We studied resting state functional connectivity of striatum and thalamus with medial frontal cortex in OCD patients and healthy controls at successive stages of development to test for differences in frontal-striatal-thalamic circuit (FSTC) maturation. The youngest patients exhibited reduced connectivity of subcortical regions with anterior cingulate (ACC) – i.e., dorsal striatum and medial-dorsal thalamus with rostral and dorsal ACC, respectively. In contrast, patients at all stages of development exhibited excessive connectivity of dorsal striatum with the medial frontal pole region of the ventral MFC. These findings suggest that differential patterns of maturation occur within specific FSTC loops over the course of development in patients with OCD.
The maturation of ACC-based FSTC plays a critical role in the development of cognitive control11
. The dorsal ACC detects conflict between competing response options7
, while the rostral ACC has been shown to activate to errors26
and conflict between emotionally salient stimuli27
. Alteration of ACC recruitment by these functions has been repeatedly demonstrated in neuroimaging studies of OCD3
, including in child patients9
. In healthy youth, subcortical connectivity with ACC decreases from childhood into adolescence12
– a pattern that we also observed and which others have suggested may reflect synaptic pruning to promote information flow through FSTC12
. The exact relationship of developmental decreases in ACC-based FSTC connectivity to the normative maturation of cognitive control remains to be determined, however, the earlier pattern of decreasing connectivity in this circuit in OCD may be of relevance to the onset and early course of illness. Given the role that developing ACC-based FSTC for cognitive control plays in capacity to suppress prepotent response sets11
, it is possible that premature reduction in its connectivity may contribute to inability to suppress the contextually inappropriate “security concerns” (e.g., contamination/washing, aggression/checking, symmetry/ordering) that occur even in healthy youth1
, but are more frequent, distressing and difficult to control in children with OCD. Consistent with this notion, reduced striatal – rostral ACC connectivity was associated with greater symptom severity among the youngest patients in our sample.
Hypoconnectivity of subcortical nodes with dorsal and rostral ACC was not observed past the earliest stage of development, suggesting that reduced connectivity in ACC-based FSTC may represent a developmentally specific pattern exhibited only by young patients within a certain critical period. This interpretation may seem at odds with evidence for altered ACC function in OCD across the age span, including during tasks requiring cognitive control3,9
. However, the development of ACC cognitive control function depends not only on the maturation of its connections within FSTC, but also on its role within other brain networks (e.g., cingulopercular network for task control13
) implicated in both pediatric9
OCD. Additional research combining MR methodologies will be needed to elucidate the relationships between developing ACC connectivity throughout the brain and ACC-based abnormalities of cognitive control in OCD across the lifespan.
It is important to note that our finding of reduced subcortical – ACC connectivity in child, but not adolescent or adult patients, may have been influenced by other factors. For instance, even though the majority of adult patients in our sample reported pediatric onset of OCD, it is still possible that a biologically distinct form of illness in the youngest patients could have influenced our findings. Earlier onset illness may define a unique subtype of OCD associated with higher rates of comorbid tic disorders, male predominance, increased familiality, and particular genetic polymorphisms29
. In addition, pediatric onset OCD may remit in up to 40% of cases30
, meaning that our youngest group could have included patients with a unique, less persistent form of illness, which might have contributed to the developmental differences in connectivity that we observed.
Our finding of reduced connectivity of dorsal striatum with rostral ACC and medial dorsal thalamus with dorsal ACC in children with OCD stands in partial contrast to recent work showing increased ventral
striatum connectivity to the ACC in adult patients5
. This apparent discrepancy may stem from different methodologies, since our study was designed to test for interactions between group and developmental stage in OCD patients compared to controls over a wide age range, while prior work tested only for group differences in adults. If decreased subcortical-MFC connectivity specifically characterizes children with OCD, then prior work limited to adult samples could not have detected it. In addition, unique connectivity patterns characterize anatomically distinct elements of FSTC (e.g., medial thalamus, dorsal and ventral striatum31,32
), such that the decreased connectivity (dorsal striatum and medial thalamus to ACC) observed in our study may be compatible with increased connectivity (ventral striatum-ACC) observed in prior work5
. Alternatively, Type II error may have contributed to our failure to show a pattern of increased dorsal striatum or medial thalamus connectivity with ACC in adult OCD although, theoretically, the larger number of adult patients included in our sample should reduce this possibility.
Type II error seems a more likely explanation for our failure to show increased ventral striatum connectivity with vMFC, since two prior studies have shown hyperconnectivity between these regions in adults with OCD5,33
. We observed a sub-threshold increase of ventral striatum connectivity with vMFC (x = 9, y = 69, z = 9; Z = 3.47, k =9) in OCD compared to healthy control subjects that, in post-hoc testing, appeared to be driven by adult patients, raising the possibility that increased ventral striatum – vMFC connectivity may be developmentally specific for adult OCD. To test this possibility, we compared adult patients and controls from our sample, finding a larger, but still sub-threshold increase in connectivity of the ventral striatum with vMFC (x = 9, y = 69, z = 3; Z = 3.83, k = 24). If ventral striatum – vMFC hyperconnectivity in OCD is unique to older patients, then the relatively younger age of the adult patients in our sample (25 +/− 7 years) compared to those in previous work (29 +/− 6 years5
; 31 +/− 9 years33
) may have reduced our power to detect this effect.
A significant increase in dorsal striatum connectivity with medial frontal pole was observed across child, adolescent and adult stages of development in patients compared to controls, partially replicating prior work showing excessive ventral (rather than dorsal) caudate connectivity with vMFC in adults with OCD5,33
. The vMFC is a broadly defined area - including medial frontal pole, subgenual ACC, and medial orbitofrontal cortex. Hyperactivity of medial and lateral orbitofrontal cortex have been among the most consistently reported findings in OCD, and have been linked to altered functional processing of reward and reversal learning, respectively, in adult patients3
. A continuum of function has been ascribed to vMFC – from discerning value in orbitofrontal cortex to value-based decision-making in the medial frontal pole34
. Although speculative, medial frontal pole involvement in OCD could relate to patients' difficulty suppressing symptoms despite insight that feared outcomes are unrealistic and compulsive behaviors unlikely to achieve outcomes of true value.
The vMFC is typically characterized by projections to the ventral striatum, particularly nucleus accumbens, whereas the dorsal striatum is more often associated with projections to the ACC. However, converging lines of evidence from animal-tracing and human neuroimaging research suggests these regions may interact through overlapping projections in dorsal and ventral striatum8
. Given the role of the vMFC in emotion processing, and the ACC-dorsal striatum in cognitive control, these overlapping striatal fibers may provide anatomical substrate for affectively salient information to modulate cognitive control in the service of the flexible behavior8
. In OCD, baseline hyperactivity of the dorsal caudate and ventral MFC associates with symptom severity and increases with symptom provocation3
, such that excessive connectivity between these regions could underlie failure to suppress the emotionally salient, but contextually inappropriate security concerns (e.g., contamination, safety, order) characteristic of illness.
Alterations of ACC-based FSTC for cognitive control and vMFC-based FSTC for emotion processing during development may increase vulnerability for OCD, but also other forms of psychopathology, including Tourette's syndrome, eating disorders, and attention deficit hyperactivity disorder35
. Presumably, certain risk factors (e.g., genetic, environmental) interact with unique FSTC loops at specific maturational stages to impact subsequent FSTC development in association with particular forms of psychopathology. For instance, premature and excessive pruning of ACC-based cognitive control circuitry in children at risk for OCD may interfere with the suppression of prepotent, security-related behaviors, which themselves trigger anxiety1
, and could lead to increased signaling in FSTC for emotion-processing, driving excessive connectivity of the striatum to the v MFC. Alternatively, decreased connectivity in cognitive loops may couple with connectivity in emotion processing loops of FSTC to trigger illness onset.
Our findings of reduced dorsal striatum-ACC connectivity in child patients along with increased dorsal striatum-ventral MFC connectivity in OCD across development should be considered in the context of our study's limitations. We have extrapolated from the functional imaging literature to interpret our findings, however, research with converging methods (i.e., fMRI, behavioral) are needed to characterize the relationship between connectivity and function. Similarly, the relationship between resting state connectivity and underlying structure remains unknown, and it is possible that atypical development of FSTC structures in OCD (e.g., ACC2
) contributed to our findings. It is also possible that warping to a common adult template could reduce normalization accuracy in younger subjects, since region-specific structural changes occur with development. Localization of striatal hyperconnectivity to medial frontal pole should be viewed with caution, given prior evidence for orbitofrontal pathology in OCD3
and the challenge that mapping orbitofrontal cortex presents for any MR study, given the signal drop-out that can occur in this region20
. Small numbers of child subjects represents another limitation of our study; yet, inspection of the data did not suggest reduced connectivity in childhood OCD to be outlier-driven. Compared to patients in other age groups, adolescents with OCD showed lower symptom severity and higher rates of medication usage, however, results withstood post-hoc tests controlling for these variables, and the primary developmental finding – reduced striatum -ACC connectivity in child patients compared to child controls – should not have been influenced by the adolescent sample. Finally, the cross-sectional design of our study raises questions that it cannot answer. Longitudinal work is needed to determine whether alterations of connectivity in any particular FSTC loop influences development in other FSTC components, and to determine how such interactions associate with illness onset, persistence and remission of OCD.