Accelerated Intermittent Theta-Burst Stimulation and Treatment-Refractory Bipolar Depression: A Randomized Clinical Trial.

Importance: Bipolar disorder (BD) is chronic and disabling, with depression accounting for the majority of time with illness. Recent research demonstrated a transformative advance in the clinical efficacy of transcranial magnetic stimulation for treatment-resistant major depressive disorder (MDD) using an accelerated schedule of intermittent theta-burst stimulation (aiTBS), but the effectiveness of this treatment for treatment-refractory BD is unknown. Objective: To evaluate the effectiveness of aiTBS for treatment-refractory BD. Design, Setting, and Participants: This randomized clinical trial, conducted from March 2022 to February 2024, included individuals with treatment-resistant BD with moderate to severe depressive episodes referred from the Penn Bipolar outpatient clinic. Included patients had 2 or more prior failed antidepressant trials by Antidepressant Treatment History Form criteria and no other primary psychiatric diagnosis, were receiving a mood stabilizer for 4 or more weeks, and had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher. Intervention: Prior to treatment, resting-state functional magnetic resonance imaging was used to compute personalized left dorsolateral prefrontal cortex target by connectivity to subgenual anterior cingulate cortex. Patients were randomized 1:1 to 10 sessions per day of imaging-guided active or sham aiTBS for 5 days with 1 session per hour at 90% resting motor threshold for 90 000 pulses total. Main Outcome and Measures: The main outcome was repeated MADRS scores before and after treatment. Results: A total of 24 participants (12 [50%] female; 12 [50%] male; mean [SD] age, 43.3 [16.9] years) were randomized to active (n = 12) or sham (n = 12) aiTBS. All participants completed treatment and 1-month follow-up. MADRS scores were significantly lower in the active group (mean [SD], 30.4 [4.8] at baseline; 10.5 [6.7] after treatment) than in the sham group (28.0 [5.4] at baseline; 25.3 [6.7] after treatment) at treatment end (estimated difference, -14.75; 95% CI, -19.73 to -9.77; P < .001; Cohen d, -2.19). Conclusion and Relevance: In this randomized clinical trial, aiTBS was more effective than sham stimulation for depressive symptom reduction in patients with treatment-resistant BD. Further trials are needed to determine aiTBS durability and to compare with other treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT05228457.

Intermittent theta-burst stimulation to the right dorsolateral prefrontal cortex may increase potentiated startle in healthy individuals.

Repetitive transcranial magnetic stimulation (rTMS) treatment protocols targeting the right dlPFC have been effective in reducing anxiety symptoms comorbid with depression. However, the mechanism behind these effects is unclear. Further, it is unclear whether these results generalize to non-depressed individuals. We conducted a series of studies aimed at understanding the link between anxiety potentiated startle and the right dlPFC, following a previous study suggesting that continuous theta burst stimulation (cTBS) to the right dlPFC can make people more anxious. Based on these results we hypothesized that intermittent TBS (iTBS), which is thought to have opposing effects on plasticity, may reduce anxiety when targeted at the same right dlPFC region. In this double-blinded, cross-over design, 28 healthy subjects underwent 12 study visits over a 4-week period. During each of their 2 stimulation weeks, they received four 600 pulse iTBS sessions (2/day), with a post-stimulation testing session occurring 24 h following the final iTBS session. One week they received active stimulation, one week they received sham. Stimulation weeks were separated by a 1-week washout period and the order of active/sham delivery was counterbalanced across subjects. During the testing session, we induced anxiety using the threat of unpredictable shock and measured anxiety potentiated startle. Contrary to our initial hypothesis, subjects showed increased startle reactivity following active compared to sham stimulation. These results replicate work from our two previous trials suggesting that TMS to the right dlPFC increases anxiety potentiated startle, independent of both the pattern of stimulation and the timing of the post stimulation measure. Although these results confirm a mechanistic link between right dlPFC excitability and startle, capitalizing upon this link for the benefit of patients will require future exploration.

Role of the intraparietal sulcus (IPS) in anxiety and cognition: Opportunities for intervention for anxiety-related disorders

Our objective was to review the literature on the parietal cortex and intraparietal sulcus (IPS) in anxiety-related disorders, as well as opportunities for using neuromodulation to target this region and reduce anxiety. We provide an overview of prior research demonstrating: 1) the importance of the IPS in attention, vigilance, and anxious arousal, 2) the potential for neuromodulation of the IPS to reduce unnecessary attention toward threat and anxious arousal as demonstrated in healthy samples; and 3) limited data on the potential for neuromodulation of the IPS to reduce hyper-attention toward threat and anxious arousal among clinical samples with anxiety-related disorders. Future research should evaluate the efficacy of IPS neuromodulation in fully powered clinical trials, as well as the value in augmenting evidence-based treatments for anxiety with IPS neuromodulation. (AU)

Interleaved TMS/fMRI shows that threat decreases dlPFC-mediated top-down regulation of emotion processing.

Background: The right dorsolateral prefrontal cortex (dlPFC) has been indicated to be a key region in the cognitive regulation of emotion by many previous neuromodulation and neuroimaging studies. However, there is little direct causal evidence supporting this top-down regulation hypothesis. Furthermore, it is unclear whether contextual threat impacts this top-down regulation. By combining TMS/fMRI, this study aimed to uncover the impact of unpredictable threat on TMS-evoked BOLD response in dlPFC-regulated emotional networks. Based on the previous findings linking the dlPFC to the downregulation of emotional network activity, we hypothesized TMS pulses would deactivate activity in anxiety expression regions, and that threat would reduce this top-down regulation. Methods: 44 healthy controls (no current or history of psychiatric disorders) were recruited to take part in a broader study. Subjects completed the neutral, predictable, and unpredictable (NPU) threat task while receiving TMS pulses to either the right dlPFC or a control region. dlPFC targeting was based on data from a separate targeting session, where subjects completed the Sternberg working memory (WM) task inside the MRI scanner. Results: When compared to safe conditions, subjects reported significantly higher levels of anxiety under threat conditions. Additionally, TMS-evoked responses in the left insula (LI), right sensory/motor cortex (RSM), and a region encompassing the bilateral SMA regions (BSMA) differed significantly between safe and threat conditions. There was a significant TMS-evoked deactivation in safe periods that was significantly attenuated in threat periods across all 3 regions. Conclusions: These findings suggest that threat decreases dlPFC-regulated emotional processing by attenuating the top-down control of emotion, like the left insula. Critically, these findings provide support for the use of right dlPFC stimulation as a potential intervention in anxiety disorders.

The maintenance of complex visual scenes in working memory may require activation of working memory manipulation circuits in the dlPFC.

Past research has shown that the bilateral dorsolateral prefrontal cortices (dlPFC) are implicated in both emotional processing as well as cognitive processing, 1,2,3 in addition to working memory 4, 5 . Exactly how these disparate processes interact with one another within the dlPFC is less understood. To explore this, researchers designed an experiment that looked at working memory performance during fMRI under both emotional and non-emotional task conditions. Participants were asked to complete three tasks (letters, neutral images, emotional images) of the Sternberg Sorting Task under one of two trial conditions (sort or maintain). Regions of interest consisted of the left and right dlPFC as defined by brain masks based on NeuroSynth 6 . Results showed a significant main effect of the 'sort' condition on reaction speed for all three trial types, as well as a main effect of task type (letters) on accuracy. In addition, a significant interaction was found between trial type (sort) and task type (letters), but not for either of the picture tasks. These results reveal a discrepancy between BOLD signal and behavioral data, with no significant difference in BOLD activity during image trials being displayed, despite longer response times for every condition. While these results show that the dlPFC is clearly implicated in non-emotional cognitive processing, more research is needed to explain the lack of BOLD activation seen here for similar emotionally valanced tasks, possibly indicating involvement of other brain networks.

Continuous Theta-Burst Stimulation to the Right Dorsolateral Prefrontal Cortex May Increase Potentiated Startle in Healthy Individuals.

Background: Convergent neuroimaging and neuromodulation studies implicate the right dorsolateral prefrontal cortex (dlPFC) as a key region involved in anxiety-cognition interactions. However, neuroimaging data are correlational, and neuromodulation studies often lack appropriate methodological controls. Accordingly, this work was designed to explore the role of right prefrontal cognitive control mechanisms in the expression/regulation of anxiety using continuous theta-burst transcranial magnetic stimulation (cTBS) and threat of unpredictable shock. Based on prior neuromodulation studies, we hypothesized that the right dlPFC contributed to anxiety expression, and that cTBS should downregulate this expression. Methods: We measured potentiated startle and performance on the Sternberg working memory paradigm in 28 healthy participants before and after 4 sessions (600 pulses/session) of active or sham cTBS. Stimulation was individualized to the right dlPFC site of maximal working memory-related activity and optimized using electric-field modeling. Results: Compared with sham cTBS, active cTBS, which is thought to induce long-term depression-like synaptic changes, increased startle during threat of shock, but the effect was similar for predictable and unpredictable threat. As a measure of target (dis)engagement, we also showed that active but not sham cTBS decreased accuracy on the Sternberg task. Conclusions: Counter to our initial hypothesis, cTBS to the right dlPFC made individuals more anxious, rather than less anxious. Although preliminary, these results are unlikely to be due to transient effects of the stimulation, because anxiety was measured 24 hours after cTBS. In addition, these results are unlikely to be due to off-target effects, because target disengagement was evident from the Sternberg performance data.

Role of the intraparietal sulcus (IPS) in anxiety and cognition: Opportunities for intervention for anxiety-related disorders.

Our objective was to review the literature on the parietal cortex and intraparietal sulcus (IPS) in anxiety-related disorders, as well as opportunities for using neuromodulation to target this region and reduce anxiety. We provide an overview of prior research demonstrating: 1) the importance of the IPS in attention, vigilance, and anxious arousal, 2) the potential for neuromodulation of the IPS to reduce unnecessary attention toward threat and anxious arousal as demonstrated in healthy samples; and 3) limited data on the potential for neuromodulation of the IPS to reduce hyper-attention toward threat and anxious arousal among clinical samples with anxiety-related disorders. Future research should evaluate the efficacy of IPS neuromodulation in fully powered clinical trials, as well as the value in augmenting evidence-based treatments for anxiety with IPS neuromodulation.

The role of dlPFC laterality in the expression and regulation of anxiety.

Anxiety disorders are the most common mental health disorder. Therefore, elucidating brain mechanisms implicated in anxiety disorders is important avenue for developing novel treatments and improving care. The dorsolateral prefrontal cortex (dlPFC) is thought to be critically involved in working memory processes (i.e. maintenance, manipulation, suppression, etc.). In addition, there is evidence that this region is involved in anxiety regulation. However, it is unclear how working memory related dlPFC processes contribute to anxiety regulation. Furthermore, we know that laterality plays an important role in working memory related dlPFC processing, however there is no current model of dlPFC mediated anxiety regulation that accounts for potential laterality effects. To address this gap, we propose a potential framework where the dlPFC contributes to emotion regulation via working memory processing. According to this framework, working memory is a fundamental process executed by the dlPFC. However, the domain of content differs across the left and right dlPFC, with the left dlPFC sensitive to primarily verbal content, and the right dlPFC sensitive to primarily non-verbal (affective content). Critically, working memory processes allow for both the retention and suppression of affective information in working memory and the overall net effect of processing on mood will depend on the balance of retention and suppression, the valence of the information being processed (positive vs. negative), and the domain of the information (verbal vs. non-verbal). If accurate, the proposed framework predicts that effects of neuromodulation targeting the dlPFC may be dependent upon the context during which the stimulation is presented. This article is part of the Special Issue on 'Fear, Anxiety and PTSD'.

Differential Impact of Anxious Misery Psychopathology on Multiple Representations of the Functional Connectome.

Background: One aim of characterizing dimensional psychopathology is associating different domains of affective dysfunction with brain circuitry. The functional connectome, as measured by functional magnetic resonance imaging, can be modeled and associated with psychopathology through multiple methods; some methods assess univariate relationships while others summarize broad patterns of activity. It remains unclear whether different dimensions of psychopathology require different representations of the connectome to generate reproducible associations. Methods: Patients experiencing anxious misery symptomology (depression, anxiety, and trauma; n = 192) received resting-state functional magnetic resonance imaging scans. Three modeling approaches (seed-based correlation analysis, edgewise regression, and brain basis set modeling), each relying on increasingly broader representations of the functional connectome, were used to associate connectivity patterns with six data-driven dimensions of psychopathology: anxiety sensitivity, anxious arousal, rumination, anhedonia, insomnia, and negative affect. To protect against overfitting, 50 participants were held out in a testing dataset, leaving 142 participants as training data. Results: Different modeling approaches varied in the extent to which they could model different symptom dimensions: seed-based correlation analysis failed to reproducibly model any symptoms, subsets of the connectome (edgewise regression) were sufficient to model insomnia and anxious arousal, and broad representations of the entire connectome (brain basis set modeling) were necessary to model negative affect and ruminative thought. Conclusions: These results indicate that different methods of representing the functional connectome differ in the degree that they can model different symptom dimensions, highlighting the potential sufficiency of subsets of connections for some dimensions and the necessity of connectome-wide approaches in others.

No increase in inflammation in late-life major depression screened to exclude physical illness.

Depression is a common and debilitating disorder in the elderly. Late-life depression (LLD) has been associated with inflammation and elevated levels of proinflammatory cytokines including interleukin (IL)-1ß, tumor necrosis factor-alpha, and IL-6, but often depressed individuals have comorbid medical conditions that are associated with immune dysregulation. To determine whether depression has an association with inflammation independent of medical illness, 1120 adults were screened to identify individuals who had clinically significant depression but not medical conditions associated with systemic inflammation. In total, 66 patients with LLD screened to exclude medical conditions associated with inflammation were studied in detail along with 26 age-matched controls (HC). At baseline, circulating cytokines were low and similar in LLD and HC individuals. Furthermore, cytokines did not change significantly after treatment with either an antidepressant (escitalopram 20 mg/day) or an antidepressant plus a COX-2 inhibitor or placebo, even though depression scores improved in the non-placebo treatment arms. An analysis of cerebrospinal fluid in a subset of individuals for IL-1ß using an ultrasensitive digital enzyme-linked immunosorbent assay revealed low levels in both LLD and HC at baseline. Our results indicate that depression by itself does not result in systemic or intrathecal elevations in cytokines and that celecoxib does not appear to have an adjunctive antidepressant role in older patients who do not have medical reasons for having inflammation. The negative finding for increased inflammation and the lack of a treatment effect for celecoxib in this carefully screened depressed population taken together with multiple positive results for inflammation in previous studies that did not screen out physical illness support a precision medicine approach to the treatment of depression that takes the medical causes for inflammation into account.

Proof of concept study to develop a novel connectivity-based electric-field modelling approach for individualized targeting of transcranial magnetic stimulation treatment.

Resting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.

Patients with anxiety disorders rely on bilateral dlPFC activation during verbal working memory.

One of the hallmarks of anxiety disorders is impaired cognitive control, affecting working memory (WM). The dorsolateral prefrontal cortex (dlPFC) is critical for WM; however, it is still unclear how dlPFC activity relates to WM impairments in patients. Forty-one healthy volunteers and 32 anxiety (general and/or social anxiety disorder) patients completed the Sternberg WM paradigm during safety and unpredictable shock threat. On each trial, a series of letters was presented, followed by brief retention and response intervals. On low- and high-load trials, subjects retained the series (five and eight letters, respectively) in the original order, while on sort trials, subjects rearranged the series (five letters) in alphabetical order. We sampled the blood oxygenation level-dependent activity during retention using a bilateral anatomical dlPFC mask. Compared to controls, patients showed increased reaction time during high-load trials, greater right dlPFC activity and reduced dlPFC activity during threat. These results suggest that WM performance for patients and controls may rely on distinct patterns of dlPFC activity with patients requiring bilateral dlPFC activity. These results are consistent with reduced efficiency of WM in anxiety patients. This reduced efficiency may be due to an inefficient allocation of dlPFC resources across hemispheres or a decreased overall dlPFC capacity.

Dimensional connectomics of anxious misery, a human connectome study related to human disease: Overview of protocol and data quality.

Disparate diagnostic categories from the Diagnostic and Statistical Manual of Mental Disorders (DSM), including generalized anxiety disorder, major depressive disorder and post-traumatic stress disorder, share common behavioral and phenomenological dysfunctions. While high levels of comorbidity and common features across these disorders suggest shared mechanisms, past research in psychopathology has largely proceeded based on the syndromal taxonomy established by the DSM rather than on a biologically-informed framework of neural, cognitive and behavioral dysfunctions. In line with the National Institute of Mental Health's Research Domain Criteria (RDoC) framework, we present a Human Connectome Study Related to Human Disease that is intentionally designed to generate and test novel, biologically-motivated dimensions of psychopathology. The Dimensional Connectomics of Anxious Misery study is collecting neuroimaging, cognitive and behavioral data from a heterogeneous population of adults with varying degrees of depression, anxiety and trauma, as well as a set of healthy comparators (to date, n = 97 and n = 24, respectively). This sample constitutes a dataset uniquely situated to elucidate relationships between brain circuitry and dysfunctions of the Negative Valence construct of the RDoC framework. We present a comprehensive overview of the eligibility criteria, clinical procedures and neuroimaging methods of our project. After describing our protocol, we present group-level activation maps from task fMRI data and independent components maps from resting state data. Finally, using quantitative measures of neuroimaging data quality, we demonstrate excellent data quality relative to a subset of the Human Connectome Project of Young Adults (n = 97), as well as comparable profiles of cortical thickness from T1-weighted imaging and generalized fractional anisotropy from diffusion weighted imaging. This manuscript presents results from the first 121 participants of our full target 250 participant dataset, timed with the release of this data to the National Institute of Mental Health Data Archive in fall 2020, with the remaining half of the dataset to be released in 2021.