Network-level dynamics underlying a combined rTMS and psychotherapy treatment for major depressive disorder: An exploratory network analysis

Background: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression, there is a limited understanding of the mechanisms of action and how potential treatment-related brain changes help to characterize treatment response. To address this gap in understanding we investigated the effects of an approach combining rTMS with simultaneous psychotherapy on global functional connectivity. Method: We compared task-related functional connectomes based on an idiographic goal priming task tied to emotional regulation acquired before and after simultaneous rTMS/psychotherapy treatment for patients with major depressive disorders and compared these changes to normative connectivity patterns from a set of healthy volunteers (HV) performing the same task. Results: At baseline, compared to HVs, patients demonstrated hyperconnectivity of the DMN, cerebellum and limbic system, and hypoconnectivity of the fronto-parietal dorsal-attention network and visual cortex. Simultaneous rTMS/psychotherapy helped to normalize these differences, which were reduced after treatment. This finding suggests that the rTMS/therapy treatment regularizes connectivity patterns in both hyperactive and hypoactive brain networks. Conclusions: These results help to link treatment to a comprehensive model of the neurocircuitry underlying depression and pave the way for future studies using network-guided principles to significantly improve rTMS efficacy for depression. (AU)

Network-level dynamics underlying a combined rTMS and psychotherapy treatment for major depressive disorder: An exploratory network analysis.

Background: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression, there is a limited understanding of the mechanisms of action and how potential treatment-related brain changes help to characterize treatment response. To address this gap in understanding we investigated the effects of an approach combining rTMS with simultaneous psychotherapy on global functional connectivity. Method: We compared task-related functional connectomes based on an idiographic goal priming task tied to emotional regulation acquired before and after simultaneous rTMS/psychotherapy treatment for patients with major depressive disorders and compared these changes to normative connectivity patterns from a set of healthy volunteers (HV) performing the same task. Results: At baseline, compared to HVs, patients demonstrated hyperconnectivity of the DMN, cerebellum and limbic system, and hypoconnectivity of the fronto-parietal dorsal-attention network and visual cortex. Simultaneous rTMS/psychotherapy helped to normalize these differences, which were reduced after treatment. This finding suggests that the rTMS/therapy treatment regularizes connectivity patterns in both hyperactive and hypoactive brain networks. Conclusions: These results help to link treatment to a comprehensive model of the neurocircuitry underlying depression and pave the way for future studies using network-guided principles to significantly improve rTMS efficacy for depression.

Implementing mental health interventions within a national nurse home visiting program: A mixed-methods evaluation.

Background: Up to half of low-income mothers experience symptoms of depression and anxiety that affect their well-being and increase their children's risk for behavioral and emotional problems. To address this problem, an engaged research/practice planning team designed the Mental Health Innovation (MHI), a multicomponent implementation strategy that integrates evidence-based mental health interventions within the national Nurse-Family Partnership (NFP). The MHI includes four implementation strategies: online training modules, clinical resources, team meeting modules, and virtual consultation. Methods: A convergent, mixed methods observational design was applied to evaluate implementation outcomes, guided by the RE-AIM framework. We operationalized Reach as the number and demographics of women enrolled in NFP agencies exposed to MHI strategies. Adoption was operationalized as the number and proportion of nurses and supervisors who used MHI implementation strategies. For implementation, we assessed multilevel stakeholders' perceptions of strategy acceptability and feasibility. Data were pulled from NFP's national data management systems and collected through focus groups and surveys. Quantitative data were analyzed using counts and summary statistics. Qualitative themes were generated through content analysis. Results: The MHI reached agencies serving 51,534 low-income mothers (31.2% African American and 30.0% Latina). Adoption rates varied across implementation strategies. Between 60% and 76% of NFP nurses (N = 2,100) completed each online module. Between 27% and 51% of nurse supervisors (n = 125) reported using each team meeting module. Of 110 teams invited to participate in virtual consultation, 40.9% (n = 45) participated. Mothers served by agencies participating in virtual consultation differed significantly from those who did not, with lower percentages of African American and Latina. Qualitative themes suggest that MHI strategies were generally viewed as acceptable; perceptions of feasibility varied across strategies. Conclusions: This study identified both strengths and opportunities for improvement. Further evaluation is needed to assess the MHI's effectiveness in improving mothers' mental health.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

On the Concurrent Use of Self-System Therapy and Functional Magnetic Resonance Imaging-Guided Transcranial Magnetic Stimulation as Treatment for Depression.

OBJECTIVES: Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar depression, its typical effect sizes have been modest, and methodological and conceptual challenges remain regarding how to optimize its efficacy. Linking rTMS to a model of the neurocircuitry underlying depression and applying such a model to personalize the site of stimulation may improve the efficacy of rTMS. Recent developments in the psychology and neurobiology of self-regulation offer a conceptual framework for identifying mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. We applied this framework to develop a multimodal treatment for depression by pairing self-system therapy (SST) with simultaneously administered rTMS delivered to an individually targeted region of dorsolateral prefrontal cortex identified via functional magnetic resonance imaging (fMRI). METHODS: In this proof-of-concept study, we examined the acceptability, feasibility, and preliminary efficacy of combining individually fMRI-targeted rTMS with SST. Using the format of a cognitive paired associative stimulation paradigm, the treatment was administered to 5 adults with unipolar depression in an open-label trial. RESULTS: The rTMS/SST combination was well tolerated, feasible, and acceptable. Preliminary evidence of efficacy also was promising. We hypothesized that both treatment modalities were targeting the same neural circuitry through cognitive paired associative stimulation, and observed changes in task-based fMRI were consistent with our model. These neural changes were directly related to improvements in depression severity. CONCLUSIONS: The new combination treatment represents a promising exemplar for theory-based, individually targeted, multimodal intervention in mood disorders.

Reprint of ''Using neuroimaging to individualize TMS treatment for depression: Toward a new paradigm for imaging-guided intervention''.

The standard clinical technique for using repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) is associated with limited efficacy to date. Such limited efficacy may be due to reliance on scalp-based targeting rather than state-of-the-science methods which incorporate fMRI-guided neuronavigation based on a specific model of neurocircuit dysfunction. In this review, we examine such a specific model drawn from regulatory focus theory, which postulates two brain/behavior systems, the promotion and prevention systems, underlying goal pursuit. Individual differences in these systems have been shown to predict vulnerability to MDD as well as to comorbid generalized anxiety disorder (GAD). Activation of an individual's promotion or prevention goals via priming leads to motivational and affective responses modulated by the individual's appraisal of their progress in attaining the goal. In addition, priming promotion vs. prevention goals induces discriminable patterns of brain activation that are sensitive to the effects of depression and anxiety: MDD is associated with promotion system failure, anhedonic/dysphoric symptoms, and hypoactivation in specific regions in left prefrontal cortex, whereas GAD is associated with prevention system failure, hypervigilant/agitated symptoms, and hyperactivation in right prefrontal cortex (PFC). These left and right PFC locations can be directly targeted in an individualized manner for TMS. Additionally, this individually targeted rTMS can be integrated with cognitive interventions designed to activate the neural circuitry associated with promotion vs. prevention, thus allowing the neuroplasticity induced by the rTMS to benefit the systems likely to be involved in remediating depression. Targeted engagement of cortical systems involved in emotion regulation using individualized fMRI guidance may help increase the efficacy of rTMS in depression.

Using neuroimaging to individualize TMS treatment for depression: Toward a new paradigm for imaging-guided intervention.

The standard clinical technique for using repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD) is associated with limited efficacy to date. Such limited efficacy may be due to reliance on scalp-based targeting rather than state-of-the-science methods which incorporate fMRI-guided neuronavigation based on a specific model of neurocircuit dysfunction. In this review, we examine such a specific model drawn from regulatory focus theory, which postulates two brain/behavior systems, the promotion and prevention systems, underlying goal pursuit. Individual differences in these systems have been shown to predict vulnerability to MDD as well as to comorbid generalized anxiety disorder (GAD). Activation of an individual's promotion or prevention goals via priming leads to motivational and affective responses modulated by the individual's appraisal of their progress in attaining the goal. In addition, priming promotion vs. prevention goals induces discriminable patterns of brain activation that are sensitive to the effects of depression and anxiety: MDD is associated with promotion system failure, anhedonic/dysphoric symptoms, and hypoactivation in specific regions in left prefrontal cortex, whereas GAD is associated with prevention system failure, hypervigilant/agitated symptoms, and hyperactivation in right prefrontal cortex (PFC). These left and right PFC locations can be directly targeted in an individualized manner for TMS. Additionally, this individually targeted rTMS can be integrated with cognitive interventions designed to activate the neural circuitry associated with promotion vs. prevention, thus allowing the neuroplasticity induced by the rTMS to benefit the systems likely to be involved in remediating depression. Targeted engagement of cortical systems involved in emotion regulation using individualized fMRI guidance may help increase the efficacy of rTMS in depression.

Prefrontal rTMS for treating depression: location and intensity results from the OPT-TMS multi-site clinical trial.

BACKGROUND: Motor cortex localization and motor threshold determination often guide Transcranial Magnetic Stimulation (TMS) placement and intensity settings for non-motor brain stimulation. However, anatomic variability results in variability of placement and effective intensity. OBJECTIVE: Post-study analysis of the OPT-TMS Study reviewed both the final positioning and the effective intensity of stimulation (accounting for relative prefrontal scalp-cortex distances). METHODS: We acquired MRI scans of 185 patients in a multi-site trial of left prefrontal TMS for depression. Scans had marked motor sites (localized with TMS) and marked prefrontal sites (5 cm anterior of motor cortex by the "5 cm rule"). Based on a visual determination made before the first treatment, TMS therapy occurred either at the 5 cm location or was adjusted 1 cm forward. Stimulation intensity was 120% of resting motor threshold. RESULTS: The "5 cm rule" would have placed stimulation in premotor cortex for 9% of patients, which was reduced to 4% with adjustments. We did not find a statistically significant effect of positioning on remission, but no patients with premotor stimulation achieved remission (0/7). Effective stimulation ranged from 93 to 156% of motor threshold, and no seizures were induced across this range. Patients experienced remission with effective stimulation intensity ranging from 93 to 146% of motor threshold, and we did not find a significant effect of effective intensity on remission. CONCLUSIONS: Our data indicates that individualized positioning methods are useful to reduce variability in placement. Stimulation at 120% of motor threshold, unadjusted for scalp-cortex distances, appears safe for a broad range of patients.

Neuropathologic examination after 91 ECT treatments in a 92-year-old woman with late-onset depression.

Whereas pathological seizure states, such as temporal lobe epilepsy, are commonly associated with cell loss and glial scarring in the hippocampus, seizures induced via electroconvulsive therapy (ECT) have not been associated with histological evidence of neuronal damage. We present a case report including the late-life medical history and postmortem histology of an elderly woman with major depression who received 91 sessions of ECT during the last 22 years of her life. Given the large number of ECT sessions, and her advanced age, this case provides a strong test of whether ECT causes detectable evidence of neuronal damage. We examined the gross morphology of the hippocampus, hippocampal cytoarchitecture, and measures of neuropathology. We found no pathological changes that could be attributed to ECT. Only expected, age-related features were present. Corpora amylacea and rare neurofibrillary tangles were evident, but we failed to detect any obvious evidence of cell loss or gliosis. Cognition in this patient was intact as indicated by a perfect score on a Mini-Mental Status Examination administered 6 days before death at the age of 92. This case adds to the considerable evidence for the safety of ECT.