There were two novel findings of this study. First, significant changes in brain activity were achieved after just 4 weeks of intensive CBT, much faster than previously seen with SRI treatment or standard, weekly CBT. Second, brief intensive CBT resulted in a unique pattern of changes in normalized regional glucose metabolism: significant increases in dACC activity that correlated with improvement in OCD symptoms, accompanied by significant declines in bilateral thalamic activity. This pattern suggests that intensive CBT shares some common sites of anti-obsessional action with SRIs but has different effects in the dACC. Reduction of thalamic activity may be a final common pathway to improvement in OCD symptoms, regardless of the treatment modality used, but CBT may lead to this end result through very different mechanisms and loci of action than pharmacotherapy.
The declines in thalamic activity seen with brief intensive CBT in this study replicated the results of several previous functional neuroimaging studies of OCD treatment using pharmacotherapy9,11,15
Taken together, the results of these studies suggest that reduction of thalamic activity, and a resultant decrease in thalamocortical excitation,18
may represent a final common pathway to response to a variety of different treatments in nondepressed OCD patients.19,38
As in many prior studies,5,8-10,12,17,36
the magnitude of change in thalamic metabolism did not correlate with the degree of response of OCD symptoms to intensive CBT. This suggests that while decreasing thalamic activity may be a marker of response to treatment in OCD it is not specifically related to the extent of symptom improvement.
However, the increase in dACC activity seen after brief intensive CBT was opposite to changes sometimes seen with pharmacotherapy of OCD. While the majority of pre- and post treatment functional neuroimaging studies published to date found no changes in cingulate activity with pharmacotherapy of OCD (see Saxena et al
for review), three of the nine pre- to posttreatment PET studies5,9,12
and three of the eight pre- to posttreatment single-photon emission computed tomography studies14,40,41
found significant decreases in cingulate activity in OCD responders to SRI treatment. Thus, decreasing cingulate activity may sometimes be associated with improvement in OCD symptoms but does not appear to be a necessary mechanism of action for treatment response. Instead, the functional changes most strongly associated with treatment response in OCD are decreases in activity in the right OFC,8,10-13,36,37,42,43
In contrast to the effects of pharmacotherapy on brain function, enhancement of dACC activity may be a primary mechanism of action of CBT for OCD. Treatment with CBT appears to enhance dACC activation in OCD patients during certain cognitive tasks.44,45
Moreover, a significant increase in glucose metabolism in the dACC was seen in responders to CBT for major depression.46
Taken together with these prior findings, our results suggest that dACC activation might be a common mechanism of action required for response to CBT across disorders.
The dorsal part of the ACC includes two anatomically and functionally distinct subregions: the perigenual ACC and the anterior middle cingulate cortex (aMCC) (see Vogt et al
for nomenclature and definitions of subregions). Our dACC ROI encompassed a relatively large section of cingulate cortex that included the aMCC and the superior half of the perigenual cingulate cortex. Different subdivisions of the cingulate cortex clearly have different roles.47-49
The aMCC, described as limbic motor cortex that governs response selection,47
has been shown to be involved in conscious regulation of emotion. The aMCC is activated by several cognitive tasks that are required and emphasized in CBT for OCD: selective attention to one’s own emotional responses,50,51
mindful awareness of one’s own emotional state, reappraisal of negative stimuli,52
and suppression of arousal53
and negative affect.54
Efferent projections from the aMCC to the amygdala appear to modulate amygdala activity.55
Activity in the aMCC is positively correlated with the magnitude of decrease in negative affect when subjects reappraise their emotional responses to negative photographs,52,54
and is negatively correlated with left amygdala activity when subjects label threatening photographs.56
Thus, in OCD patients, an increase in aMCC activity after intensive CBT could represent an improved ability to reappraise and suppress negative emotional responses, perhaps by inhibiting exaggerated amygdala responses to stimuli that previously provoked obsessional fears and compulsive urges.57-59
Other functions of the aMCC include monitoring response conflict, error detection, focused attention, executive control and willed motivation.55,60-62
Nakao et al
found that after treatment with fluvoxamine or CBT, OCD patients activated the right aMCC and left posterior MCC during a Chinese version of the Stroop task. Enhanced posttreatment aMCC activity may, therefore, also reflect improved cognitive functioning associated with response to OCD treatment.
One surprising result was the lack of significant pre- to posttreatment changes in normalized caudate or OFC metabolism in the OCD patients. This may be because 6 of the 10 OCD patients were on medications, which likely influenced pretreatment caudate and OFC activity and may have precluded further major metabolic changes in these regions. Indeed, pretreatment normalized glucose metabolism in bilateral caudate and right OFC was somewhat lower in the OCD group than in the controls, suggesting that the OCD patients’ previous and ongoing medications may have already decreased activity in these brain regions prior to their entry into the present study. However, no subject in this study had any change in medications or doses for at least 12 weeks prior to their first PET scan and initiating intensive CBT, nor were medication changes allowed during the CBT treatment period. Therefore, it is very unlikely that medication effects alone could account for the specific pre- to post-CBT changes in brain activity seen in this study. The fact that the six medicated OCD patients had not adequately responded to pharmacotherapy and still had moderate to severe OCD symptoms at study entry suggests that they might represent a relatively medication-refractory group that might be neurobiologically different from more SRI-responsive OCD patients.63
However, approximately 50% of all OCD patients have similarly inadequate responses to SRI medications,20,64
indicating that it is more the rule than the exception. So our sample is likely quite representative of the range of SRI responsivity found in among OCD patients in the ‘real world.’ Nonetheless, regional brain metabolic responses to CBT in medicated patients may well be different than those of unmedicated patients.
Another possibility is that striatal changes may take a longer time to manifest and may be preceded by changes in the aMCC and thalamus in patients treated with intensive CBT. The two previous functional imaging studies of CBT effects on brain activity in OCD, which both found decreased caudate activity after CBT, were of 12 weeks’9,16
and 7–8 months’17
durations, respectively, whereas the present study lasted only 4 weeks. Neither of those prior studies found pre- to posttreatment changes in OFC activity, suggesting that CBT might not significantly alter OFC function in OCD. Our findings suggest that activation of the aMCC occurs rapidly with intensive CBT and is strongly correlated with treatment response after 4 weeks. Unfortunately, the Nakatani et al
study did not measure cingulate activity, so it remains unknown whether prolonged weekly CBT produces similar effects in this region. Future studies that measure brain activity with multiple, serial scans during and after treatment will be required to establish the dynamics and chronological pattern of regional brain responses to CBT.
This study had several limitations. The sample size was relatively small. One OCD patient in this study had comorbid major depression, but exclusion of this patient’s data from analysis of changes in regional brain metabolism did not significantly change the results. The inter-scan interval for controls was longer than for OCD patients. However, there is no reason to suspect that the regional cerebral metabolic changes seen in controls would have been significantly different if the period between their first and second scans was shorter. The decrease in ACC metabolism seen in controls replicated the findings of several prior PET studies65-68
and likely reflects habituation to the scanning environment and procedures.67
However, this study also had several strengths that afford confidence in its findings. All OCD patients were treated by the same CBT therapist (EG), eliminating confounds from inter-therapist variance in treatment. Medication changes were not allowed for 12 weeks prior to the first PET scan, nor during the 4 weeks of intensive CBT between the first and second PET scan. As in prior studies of intensive CBT for OCD, a high proportion of patients in this responded to treatment. Of 12 OCD patients initially enrolled, only two dropped out, and nine of the ten completers were responders to brief intensive CBT. This response rate is quite typical for prior studies of intensive, daily CBT for OCD.23-25
For example, Foa et al
also studied OCD patients treated with intensive ERP for 4 weeks. Their intent-to-treat and completer response rates were 62 and 86%, respectively, similar to our response rates.
MRI-based localization of ROIs for each subject was used to measure regional activity in brain structures chosen a priori
, and to identify significant changes in regional activity, rather than relying on whole-brain voxel-based methods that may not account for structural neuroanatomical abnormalities and variability that are present in OCD.38
Several studies have found systematic errors in the localization of regional cerebral metabolic abnormalities when voxel-based methods were used, compared to individual subject MRI-based ROI methods.69,70
Such errors are often due to failed spatial alignment of small structures, such as the caudate nucleus and hippocampus, which are prone to high anatomic variability.69
Our ROI method also partially corrected for regional atrophy, because CSF and white matter were excluded from the outlines of all gray matter structures, and ensured that pre- and posttreatment values for each ROI were measured in exactly the same neuroanatomical volume in each subject. Symptom severity was assessed in each subject with standardized rating scales immediately prior to their pre- and posttreatment PET scans, so that the brain activity measured on the PET scan would reflect the current symptomatic state of the subject. Thus, we were able to correlate pre- to posttreatment changes in symptom severity with corresponding changes in regional cerebral glucose metabolism.
In conclusion, the findings of this study suggest that the rapid response of OCD to brief intensive CBT may be mediated by a distinct pattern of functional neuroanatomical changes: decreases in thalamic activity accompanied by an increase in dACC activity that correlates with the degree of symptomatic improvement. Decreasing thalamic activity may represent a common pathway to response of OCD symptoms to a variety of treatment modalities, while activation of the dACC may be a mechanism of action required for response to CBT across mood and anxiety disorders.