Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder characterized by obsessions with excessive irrational uncontrollable worries such as fears of contamination, disorder or harm and compulsions or repetitive behaviours in response to obsessions. A significant proportion remaining treatment refractory or unresponsive to conventional treatment. Neuromodulatory and ablative approaches have both shown efficacy for refractory OCD symptoms, with potentially greater efficacy and lower adverse events reported in ablative surgery (anterior capsulotomy) relative to deep brain stimulation (DBS). Understanding which white matter tracts within the internal capsule to target for neurosurgical targeting is critical to understanding mechanisms of action and precision therapeutics. Writing in Molecular Psychiatry, we ran a battery of functional magnetic resonance imaging (fMRI) and cognitive tasks assessing prefrontal regions and cognitive processes known to be implicated in OCD to ask what cognitive mechanisms might be implicated in capsulotomy effects. Our work highlights neural results of negative affective processing, underscoring an important theory in OCD of impairments in aversive conditioning.
The therapeutic mechanism underlying anterior capsulotomy is based on the circuit-based hypotheses of OCD pathophysiology disrupting the frontostriatal white matter tracts traversing the anterior limb of internal capsule (ALIC). This impairment interrupts the bidirectional communication between key structures in the prefrontal cortex (i.e., anterior cingulate cortex, orbitofrontal cortex, ventral medial prefrontal cortex, and lateral prefrontal cortices) and subcortical areas (striatum, thalamus and subthalamic nucleus). Studies using diffusion MRI based tractography and resting-state functional MRI data have focused on identifying optimal nodes/networks to target during ablative surgery or DBS in relation to clinical outcomes. Converging evidence have suggested targeting the ventral internal capsule white matter tracts traversing the rostral cingulate and ventrolateral prefrontal cortex and thalamus to be associated with better clinical efficacy for DBS for OCD. However, the functional mechanism of action for effective capsulotomy treatment remains unknown. Specifically, it is not clear which potential cognitive processes associated with the prefrontal connections to target might be implicated in the therapeutic outcomes after capsulotomy.
To answer these questions, we first evaluated the behavioural and cognitive tasks performance in OCD patients who underwent capsulotomy surgery, age- and gender-matched OCD controls, and healthy controls (HC). We found major improvements in OCD symptoms and clinically relevant improvements of quality of life and disability after capsulotomy, without differences in depression and anxiety. Using the Cambridge Neuropsychological Test Automated Battery (CANTAB), we examined cognitive functions including working memory, planning, set shifting, inhibition, associative learning and attention which have been shown to be impaired in OCD and could be subsequently affected by ablative capsulotomy procedure. We found no group differences in cognitive tasks outcomes that survived correction following multiple comparisons, which highlighted the relative safety of the capsulotomy procedure, consistent with previous findings of no major cognitive long term effects following capsulotomy. In the present study, post-capsulotomy subjects showed a tendency towards greater inhibitory impairments relative to OCD controls with the addition of YBOCS scores as a covariate. This finding may or may not be related to capsulotomy itself, as the OCD control group in the current cohort might be atypical since it showed no differences in response inhibition relative to HC as one might expect with more severe OCD.
We went on using fMRI tasks to assess OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the ALIC tracts targeted in capsulotomy. The fMRI task battery consisted of tasks assessing negative affect processing (ventromedial prefrontal cortex/nucleus accumbens), set shifting (ventrolateral prefrontal cortex), reversal (orbitofrontal cortex), uncertainty (dorsal cingulate), working memory (dorsolateral prefrontal cortex) and conflict (dorsal cingulate), all of which have shown to be affected and impaired in OCD patients. We found fMRI task differences as a function of capsulotomy only in the negative affect processing, using a modified monetary incentive delay task investigating the anticipation and experience of uncertain negative affective stimuli along with a within session extinction trial. In OCD patients, it is hypothesized that the anticipation of a potential aversive outcome might enhance anxiety-generating obsessions through aberrant fear and anxiety conditioning with hypervigilance for aversive stimuli and aberrant avoidance of aversive stimuli. In the task we first showed validation in OCD patients of excessive reactivity and saliency to an uncertain negative affective outcome. Together these findings are consistent with abnormalities in hyperactivity and functional connectivity in aversive affective processing identified in OCD.
Critically, in post-capsulotomy OCD patients, we found lower nucleus accumbens activity to aversive anticipation compared to HC, which is consistent with remediation of excessive reactivity to uncertain aversive stimuli. We also found a between-group decrease in hyperactivity to aversive outcomes in the left IFG compared to OCD controls. In response to aversive extinction outcomes, post-capsulotomy patients relative to both OCD patients and HC showed lower rostral anterior cingulate activity with this activity shown to mediate the effects of capsulotomy and OCD obsessional severity changes (mediation analysis). Thus, capsulotomy appears to reverse the excessive reactivity to uncertain aversive outcomes in OCD and normalize rACC activity that might be relevant to the learning of safety signals or extinction processes.
Functional connectivity analysis using generalized psychophysiological interaction (gPPI) demonstrated enhanced functional coupling between rostral anterior cingulate and nucleus accumbens during aversive versus neutral anticipation in OCD controls relative to HC. Crucially, this connectivity decreases in post-capsulotomy patients. Thus, the tracts between rostral anterior cingulate and nucleus accumbens appear to be critical to the effects of capsulotomy on obsessional symptoms. Complementing previous studies highlighting abnormalities in hyperconnectivity along the cortico-striatal axis in OCD, here we highlighted a valence dependent interventional effect to be a potential underlying mechanistic effect of anterior capsulotomy. These findings also converge with the rostral cingulate tract through ALIC which have been shown to be the optimal clinical target for OCD DBS across multiple DBS sites.
Taken together, the present study contributes to the available literature of anterior capsulotomy as an effective and reasonably tolerated treatment option for selected patients with severe refractory OCD. These evidence extend our current understanding of the therapeutic mechanism of capsulotomy which may implicate functional modulation of the ventral striatum and rostral cingulate during negative affective processing. This mechanism of excessive aversive anticipation and impaired extinction has also been suggested to underlie OCD exposure and response prevention psychotherapeutic processes thus potentially linking ablative, DBS and psychotherapeutic mechanistic processes.
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