OCD patients. Putamen volumes correlated inversely with obsessive but not compulsive symptom severity, whereas caudate volumes showed no relationship with OCD symptom severity. There were no gender-related differences or cerebral asymmetries observed in OCD patients.

We speculated that the putaminal but not caudate involvement resulted from the putamen receiving more projections from the amygdala than does the caudate, since significant positive correlations were observed between putamen and amygdala volumes but not between amygdala and caudate volumes Rosenberg et al 1997a. Damage to the amygdala has been shown to result in reduction of putamen volumes, while damage to frontal cortex leads to reduction of caudate volumes Shedlack et al 1994. More recently, functional neuroimaging studies in adults with OCD Breiter et al 1996; Cottraux et al 1996; McGuire et al 1994 have identified abnormal activation levels in inferior temporal lobe regions including the amygdala and hippocampus. There are extensive reciprocal connections between VPFC and inferior temporal lobe regions Weinberger 1993.

Although OCD commonly emerges during childhood and adolescence, no prior study has evaluated the regional morphology of prefrontal and temporal association cortices in treatment-naive pediatric OCD patients near illness onset. Since abnormalities of prefrontal and temporal association cortices have been observed in adults with OCD Baxter 1992; Breiter et al 1996, we hypothesized that pediatric OCD may be associated with regional anatomic alterations that reflect prefrontal cortical and inferior temporal dysmaturation. Consistent with a previous investigation in adult OCD patients Robinson et al 1995, we did not observe a significant difference between pediatric OCD patients and controls in total prefrontal cortical gray or white matter volumes Rosenberg et al 1997a; however, our prior studies of cognitive function Rosenberg et al 1997b and regional corpus callosal morphology Rosenberg et al 1997c suggested abnormalities in VPFC and striatum, regions of suspected pathology in OCD. Prior functional neuroimaging studies have demonstrated abnormalities localized to VPFC and not dorsal prefrontal cortical regions Baxter 1992; thus, our measurement of total prefrontal cortical volume may have “drowned out” subtle localized volumetric differences of this region. We, therefore, performed a morphometric MRI study in pediatric OCD patients near illness onset focusing on the regional morphology of prefrontal and temporal association cortices. We predicted abnormalities in selected VPFC regions (anterior cingulate) and inferior temporal lobe regions (amygdala and hippocampus), but no abnormalities in heteromodal association cortex, i.e., DLPFC, posterior cingulate cortex, or superior temporal gyrus.

Section snippets

Methods and Materials

Twenty-one psychotropic-naive, pediatric OCD outpatients (13 male and 8 female), 7.2–17.7 years old, and 21 healthy controls were case matched for age, sex, weight, and height. Patient–control pairs were matched within 1 year of age. Diagnoses were made utilizing DSM-III-R APA 1987 criteria with the child version of the Schedule for Affective Disorders and Schizophrenia–Present Episode (K-SADS-P) and SADS–Epidemiologic version Chambers et al 1985; Orvaschel et al 1982. A board-certified child

Volumetric Comparisons between OCD Patients and Controls

OCD patients had significantly larger anterior cingulate volumes than did controls [F(1,32) = 4.4, p = .04] (Fig. 1) but did not differ significantly in posterior cingulate, DLPFC, amygdala, hippocampal, superior temporal gyral, or whole temporal lobe volumes (Table 2). There were no gender-related differences between OCD patients and controls in any of these structural volumes.

Clinical Correlations

Significant positive correlations were observed in OCD patients between anterior cingulate volumes and severity of

Discussion

To our knowledge, this is the first morphometric MRI study of treatment-naive pediatric OCD patients investigating detailed regional morphology of prefrontal and temporal association cortex in OCD. Our results support the hypothesis that abnormalities in VPFC–striatal anatomy may be associated with the clinical presentation of OCD, and that this pathological involvement may be a central neurobiologic deficit in this disorder. The main finding of this study was the abnormal VPFC anterior

What is the Nature of Physiological Abnormality in OCD?

The repetitive, ritualistic thoughts and behaviors characteristic of OCD suggest a critical deficit in their inhibition. Animal models and clinical neuropsychological studies of patients with brain lesions suggest that VPFC and its striatal target fields play a crucial and possibly selective role in suppression of irrelevant response Diamond and Goldman-Rakic 1989; Goodglass and Kaplan 1972; Luria 1966; Passingham 1972; Rosvold and Mishkin 1961; Stuss and Benson 1983. Our prior investigation

Serotonin

Pharmacologic treatment studies have provided compelling evidence of a serotonergic role in OCD (For a review see Pigott 1996. Zohar and Insel (1987) demonstrated that administration of the novel serotonin postsynaptic receptor 5-hydroxytryptophan (5-HT)-1 agonist, m-chlorophenylpiperazine (m-CPP) to OCD patients but not controls exacerbated OCD symptoms, whereas administration of a serotonergic receptor antagonist, metergoline decreased the problematic symptoms induced by m-CPP.

This

Dopamine

A role for dopamine in the pathophysiology of OCD has been previously suggested Goodman et al 1990. High doses of the dopamine agonist, amphetamine, can cause repetitive stereotypies in animals Creese and Iversen 1974; Wallach 1974. Acute administration of dopamine agonists lead to perseverative behaviors in rodents, while chronic administration results in increasing rigidity in the performance of the perseverative behavior Eilam et al 1989. Hoarding behavior also appears to be dependent on

Serotonin–Dopamine Interactions

Serotonin has been shown to exert a significant inhibitory effect on dopamine neurons Baldessarini and Marsh 1990. The inverse relationship between brain serotonin and dopamine is further supported by the observation of Marazziti et al (1992) of a lower number of 3H-imipramine binding sites suggestive of a dysfunction of the serotonergic system at the presynaptic level and a higher level of sulfotransferase activity, an enzyme involved in the catabolism of catecholamines such as dopamine, in

Glutamate

Glutamatergic pathways, which are the major corticospinal neurons, project from the medial prefrontal cortex to the anterior striatum, nucleus accumbens, and substantia nigra Carter 1980; Kalivas et al 1989; Taber and Fibiger 1993, Taber and Fibiger 1995, neuroanatomic regions that may be especially relevant to OCD Khanna 1988; Modell et al 1989; Insel 1992. Glutamate may be involved in a wide range of neurophysiological and pathological processes relevant to neuropsychiatric disorders such as

What Is the Risk Period for Development of OCD?

Our data in a large sample of 131 medically and psychiatrically healthy pediatric and adult controls 6–40 years of age (Rosenberg et al in preparation) suggest that 5-HT-mediated saccade velocity plateaus out early so that by 7 years of age, healthy children are performing at levels comparable to those observed in healthy adults. In contrast, the development of the core prefrontal function that we believe to be most relevant to OCD, neurobehavioral response inhibition, continues through late

Summary and Conclusions

In summary, our studies indicate evidence for VPFC–striatal dysfunction in OCD at neuroanatomical, physiological, and behavioral levels, which are meaningfully related to each other. At a neurochemical level, these dysfunctions may be mediated by alterations in serotoninergic, dopaminergic, and glutamatergic systems. Such changes in VPFC–striatal circuitry may occur as a function of abnormal neurodevelopment, and lead to the initial onset and presentation of OCD. We have proposed that the

Acknowledgements

This work was supported by grants from the National Institute of Mental Health (MH-01372) (DRR) and (MH-01180) (MSK).

We thank Drs. Lewis Baxter, Ranga Krishnan, David Kupfer, David Lewis, and Judith Rapoport for their guidance and consultation throughout these studies and Frank P. MacMaster, BA and Elizabeth L. Dick, BS for their assistance with MRI image analysis.

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