The studies reviewed below implemented a variety of different imaging techniques and data analytic approaches. Early studies tended to use positron emission tomography (PET) and fluorodeoxyglucose (FDG) to measure rCMRglu while patients rested with eyes open. Although such resting state studies are relatively easy to administer because they require no explicit cognitive task, they are also limited by a lack of control over the mental processes in which subjects engage during the radiotracer uptake period. This can lead to greater variability in the data, perhaps increasing the risk of type II errors (depending on the kinds of analyses used), as well as some difficulty interpreting the meaning of the rCMRglu findings. In general, PET-FDG imaging is also limited by relatively poor temporal resolution as rCMRglu data are typically averaged across long periods of time (~30-45 minutes).

Many older PET-FDG studies also used region-of-interest (ROI) based analyses in which researchers draw boundaries around brain regions based on structural anatomy, “extract” functional imaging data from those drawn regions, and submit the extracted data to external statistical software. One disadvantage of this technique is that it involves averaging functional imaging data across very large brain structures, increasing the risk of type II error if only a small portion of that large brain structure is actually important in the prediction of treatment response. More recent neuroimaging studies employ voxelwise analyses that can assess the relationship between brain activation (or gray matter volume) and treatment response at every voxel (e.g., 3 mm × 3 mm × 3 mm cube) in the brain. However, in order to complete such analyses, one must “normalize” or morph the functional (and/or structural) brain images to a standard brain template, which introduces some amount of error. In addition, voxelwise analyses involve conducting thousands of analyses (one per voxel) across the brain, so correction for multiple comparisons must be applied.

More recent studies have implemented functional magnetic resonance imaging (fMRI) to measure brain activation in response to cognitive and/or affective tasks. These types of studies afford more control over the cognitive state of the participant during scanning and, if well designed, allow for a more clear interpretation of the meaning of the imaging findings.

The methodological considerations described above apply to most functional neuroimaging studies, not just those assessing the prediction of treatment response. With regard to the latter specifically, researchers have used two different data analytic approaches. The first approach involves comparing treatment responders to non-responders on a pre-treatment neuroimaging measure (e.g., amygdala activation). For example, if treatment responders as a group were found to have lower pre-treatment amygdala activation than non-responders, then lower amygdala activation would be considered to be predictive of a better response to treatment. This type of between-group analysis typically involves analysis of variance (ANOVA) or analysis of covariance (ANCOVA), and requires (1) a very clear and well-accepted definition of treatment response and (2) sufficiently large numbers of participants per group (responders and non-responders). Because the relative size of these post-treatment groups cannot be completely planned a priori, these studies should begin with a very large number of participants.

The second approach is to run a correlation (or a regression) between a continuous pre-treatment neuroimaging measure and a continuous measure of symptomatic improvement (e.g., symptom change score, percent improvement, or clinical global impression (CGI) improvement score). This type of analysis takes advantage of the inherent variability in both the imaging and treatment response data and is therefore likely to be more powerful than the between-group approach. Regression analyses also obviate the need to form responder and non-responder groups and permit the investigation of multiple pre-treatment imaging (and non-imaging) variables in the prediction of treatment response. For example, baseline symptom severity and comorbidity measures (either categorical or continuous) can be entered into the regression along with pre-treatment imaging measures to predict symptom change scores. Several studies reviewed below included both types of approaches.

1 Article Disorder Imaging Treatment type Sample sizes Outcome measure Findings Swedo et al. [32] OCD PET-FDG: resting state Clomipramine (dose and duration not specified) OCD: 18 Healthy: 18 OCR Responders: ≥ 40% reduction in OCR (11 R, 6 NR) Pre-treatment rCMRglu in the right ACC and right OFC was lower in clomipramine R vs. NR. Saxena et al. [33] OCD PET-FDG: resting state Paroxetine (8-12 weeks; 40 mg/d max) OCD: 20 YBOCS and CGI Responders: ≥ 25% reduction in YBOCS and CGI of much improved or very much improved (11 R, 9 NR) Lower pre-treatment rCMRglu in bilateral OFC predicted better response to paroxetine. Saxena et al. [34] OCD, MDD, OCD + MDD PET-FDG: resting state Paroxetine (8-12 weeks; 30-60 mg/d) OCD: 27 MDD: 27 OCD + MDD: 17 YBOCS, HAM-D Greater pre-treatment rCMRglu in the caudate predicted greater improvement in OCD symptoms in the OCD groups. Lower rCMRglu in the amygdala predicted more improvement in MDD symptoms in MDD group and in all Ss combined. Greater pre-treatment rCMRglu in the medial frontal gyrus predicted improvement in MDD symptoms in all Ss. Hendler et al. [35] OCD SPECT: symptom provocation vs. relax Sertraline (6 months; 200 mg/d max) OCD: 26 YBOCS Responders: ≥ 30% reduction in YBOCS (13 R, 13 NR) R had lower pre-treatment perfusion during symptom provocation in dorsal/caudal ACC and higher perfusion in right caudate vs. NR. Rauch et al. [36] OCD PET-015: symptom provocation vs. neutral Fluvoxamine (12 weeks; 300 mg/d max) OCD: 9 YBOCS Lower rCBF in OFC and higher rCBF in PCC predicted better response. Sanematsu et al. [37] OCD fMRI: symptom provocation vs. neutral Fluvoxamine (12 weeks; 200 mg/d max) OCD: 17 YBOCS Pretreatment activation of right cerebellum and left superior temporal gyrus was positively correlated with YBOCS improvement. Ho Pian et al. [38] OCD SPECT: resting state Fluvoxamine (12 weeks; 300 mg/d max) OCD: 15 YBOCS Responders: ≥25% reduction in YBOCS (7 R, 8 NR) Pre-treatment cerebellar and whole brain rCBF was significantly higher in R vs. NR. Buchsbaum et al. [39] OCD PET-FDG: resting state Risperidone or placebo augmentation (8 weeks; 3 mg/d max) OCD: 15 Risperidone: 9 Placebo: 6 YBOCS Responders: ≥ 25% reduction in YBOCS and/or CGI Improvement rating of very much improved or much improved (4 R, 5 NR) Pre-treatment rCMRglu was lower in the striatum and higher in the ventral ACC in R vs. NR. Brody et al. [40] OCD PET-FDG: resting state Fluoxetine (10 weeks; 60 mg/d) or group BT (10 weeks) OCD: 27 Fluoxetine: 9 CBT: 18 YBOCS Greater pre-treatment rCMRglu in the left OFC was associated with a better response to BT. In this same region, lower rCMRglu was associated with better response to fluoxetine. Hoexter et al. [41] OCD mMRI Fluoxetine (12 weeks; 80 mg/d max) or group CBT (12 weekly sessions) OCD: 29 Fluoxetine: 14 CBT: 15 YBOCS Lower pre-treatment gray matter density in ventrolateral prefrontal cortex predicted better response to fluoxetine. Greater gray matter density in subgenual ACC predicted better response to CBT. Rauch et al. [44] OCD PET-FDG: resting state Anterior cingulotomy OCD: 11 YBOCS Greater pre-operative rCMRglu in posterior cingulate predicted greater improvement. Van Laere et al. [45] OCD PET-FDG: resting state Stimulation of anterior capsule OCD: 6 Controls: 20 YBOCS Greater pre-operative rCMRglu in the subgenual ACC predicted greater improvement. Bryant et al. [68] PTSD mMRI CBT (8 weekly sessions) PTSD: 13 TENP: 13 Healthy: 13 CAPS Responders: no longer met diagnostic criteria (7 R, 6 NR) Greater pre-treatment gray matter density in the rACC predicted greater improvement. Bryant et al. [19] PTSD fMRI: masked fearful vs. neutral faces CBT (8 weekly sessions) PTSD: 14 Healthy: 14 CAPS Responders: ≥ 50% reduction in CAPS (7 R, 7 NR) Lower pre-treatment amygdala and rACC activation predicted greater improvement. Nardo et al. [69] PTSD mMRI EMDR (5 sessions) PTSD: 21 TENP: 22 Responders: no longer met diagnostic criteria (10 R, 5 NR) R had greater gray matter density in the insula, amygdala/parahippocampal gyrus, posterior cingulate, and middle, precentral, and dorsal medial frontal gyri. Whalen et al. [75] GAD fMRI: fearful vs. neutral/happy faces Venlafaxine (8 weeks; 225 mg/d max) GAD: 15 Healthy: 15 HAM-A Lower pre-treatment amygdala activation and greater rACC activation predicted greater improvement in anxiety. Nitschke et al. [73] GAD fMRI: anticipation of aversive vs. neutral images Venlafaxine (8 weeks; 225 mg/d max) GAD: 14 Healthy: 12 HAM-A and Penn State Worry Questionnaire Greater pre-treatment rACC activation predicted greater improvement in anxiety. McClure et al. [76] GAD fMRI: fearful vs. happy faces Fluoxetine (8 weeks; 40 mg/d max) or CBT (8 weekly sessions) GAD: 12 Fluoxetine: 5 CBT: 7 CGI Greater pre-treatment amygdala activation predicted greater improvement. Evans et al. [87] SAD PET-FDG: resting state Tiagabine (6 weeks; 16 mg/d max) SAD: 12 Healthy: 10 LSAS Responders: ≥ 50% reduction in LSAS scores (7 R, 5 NR) Voxelwise correlations were not significant. Pre-treatment rCMRglu was lower in subcallosal ACC in R compared to healthy controls. Doehrmann et al. [13] SAD fMRI: 1-back task, angry vs. neutral faces CBT (12 weekly sessions) SAD: 39 LSAS Greater pre-treatment activation in dorsal and ventral occipitotemporal cortex predicted greater improvement. In the following text, we review studies that have assessed whether pre-treatment structural or functional neuroimaging measures can predict treatment response in OCD, PTSD, GAD, and SAD (See Table). (We were able to find no such studies of panic disorder or specific phobia). We did not include studies that assessed the change in neuroimaging measures with treatment as those studies address a different question.

Obsessive-compulsive disorder (OCD) In contrast to other anxiety disorders, OCD appears to be marked by structural and functional abnormalities in thalamo-cortico-striatal loops. One neurocircuitry model of OCD [23, 24] posits that the striatum (caudate nucleus) functions abnormally, leading to inefficient gating in the thalamus. This leads to hyperactivity in the orbitofrontal cortex and the ACC, which may mediate intrusive thoughts and anxiety, respectively. Compulsions recruit the striatum to achieve thalamic gating, thereby neutralizing the obsessions and reducing anxiety. Indeed, several resting state and symptom provocation functional neuroimaging studies have revealed greater activation of the caudate, thalamus, orbitofrontal cortex, and/or ACC in OCD (e.g., [25–28], although the direction of the abnormalities is not entirely uniform across studies). Pre-treatment functional abnormalities in these structures appear to resolve with successful treatment (e.g., [29–31]). Several studies have examined pre-treatment neuroimaging predictors of response to medication and/or behavioral therapy (BT) or cognitive-behavioral therapy (CBT) in OCD. Medication In a very early PET study of OCD, Swedo and colleagues [32] found that pre-treatment rCMRglu in the right ACC and right orbitofrontal cortex was lower in clomipramine responders vs. non-responders. They also reported a positive correlation between pre-treatment symptom severity and pre-treatment rCMRglu in the orbitofrontal cortex, suggesting that treatment response is likely better in those participants with less severe symptoms. Saxena and colleagues [33] reported similar findings in a PET study of paroxetine. Specifically, lower pre-treatment rCMRglu in bilateral orbitofrontal cortex was associated with better improvement. Another PET study of response to paroxetine [34] examined the more complicated question of whether pre-treatment rCMRglu could differentially predict improvement in OCD symptoms vs. depression symptoms in patients with OCD alone, comorbid OCD and MDD, and MDD alone. This study was unique in that it utilized both ROI-based and voxelwise analyses, the results of which were partially but not completely convergent. ROI-based analyses showed that greater pre-treatment rCMRglu in the caudate predicted greater improvement in OCD symptoms in the groups with OCD, but did not predict improvement in depression symptoms in any group. These findings were not replicated in the voxelwise analyses. ROI-based analyses also showed that lower pre-treatment rCMRglu in the amygdala predicted greater improvement in depression symptoms in the MDD group and in all subjects combined. Voxelwise analyses confirmed this finding in all subjects and further showed that greater pre-treatment rCMRglu in the medial frontal gyrus (just anterior to the rostral ACC [rACC]) predicted improvement in depression symptoms in all subjects regardless of diagnostic group. These findings are important because they suggest that (1) rCMRglu predictors of improvement differ for different types of symptoms even in the same subjects, and (2) rCMRglu predictors of improvement can cut across diagnostic lines. Hendler et al. [35] used single photon emission computed tomography (SPECT) to determine whether pre-treatment regional cerebral perfusion during symptom provocation could predict response to sertraline in individuals with OCD. Treatment responders showed lower pre-treatment perfusion in dorsal/caudal ACC and higher pre-treatment perfusion in right caudate compared to non-responders. These findings were not observed when the SPECT measures were obtained during the relaxed (unprovoked) state. Thus, these findings suggest that functional imaging-based measures obtained in one state (e.g., symptomatic) may predict treatment response in only that state and not others. In contrast, Rauch and colleagues [36] found that state of the participants did not affect the prediction of response to fluvoxamine in OCD. In a PET study, these authors found that pre-treatment regional cerebral blood flow (rCBF) measured in neutral and symptomatic states similarly predicted treatment response: lower pre-treatment rCBF in orbitofrontal cortex and greater pre-treatment rCBF in the posterior cingulate cortex predicted better response to fluvoxamine. Unlike previous studies of treatment response in OCD, Sanematsu and colleagues [37] used fMRI to examine neural predictors of improvement. Functional MRI data were collected while participants generated either words related to their OCD symptoms or control words (relating to flowers and vegetables). Greater pre-treatment activation in the right cerebellum and left superior temporal gyrus was associated with better response to fluvoxamine. Similarly, Ho Pian and colleagues [38] found that pre-treatment activity (as measured by 99mTc-HMPAO tracer uptake) in the cerebellum was greater in responders vs. non-responders to fluvoxamine. In a study of OCD patients who were non-responders to SRIs, Buchsbaum and colleagues [39] found that responders to risperidone augmentation had lower pre-treatment rCMRglu in the striatum and higher pre-treatment rCMRglu in the ventral ACC. These findings differ from those of previous studies of OCD most likely because of the nature of both the patient group (SRI non-responders) and the treatment (antipsychotic augmentation). Medication and BT/CBT In what appears to be the first study to examine the neuroimaging predictors of response to two different treatments for OCD, Brody et al. [40] studied pre-treatment rCMRglu in patient groups who chose to receive either BT or fluoxetine. They found that greater pre-treatment rCMRglu in the left orbitofrontal cortex was significantly associated with greater symptomatic improvement after BT. Interestingly, within this same ROI, lower pre-treatment rCMRglu was associated with greater improvement after treatment with fluoxetine. In a similar study, Hoexter and colleagues [41] examined structural imaging predictors of treatment response in treatment-naïve patients randomly assigned to receive either fluoxetine or group CBT. Using voxel-based morphometry, they found that lower pre-treatment gray matter density in ventrolateral frontal cortex predicted greater improvement in OCD symptoms after treatment with fluoxetine. In contrast, greater pre-treatment gray matter density in subgenual ACC predicted greater improvement in OCD symptoms after CBT. When the two treatment groups were combined, there were no significant effects. Given that CBT involves extinction-like processes and that ventral medial prefrontal cortex (mPFC) is critical for the retention of extinction memory [42, 43], it makes sense that patients with greater pre-treatment gray matter volume in ventral mPFC would show greater symptomatic improvement with CBT. Along with Brody et al. [40], this study suggests different imaging predictors of response to medication vs. CBT in OCD. Neurosurgery Identifying reliable and valid predictors of treatment response is even more critical when the treatment is invasive and associated with elevated risk, such as the case with neurosurgery. Rauch and colleagues [44] evaluated the PET predictors of response to anterior cingulotomy and found that relatively greater pre-treatment rCMRglu in the posterior cingulate cortex predicted greater improvement in OCD symptom severity after surgery. These findings were consistent with those of Rauch et al. [36] in the prediction of response to fluvoxamine. In a study of anterior capsule stimulation, Van Laere and colleagues [45] found that greater pre-operative rCMRglu in the subgenual ACC predicted greater improvement in OCD symptom severity. In summary, lower pre-treatment activity in the orbitofrontal cortex and greater activity in the caudate and posterior cingulate cortex predict a more favorable response to SRIs or neurosurgery in OCD. In contrast, greater pre-treatment activity or gray matter volume in ventral mPFC appears to predict better response to BT/CBT. This latter finding has also been reported in PTSD.

Posttraumatic stress disorder (PTSD) Some neurocircuitry models [46, 47] posit that the amygdala is hyperresponsive in PTSD, perhaps accounting for hypervigilance, increased arousal, and the persistence of trauma-related memories. In addition, the mPFC (including the rACC) is thought to be hyporesponsive, with diminished inhibition over the amygdala, and this may underlie extinction memory deficits and difficulty ignoring trauma-related reminders. Neuroimaging studies of PTSD have generally reported increased activation in the amygdala, insular cortex, and dorsal anterior cingulate cortex (dACC), and decreased activation in the mPFC [48–51]. In addition, structural neuroimaging studies have reported decreased volume or gray matter density in the amygdala, mPFC, and hippocampus in this disorder (e.g., [52–55]). Furthermore, PTSD symptom severity measures are often correlated positively with amygdala activation (e.g. [56, 57]) and negatively with mPFC activation (e.g., [58–61]). A few studies have suggested that amygdala activation decreases and mPFC activation increases with successful treatment [62–65]. The use of exposure-based techniques to treat PTSD is well supported in the literature (e.g., [66, 67]) and most studies that have examined neuroimaging predictors of treatment response have implemented such techniques. Bryant et al. [68] used structural MRI and voxel-based morphometry to determine whether pre-treatment gray matter density predicted response to CBT in participants with PTSD. Correlational analyses revealed that pre-treatment gray matter density in the rACC was positively correlated with symptomatic improvement, even after controlling for depression and baseline PTSD symptom severity. Indeed, treatment responders, trauma-exposed comparison subjects without PTSD, and healthy comparison subjects had higher pre-treatment gray matter density in the rACC than did treatment non-responders. In an fMRI study, Bryant and colleagues [19] presented backwardly-masked fearful vs. neutral facial expressions to participants with PTSD before they completed eight sessions of CBT. Treatment response was assessed 6 months after treatment completion. Voxelwise correlational analyses revealed that lower pre-treatment activation in the amygdala and rACC predicted better symptomatic improvement after CBT. Between-group comparisons (non-responders vs. responders) confirmed these findings. Of note, the finding in the rACC was opposite of prediction. In a voxel-based morphometry study of railway workers with PTSD, Nardo et al. [69] found that compared to non-responders, responders to eye-movement desensitization and reprocessing (EMDR) treatment had greater pre-treatment gray matter density in large territories of the brain including the insula, amygdala/parahippocampal gyrus, posterior cingulate, and middle, precentral, and dorsal medial frontal gyri. In summary, pre-treatment neuroimaging measures of the amygdala and mPFC (specifically, the rACC) predict response to BT/CBT in PTSD, although additional studies are needed to specify the direction of the findings. Interestingly, mPFC activation also appears to predict treatment response in GAD, as shown below.

Generalized anxiety disorder (GAD) Although relatively few functional neuroimaging studies of GAD exist in the literature, there has been some support for increased activation in the amygdala and mPFC in GAD relative to comparison groups ([70–73], but see also [74, 75]). One study reported a positive correlation between amygdala activation and GAD symptom severity [72]. Three fMRI studies have examined neuroimaging predictors of treatment response in GAD. Whalen and colleagues [75] found that pre-treatment activation in the amygdala in response to fearful (vs. neutral or happy) facial expressions was negatively correlated with symptomatic change after treatment with venlafaxine in GAD. Specifically, relatively lower pre-treatment amygdala responses were associated with relatively greater improvement. Interestingly, the opposite relationship was found in the rACC: the greater the pre-treatment rACC activation, the greater the improvement. Using a different fMRI paradigm, Nitschke and colleagues [73] found that pre-treatment rACC activation during the anticipation of aversive and neutral pictures was inversely correlated with post-treatment symptoms of anxiety and worry (controlling for pre-treatment symptoms) in participants treated with venlafaxine. Thus, consistent with the findings of Whalen et al. [75], relatively greater pre-treatment rACC activation predicted relatively greater improvement. The authors found no significant association between pre-treatment amygdala responses and symptomatic change. In contrast to the findings of Whalen et al. [75], McClure and colleagues [76] examined amygdala activation in twelve adolescents with anxiety disorders (nine had primary GAD) before treatment with either CBT or fluoxetine. Participants viewed fearful and happy faces in the scanner and responded to the question “How afraid are you?” Pre-treatment amygdala activation to fearful vs. happy faces was inversely associated with post-treatment symptom severity, even after controlling for pre-treatment symptom severity. That is, the greater the pretreatment amygdala activation, the better the treatment response. The discrepancy between this finding and that of Whalen et al. [75] could have been due to the younger age and/or the diagnostic heterogeneity in the McClure et al. sample (not all of the participants had GAD). In summary, the amygdala and mPFC appear to predict treatment response in GAD, although the direction of the findings remains to be confirmed. Two of the three studies, however, suggest that greater pre-treatment mPFC (specifically, rACC) activation is related to better response to venlafaxine.