Functional connectivity of the subcallosal cingulate cortex and differential outcomes to treatment with cognitive- behavioral therapy or antidepressant medication for major depressive disorder

“Symptom severity using the HDRS, Hamilton Anxiety Rating Scale (43), and Beck Depression Inventory (44) was assessed weekly by blinded raters for the first 6 weeks after randomization and then every other week until week 12.”

“Patients Adults aged 18–65 years were eligible to participate if they met DSM-IV criteria for a primary current diagnosis of nonpsychotic major depression as assessed by the Structured Clinical Interview for DSM-IV (40) and a psychiatrist’s evaluation, and if they scored $18 on the 17-item Hamilton DepressionRatingSca…”

“The SCC volume was defined using the Harvard-Oxford atlas (49), and the SCC was thresholded at 50% probability centered on MNI coordinates ±6, 24, −11 consistent with seeds used in our other studies of SCC (38,50).”

“Symptom severity using the HAM-D, Hamilton Anxiety Rating Scale (43), and Beck Depression Inventory (44) was assessed weekly by blinded raters for the first 6 weeks after randomization and then every other week until week 12.”

“The ventromedial portion of BA 10 in the prefrontal cortex is an important component of the default mode network (80) and is extensively connected to the SCC (via the fronto-medial extent of the uncinate fasciculus) (38), FIGURE 3.”

“Mean head motion of included subjects, assessed by framewise displacement (47), did not significantly differ between the treatment outcome groups.”

“Finally, deep brain stimulation to the SCC and its cortical and subcortical connections may be efficacious in patients with highly treatment-resistant depression (37, 38).”

“as well as the periaqueductal gray and hypothalamus (81, 82).”

“The SCC is an extensively connected component of the limbic system that modulates emotional behavior and is particularly involved in feelings of sadness (30,31).”

“Several prior studies have implicated dysregulation in themedial portion of BA 10 in patientswithmajor depression (77, 78), and thepolar components ofVMPF10maybe smaller in patients with major depression compared with healthy controls (79).”

“Greater functional connectivity between the SCCand the defaultmodenetwork is present in patientswith treatment-resistant depression (32).”

“The VLPFC activity in healthy controls has been linked repeatedly to emotion regulation (58, 59) and sustained attention (60).”

“From a clinical perspective, cases of major depression more associated with signals from the body (“gut feelings”) may be more resistant to pure psychotherapy approaches, whereas major depression that does not involve strong interoceptive experiences may be particularly responsive to CBT (68).”

“TheVLPFCis involved in stimulus selection, and reducedVLPFCactivation in response to stimuli is associated with inability to disengage from negative stimuli (61).”

“Several prior studies have implicated dysregulation in the medial portion of BA 10 in patients with major depression (77,78), and the polar components of VMPF10 may be smaller in patients with major depression than healthy controls (79).”

“The syndrome of major depressive disorder, a highly heterogeneous clinical condition, has largely defied meaningful subtyping (1).”

“, increasedmetabolism in the dorsolateral prefrontal cortex) (14).”

“Among patients with major depression compared with healthy control subjects, relative hyperactivity of limbic brain regions, including the amygdala, insula, and subcallosal cingulate cortex (SCC), is consistently reported; hypoactivity in the dorsolateral prefrontal cortex is another replicated finding (12).”

“Moreover, VMPF10 and VLPF47 are bidirectionally connected by lateral branches of the uncinate fasciculus, disruptions of which are associated with impairments in use of memory to guide decision making and socio-emotional difficulties (83).”

“VLPFC activity in healthy controls has been linked repeatedly to emotion regulation (58,59) and sustained attention (60).”

“Sufficient connectivity between the SCCand themidbrain may also reflect the importance of the structural connections between the ventromedial prefrontal cortex and the dorsal raphe (73).”

“However, average differences between groups may mask important heterogeneitybetween individuals (13),withsomepatientsnot showing these changes, or even demonstrating opposite patterns (e.”

“In healthy controls, periaqueductal gray activity can be modulated by placebo-induced expectation of pain relief, and functional connectivity between SCC and periaqueductal gray is increasedduringa coldpressor task (72).”

“Metabolic activity in the right anterior insula emerged as the best candidate for use as a treatment selection biomarker (26), with support provided by the finding that, among nonremitters to monotherapy, the same biomarker predicted eventual remission after addition of the alternative treatment (27).”

“Weak or absent connectivity between the SCC and dorsal raphe may reflect a biological inability of a patient to achieve effortful control over stress responses, and thus indicate the need for a direct effect on the serotonergic transporters and autoreceptors of the raphe by antidepressant medication (76).”

“Impaired emotion regulation is linked to activity in the VLPFC among patients with major depression (62), and rumination is associated with VLPFC activity (63, 64) and volume (65).”

“The operculo-insular cortex (VLPF47/INS region) is important for interoceptive and emotional processing (66,67).”

“The SCC volume was defined using the Harvard-Oxford atlas (49), and the SCC was thresholded at 50% probability centered on MNI coordinates ±6, 24, −11 consistent with seeds used in our other studies of SCC (38,50).”

“Recent reviews have found inconsistent results for potential neuroimaging predictors of treatment outcomes in major depression (15, 16).”

“Impaired emotion regulation is linked to activity in the VLPFC among patients with major depression (62), and rumination is associated with VLPFC activity (63, 64) and volume (65).”

“Others have found better response to CBT among major depressivedisorderpatientswhowereclosest tohealthycontrols in terms of reactivity to emotional stimuli in the ventromedial prefrontal cortex (56), VLPFC, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex (57).”

“In our previous report using PET, resting state metabolic activity in the right anterior insula (with the cluster extending into the frontal operculum) differentially predicted remission and treatment failure with CBT and escitalopram (27,28).”

“Impaired emotion regulation is linked to activity in the VLPFC among patients with major depression (62), and rumination is associated with VLPFC activity (63,64) and volume (65).”

“Others have found better response to CBT among major depressivedisorderpatientswhowereclosest tohealthycontrols in terms of reactivity to emotional stimuli in the ventromedial prefrontal cortex (56), VLPFC, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex (57).”

“Prior studies have shown that antidepressant medication treatment alters reactivity of the SCC, VLPFC, and insula (85), as well as the functional connectivity between cortical and limbic regions in major depression patients (86).”

“The ventromedial prefrontal cortex (incorporating the SCC) is crucial for regulating an organism’s response to both controllable and uncontrollable stressors, mediated in part by its regulation of dorsal raphe activity in response to stress (73, 74).”

“Contrasts were performed using a whole-brain voxel-wise 232 analysis of variance (ANOVA) (3dMVM) (53) with treatment (medication or CBT) and 12-week outcomes (remission or treatment failure).”

“TheSCCvolumewas defined using the Harvard-Oxford Atlas (49), and the SCC was thresholded at 50% probability centered on MNI coordinates66, 24, –11, consistent with seeds used in our other studies of SCC (38, 50).”

“Further, serotonin transporter concentrations may be elevated in the periaqueductal grey of major depression patients versus healthy controls (71).”

“Prior studies have shown that antidepressant medication treatment alters reactivity of the SCC, VLPFC, and insula (85), as well as the functional connectivity between cortical and limbic regions in major depression patients (86).”

“Utilizing 3dNetCorr (51), the mean time course of the bilateral seed was correlated voxel-wise with the rest of the brain.”

“Studies The design of the Emory Predictors of Remission in Depression to Individual andCombinedTreatments (PReDICT) study has been published previously (39), and the clinical results of the trial are presented elsewhere (10).”

“Importantly, some patients who do not respond to one treatment intervention exhibit an excellent response when switched to the alternative (4, 5).”

“Based on prior work (26, 27, 36),wehypothesized that pretreatment levels of SCC resting-state functional connectivity to other cortical and limbic regions would differentially predict the clinical outcomes of the CBT and antidepressant medication treatments.”

“Studies The design of the Emory Predictors of Remission in Depression to Individual andCombinedTreatments (PReDICT) study has been published previously (39), and the clinical results of the trial are presented elsewhere (10).”

“Combination treatment with psychotherapy and antidepressant medication improves remission rates, but barriers such as cost, time, andpatientpreferencepreclude this option formany patients (3).”

“We have previously proposed that psychotherapy-responsive depression may represent a brain state with sufficiently adequate connectivity in mood-regulating systems such that engagement of these systems via psychotherapy can reduce negative emotional states (25).”

“Furthermore, in a chronic social defeat model of depression inmice, deep brain stimulation to the ventromedial prefrontal cortex induces neuroplastic changes in the serotonergic neurons in the dorsal raphe (75).”

“Intriguingly, metabolic activity in the anterior insula and periaqueductal gray of rhesus monkeys correlates positively with anxious temperament behaviors in animals exposed to threat (84).”

“The operculo-insular cortex (VLPF47/INS region) is important for interoceptive and emotional processing (66,67).”

“Several prior studies have implicated dysregulation in themedial portion of BA 10 in patientswithmajor depression (77, 78), and thepolar components ofVMPF10maybe smaller in patients with major depression compared with healthy controls (79).”

“Resting-state fMRI datawere acquired using a Z-SAGA sequence (46) to recover areas affected by susceptibility artifact, with the following parameters: 150 measurements; 30 axial slices; voxel resolution=3.”

“pre-treatment resting state metabolism in the midbrain did predict remission to standard antidepressant medications (69).”

“Furthermore, because combination treatment with both psychotherapy and medication formajor depression is often not required or not feasible, selectionof the initial treatment is typically a forced choice between psychotherapy and medication (5).”

“Recent reviews have found inconsistent results for potential neuroimaging predictors of treatment outcomes in major depression, (15,16).”

“The present results, in conjunction with our prior CBT compared with antidepressant medication study using FDGPET (26, 27), argue strongly that brain state subtypes of heterogeneous major depressive disorder patients may reflect their biological capacity to benefit differentially from treatments with differingmechanis…”

“found no difference in outcome among patients treated with CBT or antidepressant medication based on severity (7) or depressive clinical subtype (8).”

“The SCC is an extensively connected component of the limbic system that modulates emotional behavior and is particularly involved in feelings of sadness (30,31).”

“Impaired emotion regulation is linked to activity in the VLPFC among patients with major depression (62), and rumination is associated with VLPFC activity (63, 64) and volume (65).”

“Unfortunately, genetic testing, neuroimaging, and psychophysiological approaches, though promising, have not yet proven sufficiently accurate or replicable to warrant clinical application to individual patients (11).”

“Several studies support the conclusion that, on average, patients with major depression have reduced prefrontal control over emotion-generating limbic structures (29).”

“However, avoiding treatment failure is also a vitally important outcome (24).”

“as in [38], see also [47]) may not generalize to independent datasets across different sites[48], and therefore require additional independent validation (see Box: 3).”

“stimulation affects pathways that connect with the OFC (Johansen-Berg et al., 2008; Lujan et al., 2013; Dunlop et al., 2017; Riva-Posse et al., 2018).”

“Variability in baseline patterns can be further evaluated against known clinical phenotypes (Mayberg, 2003; McGrath et al., 2014; Williams, 2016; Dunlop et al., 2017).”