Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders.

Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Finally, we survey cutting-edge research in therapeutic circuit modulation using novel paradigms and next-generation devices.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity.

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.

Exercise modulates the interaction between cognition and anxiety in humans.

Despite interest in exercise as a treatment for anxiety disorders the mechanism behind the anxiolytic effects of exercise is unclear. Two observations motivate the present work. First, engagement of attention control during increased working memory (WM) load can decrease anxiety. Second, exercise can improve attention control. Therefore, exercise could boost the anxiolytic effects of increased WM load via its strengthening of attention control. Anxiety was induced by threat of shock and was quantified with anxiety-potentiated startle (APS). Thirty-five healthy volunteers (19 male, age M = 26.11, SD = 5.52) participated in two types of activity, exercise (biking at 60-70% of heart rate reserve) and control-activity (biking at 10-20% of heart rate reserve). After each activity, participants completed a WM task (n-back) at low- and high-load during safe and threat. Results were not consistent with the hypothesis: exercise vs. control-activity increased APS in high-load (p = .03). However, this increased APS was not accompanied with threat-induced impairment in WM performance (p = .37). Facilitation of both task-relevant stimulus processing and task-irrelevant threat processing, concurrent with prevention of threat interference on cognition, suggests that exercise increases cognitive ability. Future studies should explore how exercise affects the interplay of cognition and anxiety in patients with anxiety disorders.

Effect of Threat on Right dlPFC Activity during Behavioral Pattern Separation.

It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to nonfearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC, but not the hippocampus, showed increased activity for altered images compared with old images when retrieval occurred during periods of threat compared with safety. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together, these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat.SIGNIFICANCE STATEMENT Anxiety and posttraumatic stress disorder patients generalize fear to nonfearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock affects neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat affected activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly, this dlPFC activity predicted performance for these items. Together, these results suggest that the dlPFC is important for discrimination during elevated anxiety and that overgeneralization may reflect a deficit in dlPFC-mediated cognitive control.

Resting state connectivity of the human habenula at ultra-high field.

The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network.

Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat.

BACKGROUND: Anxiety patients exhibit deficits in cognitive tasks that require prefrontal control of attention, including those that tap working memory (WM). However, it is unclear whether these deficits reflect threat-related processes or symptoms of the disorder. Here, we distinguish between these hypotheses by determining the effect of shock threat versus safety on the neural substrates of WM performance in anxiety patients and healthy controls. METHODS: Patients, diagnosed with generalized and/or social anxiety disorder, and controls performed blocks of an N-back WM task during periods of safety and threat of shock. We recorded blood-oxygen-level dependent (BOLD) activity during the task, and investigated the effect of clinical anxiety (patients vs. controls) and threat on WM load-related BOLD activation. RESULTS: Behaviorally, patients showed an overall impairment in both accuracy and reaction time compared to controls, independent of threat. At the neural level, patients showed less WM load-related activation in the dorsolateral prefrontal cortex, a region critical for cognitive control. In addition, patients showed less WM load-related deactivation in the ventromedial prefrontal cortex and posterior cingulate cortex, which are regions of the default mode network. Most importantly, these effects were not modulated by threat. CONCLUSIONS: This work suggests that the cognitive deficits seen in anxiety patients may represent a key component of clinical anxiety, rather than a consequence of threat.

Effect of anxiety on behavioural pattern separation in humans.

Behavioural pattern separation (BPS), the ability to distinguish among similar stimuli based on subtle physical differences, has been used to study the mechanism underlying stimulus generalisation. Fear overgeneralisation is often observed in individuals with posttraumatic stress disorder and other anxiety disorders. However, the relationship between anxiety and BPS remains unclear. The purpose of this study was to determine the effect of anxiety (threat of shock) on BPS, which was assessed across separate encoding and retrieval sessions. Images were encoded/retrieved during blocks of threat or safety in a 2 × 2 factorial design. During retrieval, participants indicated whether images were new, old, or altered. Better accuracy was observed for altered images encoded during periods of threat compared to safety, but only if those images were also retrieved during periods of safety. These results suggest that overgeneralisation in anxiety may be due to altered pattern separation.

Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression during periods of threat and no-threat. We hypothesized that threat would impair performance when subjects had to filter out large numbers of distractors. The VSTM task required subjects to attend to one array of squares while ignoring a separate array. The number of target and distractor squares varied systematically, with high (four squares) and low (two squares) target and distractor conditions. This study comprised two separate experiments. Experiment 1 used startle responses and white noise as to directly measure threat-induced anxiety. Experiment 2 used BOLD to measure brain responses. For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. For Experiment 2, we found that accuracy was affected by threat, such that the distractor load negatively impacted accuracy only in the threat condition. We also found threat-related differences in parietal cortex activity. Overall, these findings suggest that threat affects distractor susceptibility, impairing filtering of distracting information. This effect is possibly mediated by hyperarousal of parietal cortex during threat.

Neuromodulatory transcranial magnetic stimulation (TMS) changes functional connectivity proportional to the electric-field induced by the TMS pulse.

OBJECTIVE: Transcranial magnetic stimulation (TMS) can efficiently and robustly modulate synaptic plasticity, but little is known about how TMS affects functional connectivity (rs-fMRI). Accordingly, this project characterized TMS-induced rsFC changes in depressed patients who received 3 days of left prefrontal intermittent theta burst stimulation (iTBS). METHODS: rs-fMRI was collected from 16 subjects before and after iTBS. Correlation matrices were constructed from the cleaned rs-fMRI data. Electric-field models were conducted and used to predict pre-post changes in rs-fMRI. Site by orientation heatmaps were created for vectors centered on the stimulation site and a control site (contralateral motor cortex). RESULTS: For the stimulation site, there was a clear relationship between both site and coil orientation, and connectivity changes. As distance from the stimulation site increased, prediction accuracy decreased. Similarly, as eccentricity from the optimal orientation increased, prediction accuracy decreased. The systematic effects described above were not apparent in the heatmap centered on the control site. CONCLUSIONS: These results suggest that rs-fMRI following iTBS changes systematically as a function of the distribution of electrical energy delivered from the TMS pulse, as represented by the e-field model. SIGNIFICANCE: This finding lays the groundwork for future studies to individualize TMS targeting based on how predicted rs-fMRI changes might impact psychiatric symptoms.

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.

pNet: A toolbox for personalized functional networks modeling.

Personalized functional networks (FNs) derived from functional magnetic resonance imaging (fMRI) data are useful for characterizing individual variations in the brain functional topography associated with the brain development, aging, and disorders. To facilitate applications of the personalized FNs with enhanced reliability and reproducibility, we develop an open-source toolbox that is user-friendly, extendable, and includes rigorous quality control (QC), featuring multiple user interfaces (graphics, command line, and a step-by-step guideline) and job-scheduling for high performance computing (HPC) clusters. Particularly, the toolbox, named personalized functional network modeling (pNet), takes fMRI inputs in either volumetric or surface type, ensuring compatibility with multiple fMRI data formats, and computes personalized FNs using two distinct modeling methods: one method optimizes the functional coherence of FNs, while the other enhances their independence. Additionally, the toolbox provides HTML-based reports for QC and visualization of personalized FNs. The toolbox is developed in both MATLAB and Python platforms with a modular design to facilitate extension and modification by users familiar with either programming language. We have evaluated the toolbox on two fMRI datasets and demonstrated its effectiveness and user-friendliness with interactive and scripting examples. pNet is publicly available at https://github.com/MLDataAnalytics/pNet.

The interplay of attention and emotion: top-down attention modulates amygdala activation in psychopathy.

Psychopathic behavior has long been attributed to a fundamental deficit in fear that arises from impaired amygdala function. Growing evidence has demonstrated that fear-potentiated startle (FPS) and other psychopathy-related deficits are moderated by focus of attention, but to date, no work on adult psychopathy has examined attentional modulation of the amygdala or concomitant recruitment of relevant attention-related circuitry. Consistent with previous FPS findings, here we report that psychopathy-related differences in amygdala activation appear and disappear as a function of goal-directed attention. Specifically, decreased amygdala activity was observed in psychopathic offenders only when attention was engaged in an alternative goal-relevant task prior to presenting threat-relevant information. Under this condition, psychopaths also exhibited greater activation in selective-attention regions of the lateral prefrontal cortex (LPFC) than did nonpsychopaths, and this increased LPFC activation mediated psychopathy's association with decreased amygdala activation. In contrast, when explicitly attending to threat, amygdala activation did not differ in psychopaths and nonpsychopaths. This pattern of amygdala activation highlights the potential role of LPFC in mediating the failure of psychopathic individuals to process fear and other important information when it is peripheral to the primary focus of goal-directed attention.

The interactive effects of different facets of threat uncertainty and cognitive load in shaping fear and anxiety responses.

A large body of research indicates that exaggerated response to uncertainty of a future threat is at the core of anxiety and related disorders, underscoring the need for a better understanding of the underlying mechanisms. Although behavioral and neuroimaging studies have suggested a close relationship between uncertainty responses and cognitive control, little is known about what elements of uncertainty are more or less vulnerable to cognitive modulation in shaping aversive responses. Leveraging a novel paradigm, an n-back working memory task embedded within a modified threat-of-shock paradigm, we examined how the influences of different facets of uncertainty (i.e., occurrence and timing) on psychophysiological responses were modulated by cognitive load. Psychophysiological responses were assessed using the acoustic startle reflex. Replicating prior work, the effects of cognitive load and temporal unpredictability of threat on startle responses were evident. The effect of occurrence unpredictability appears to depend on other factors. Under low cognitive load, startle response was potentiated when both the occurrence and the timing of threat were predictable. Under high cognitive load, startle response was significantly reduced, especially when a threat context involves uncertainty in both temporal and probability domains. These observations provide a framework for refining the model of fear and anxiety and for understanding the etiology of psychological disorders characterized by maladaptive uncertainty responses.

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.

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'.

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.

Functional connectomics in depression: insights into therapies.

Depression is a common mental disorder characterized by heterogeneous cognitive and behavioral symptoms. The emerging research paradigm of functional connectomics has provided a quantitative theoretical framework and analytic tools for parsing variations in the organization and function of brain networks in depression. In this review, we first discuss recent progress in depression-associated functional connectome variations. We then discuss treatment-specific brain network outcomes in depression and propose a hypothetical model highlighting the advantages and uniqueness of each treatment in relation to the modulation of specific brain network connectivity and symptoms of depression. Finally, we look to the future promise of combining multiple treatment types in clinical practice, using multisite datasets and multimodal neuroimaging approaches, and identifying biological depression subtypes.

Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

BACKGROUND: Work on anxiety related attention control deficits suggests that elevated arousal impacts the ability to filter out distractors. To test this, we designed a task to look at distractor suppression during periods of threat. We administered trials of a visual short-term memory (VSTM) task, during periods of unpredictable threat, and hypothesized that threat would impair performance during trials where subjects were required to filter out large numbers of distractors. METHOD: Experiment 1 involved fifteen healthy participants who completed one study visit. They performed four runs of a VSTM task comprising 32 trials each. Participants were presented with an arrow indicating left or right, followed by an array of squares. They were instructed to remember the target side and disregard the distractors on the off-target side. A subsequent target square was shown, and participants indicated whether it matched one of the previously presented target squares. The trial conditions included 50% matches and 50% mismatches, with an equal distribution of left and right targets. The number of target and distractor squares varied systematically, with high (4 squares) and low (2 squares) target and distractor conditions. Trials alternated between periods of safety and threat, with startle responses recorded using electromyography (EMG) following white noise presentations. Experiment 2 involved twenty-seven healthy participants who completed the same VSTM task inside an MRI scanner during a single study visit. The procedure mirrored that of Experiment 1, except for the absence of white noise presentations. RESULTS: For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. However, results suggested that the white noise probes interfered with performance. For Experiment 2, we found that both accuracy was affected by threat, such that distractor load negatively impacted accuracy only in the threat condition. CONCLUSION: Overall, these findings suggest that threat affects distractor susceptibility during the short-term maintenance of visual information. The presence of threat makes it more difficult to filter out distracting information. We believe that this is related to hyperarousal of parietal cortex, which has been observed during unpredictable threat.

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.