Brain Resilience and Obsessive-Compulsive Disorder: Defining the Neuroanatomical Pathways of Vulnerability

To the Editor: Obsessive-compulsive disorder (OCD) is highly prevalent, affecting up to 2% of the world population, and presenting an important genetic component, which has been consistently suggested by several genetic−epidemiological studies, and especially inferred from comparative analysis of twin studies.^1,2 Different studies estimate heritability rates as varying between 27% and 47% in adults with OCD and 45%−65% in pediatric forms.^1,2 These findings suggest that environmental factors or gene factors dependent on environment interactions should be accounted for a variability ranging between 35% and 73%.^1,2

However, recent studies have highlighted the possibility of additional reasons for the discordant OCD findings in twin studies, and we summarize in this letter the most relevant evidence suggesting that “brain resilience” could be a promising paradigm to understand why apparently some subjects with the same genetic background might present variable vulnerability to OCD.

The biological basis of OCD is highly correlated with neuroanatomical and neurochemical models of basal ganglia dysfunction, with a particular involvement of cortico−striato−thalamo−cortical loops. Curiously, this loop is part of the main neuronal circuitry involved with brain resilience, which has been better described until nowadays in other disorders that affect the basal ganglia.³

The term “resilience” was originally borrowed from classic mechanics studies of past centuries, developed by Thomas Young, and it has been used in various ways to approach the fascinating ability to handle insults of different sources. Resilience was initially defined as the property of a given material to absorb energy when elastically deformed and then, upon unloading, to have this energy recovered. However, neuropsychology studies consider resilience ultimately as the ability to cope with stressful events in both humans and animal models.⁴

A wide body of evidence shows that the brain has an intriguing ability to modulate cognitive and motor skills after acute insults, during insidious neurodegenerative processes, psychological stress, or even in the aging course. Permanent and transient lesions caused by strokes, hydrocephalus, tumors, or head trauma are good models to understand how the behavioral compensation, after focal or even broader damage, might be achieved, depending on neuronal plasticity.⁵ The fact that such affected regions may maintain functional ability without causing any symptoms over several decades reveals a unique underlying compensation mechanism.^6,7

This phenomenon can be explained in terms of “degeneracy,” pluri-potentiality, and redundancy. However, this is also heterogeneous, with an important variability among different subjects.⁸

From a genetic point of view, resilience might somewhat overlap with the concept of genetic penetrance. The increasing use of neuroimaging techniques have surprisingly revealed clinically asymptomatic carriers of mutations or high genetic risk for neuropsychiatric conditions presenting anatomical or functional changes associated with disease progression or compensation mechanisms.^4,9

Abnormal metabolic findings in neuroimaging analyses of asymptomatic carriers show that the definition of genetic penetrance based only on clinical parameters may be flawed, especially when dealing with complex genetic disorders, suggesting the existence of metabolic endophenotypes.¹⁰

Recent studies show that even asymptomatic carriers might present neuroimaging findings suggesting mechanisms of brain resilience. Despite extensive evidence of neuronal loss in some asymptomatic cases, the apparent functionality of affected brain structures is remarkably efficient, suggesting an intrinsic compensation mechanism and also a threshold for triggering symptoms.⁷ Curiously, some studies have suggested additional regions or neuronal circuitries as relevant to maintaining brain resilience. Of note, a resilience mechanism modulated by the cerebellum and the cortico−striato−thalamo loop has been recently hypothesized in conditions such as dystonia, familial idiopathic basal ganglia calcification, and bipolar disorder.^10,11

On the other hand, however, no resilience model explains completely the complexity of these intriguing findings. Imaging genetics is a promising strategy to integrate genotypic and phenotypic data, and additional models of brain functionality and efficiency suggest that theoretical models, such as the “small world” network might explain such clinical phenomena.¹² The “small world” theory suggests that the brain is a highly efficient functional network, when compared with random networks. Thus, even with the deletion of some nodes, such networks would be able to redistribute the lost functions, with an increase in path-length and loss of efficiency.^12,13

Given the current scarcity of models to explain brain resilience, our group is proposing a new model to explain it, based on neurogenetic studies of patients with familial idiopathic basal ganglia calcification (IBGC), since they present various different forms of movement disturbances and great clinical variability. Most of IBGC patients met standard clinical criteria for obsessive-compulsive disorder, bipolar disorder, or major depression, or had significant impairment on tests of frontal-executive functions, similarly to other diseases associated with basal ganglia dysfunction.^4,14–16

Because of the increasing use of neuroimaging procedures, brain calcifications are currently visualized more often than ever before in patients who undergo computerized tomography (CT). A number of systemic and neurological disorders can lead to a diffuse pattern of brain calcifications and “Fahr-type” calcification (striato-pallido-dentate calcifications), which are often found in idiopathic cases associated with normal biochemical and endocrinologic profiles.^16,17

Patients with these calcifications present a wide variety of motor and cognitive impairment, but some individuals may be symptom-free, despite extensive signs of calcification; however, studies measuring the total volume of calcification suggest that there are far more deposits in symptomatic individuals than in asymptomatic subjects.⁹

We conclude, thus, that degeneracy and resilience are continuous processes, probably with two levels of penetrance. Theoretical analysis of complex brain networks suggests that a “small-world network” may explain cerebral resilience. This model proposes that neurons engage in clustered local connectivity with relatively few long-range connections. Thus, there would be a short path-length between any pair of neurons or regions, resulting in lower “wiring costs,” higher dynamical complexity, and resilience to tissue damage.¹²

Recent studies are extending the notion of “small-worldness” in association studies of OCD and serve to validate the current network models that aim to explain the remarkable robustness of brain tissue against all sorts of pathological states.^18,19

Jang et al.¹⁸ found that, when compared with a control group, patients with OCD showed decreased functional connectivity in the posterior temporal regions. An increased connectivity in thalamus, cingulate, precuneus, and cerebellum was detected in controls. Also, small-world architecture, characterized by high clustering coefficients and short path-lengths, were detected at the brain's control networks, but patients with OCD showed significantly higher local clustering, suggesting abnormal functional organization. Further analysis revealed that the changes in network properties occurred in regions of increased functional connectivity strength in patients with OCD, suggesting an optimal balance between modularized and distributed information-processing.^18,19

Additional research suggests that the organizational patterns of intrinsic brain activity in the control networks are altered in patients with OCD and thus provides empirical evidence for aberrant functional connectivity in the large-scale brain systems in people with this disorder.¹⁹

The “small-world” theory allows us to understand the brain as a highly efficient functional network, as compared with a random network. Thus, even with the deletion of some nodes of the network, the small-world network is able to redistribute the lost functions, with an increase in path-length and some loss of efficiency.¹²

This would be possible only if additional brain regions were continuously accessed, to better support the progressive and simultaneously damaged areas. Another possible explanation would be the local neurogenesis already reported in structures such as the basal ganglia, with preferential distribution in subregions of the ventral striatum, even during postnatal development. The level of brain resilience toward calcifications provides additional evidence to support a model of neural networks robust enough to allow continuous brain function, even under massive insults. This will enhance our understanding about the limits and mechanisms of brain resilience.^13,20

The study of discordant identical twins is essential to shedding light on neuronal tracts that might be involved in the brain resilience in OCD. The studies of Braber et al.³ suggest that different white-matter regions were affected by environmental and genetic risk factors for obsessive-compulsive symptomatology, but both classes of risk factors might jointly create an imbalance between the indirect loop of the cortico–striato–thalamo–cortical network to the dorsolateral-prefrontal region and the direct loop, involving the inferior frontal region. Previous studies from the same group suggested differences between genetic and environmental etiologies related to the level of reduced striatal responsiveness.²¹

These two previous works suggest that specific neuronal tracts might be relevant to the brain resilience in OCD, paving the neuroanatomical pathways of vulnerability.

The thorough understanding of this process can only be achieved with a multidisciplinary and integrative approach and a strong collaborative network that builds a new methodological paradigm to study brain strain. As our understanding of this phenomenon improves, new therapeutic approaches may be planned to restore neuronal function in the affected regions, also fulfilling crucial scientific gaps about brain self-reorganization, and providing solid ground for new diagnostic and therapeutic tools for OCD.