In OCD, interruption of reciprocal projections between OFC and thalamus would theoretically decrease reverberating (amplified) activity in the OFC–caudate–pallidal–thalamic circuit, possibly leading to reduced OCD symptoms. However, studies comparing postsurgical with presurgical regional cerebral metabolism must take into account the potential confounds of symptomatic improvement in OCD, which characteristically yield a profile of attenuated hyperactivity throughout the circuit. Improvement in co-occurring mood and anxiety symptoms (defined either categorically or dimensionally) after surgery may also affect activity on neuroimaging measures.
Capsulotomy, subcaudate tractotomy, limbic leucotomy, and DBS at the VC/VS and related targets, all target reciprocal excitatory midline thalamic/orbital and medial cortex links, as well as orbital and medial projections to the VS. These three procedures also affect connections between midline thalamus and the subgenual and pregenual cingulate, and may have actions overlapping those of cingulotomy, especially because the cingulate has multiple reciprocal links with OFC (for reviews see Rauch, 2003
; Zald and Kim, 2001
). Thus, disruption of pathological OFC–caudate or reciprocal OFC–thalamic communications could underlie therapeutic effects of anterior capsulotomy. Consistent with this view, acute DBS produced increased regional cerebral blood flow, as measured by O15-PET, in OCD patients within the hypothesized circuitry, including OFC, thalamus, subgenual cingulate, striatum, and globus pallidus, when active stimulation at the most ventral contact was compared with control conditions (Rauch et al, 2006
). Note that the increase in perfusion observed could be due to a number of different changes at the cellular and microcircuit level, including, for example, facilitation of inhibitory processes.
In terms of chronic changes after surgery, functional imaging in a small cohort of patients with severe anxiety disorders showed reductions in activity within orbitomedial frontal cortex after anterior capsulotomy (Mindus et al, 1986
). A small study of chronic DBS near the thermocapsulotomy target found reduced FDG-PET metabolism in the orbital and medial cortex in two out of three patients (Abelson et al, 2005
). DBS at the more posterior VC/VS site was also associated with prefrontal metabolic activity on FDG-PET, especially in the subgenual ACC. Interestingly, preoperative resting metabolic activity in the subgenual ACC predicted the reduction in YBOCS OCD severity after chronic stimulation (Van Laere et al, 2006
). Note that in the case of limbic leucotomy, lesions similar to those of anterior cingulotomy and those of subcaudate tractotomy are combined. Hence, this multi-site operation would presumably combine the benefits (as well as potential adverse effects) of those two procedures. A single case study of limbic leucotomy has demonstrated reduced activity within the caudate nuclei in a patient with OCD and Tourette Syndrome (TS), when comparing postsurgical to presurgical regional cerebral oxygen metabolism (Sawle et al, 1993
). Both OCD and TS symptoms improved in this patient after limbic leucotomy.
In capsulotomy, especially the original thermocapsulotomy procedure, which produces larger lesions than gamma ventral capsulotomy, the ventral portion of the lesion may compromise adjacent territories of the striatum as well as interrupting OFC/subgenual ACC–thalamic connections. This can occur if the lesions interrupt fronto-striatal projections, if the lesions themselves impinge on the striatum, or if infiltration of edema surrounding the lesions encroaches on the striatum itself or fronto-striatal projections. Again, for OCD disruption of pathological CSTC circuitry at the level of OFC–caudate or reciprocal OFC–thalamic communications could underlie the therapeutic effects of anterior capsulotomy. Interestingly, an MRI study of anterior capsulotomy for OCD indicated that appropriate placement of lesions within the right anterior capsule was critical to subsequent therapeutic response (Lippitz et al, 1999
). Furthermore, functional imaging data from a small cohort of patients with severe anxiety disorders undergoing anterior capsulotomy showed reductions in activity within orbital and medial frontal cortex from presurgical to postsurgical scans (Mindus et al, 1986
). Most recently, a pilot study using voxel-based MRI morphometry found that the volume of gray matter in the right inferior frontal gyrus had increased after gamma ventral capsulotomy (Cecconi et al, 2008
In anterior cingulotomy, the lesions are within dorsal ACC and typically impinge on the cingulum bundle. Thus, in addition to reducing cortical mass and activity within dorsal ACC, these lesions will likely modify cingulo–striatal projections, and possibly disinhibit pregenual ACC. Given the constituents of the cingulum bundle, it is also possible that its disruption in cingulotomy could influence reciprocal connections between the ACC and several other structures, including OFC, amygdala, hippocampus, and posterior cingulate cortex (Mufson and Pandya, 1984
). In fact, comparisons of presurgical with postsurgical MRI data indicate that, 6–12 months after cingulotomy, volume appeared reduced within the caudate nucleus and posterior cingulate cortex (Rauch et al, 2000
). Given the prevailing neurocircuitry model of OCD, any of these changes after surgery could relate to therapeutic improvement. Posterior cingulate cortex, which is not typically central in OCD circuitry models, is well positioned to modulate activity within the OFC–caudate frontal–basal ganglia–-thalamic circuit (Cohen et al, 1992
; Kemp and Powell, 1970
; Vogt and Pandya, 1987
; Zald and Kim, 1996
). Interestingly, a functional neuroimaging study of OCD demonstrated that presurgical activity within posterior cingulate cortex correlated with subsequent response after anterior cingulotomy (Rauch et al, 2001a
). In addition, lesions of the cingulum might interrupt ascending influences of the amygdala on dorsal brain structures.
Metabolic and neurochemical changes in regions functionally connected to lesion or DBS targets can also be studied before and after surgery, and also by comparing different DBS parameter sets with each other and with no stimulation control conditions. Such experimental paradigms can also be implemented to take advantage of cognitive tasks to probe nodes of the neurocircuitry during imaging acquisitions. As abnormalities in dopaminergic function have been reported in OCD (Denys et al, 2004
; van der Wee et al, 2004
), imaging this neurochemical system in the context of neurosurgery may be of considerable interest. Specific examples include using dopamine transporter ligands to probe transporter or receptor levels or displacement. Here, it is of interest that dopamine transporter ligand binding was elevated in unmedicated OCD patients in striatal nodes of the network of interest (van der Wee et al, 2004
). Dopamine and serotonin probe ligands could be combined, as in a study that found that 5-HT(2A) receptor availability was reduced in frontal polar, dorsolateral, medial frontal, parietal, and temporal associative cortex of OCD patients. It was intriguing that 5-HT(2A) ligand binding in orbitofrontal and dorsolateral frontal cortex correlated with clinical severity (Perani et al, 2008
; Reimold et al, 2007
). In addition, that same study found a concomitant reduction in D2 ligand ([11C]raclopride) uptake in the striatum, and especially in VS. The results were consistent with a possible decrease in activity in a serotonergic subsystem together with elevated synaptic dopamine in the psychotropic-naïve patients studied, who were also free of comorbid disorders. Recently another interesting approach has been shown to be feasible, that is the study of radiotracer displacement during probe tasks compared with control conditions. Such tasks could be designed to probe anatomically selective parts of the neurocircuitry of interest. For example, Lappin et al (2009)
found that a sequential motor learning paradigm and a spatial planning task were both associated with increased displacement of [11C]raclopride in the striatum compared with a control (rest) condition. This change in ligand dynamics, an indirect measure of synaptic dopamine, was seen in both sensorimotor and associative, but not limbic striatum. These and other behavioral challenges could be used, for example, before and after DBS to elucidate functional changes in neurotransmitter systems localized within specific regions of the neural networks of interest.
Thus, ligand-based imaging (or MRS imaging of glutamate systems as described above) before and after DBS or stereotactic ablation may reveal changes in dopamine, serotonin, glutamate, or other neurotransmitter systems. However, a potential confound for molecular imaging methodologies is that patients undergoing neurosurgery will virtually by definition be receiving complex, multi-drug treatment regimens that may be difficult to change on clinical grounds and which can complicate interpretation of radioligand experiments. Moreover, the subpopulation of OCD patients who might be considered surgical candidates may also differ from the more general population of OCD patients in terms of clinical phenotypes, patterns of co-occurring categorical disorders or personality dimensions, or on any of the indices of neurotransmitter function that radioligand studies can assess. Given such limitations, converging evidence using multiple methods in patients and in parallel basic research will be essential to develop a coherent model of changes associated with DBS that are most important for therapeutic change.