|
1
|
Powers MB, Sa H, D R, Al P, Hl G, Gv C, Jaj S, Warren AM, M D, Naftalis R, Jg W, M F, Mp K, Rl R. Vagus Nerve Stimulation Therapy for Treatment-Resistant PTSD. Brain Stimul 2025:S1935-861X(25)00060-9. [PMID: 40097094 DOI: 10.1016/j.brs.2025.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 03/03/2025] [Accepted: 03/09/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Posttraumatic stress disorder (PTSD) is common and debilitating, and many individuals do not respond to existing therapies. We developed a fundamentally novel neuromodulation-based therapy for treatment-resistant PTSD. This approach is premised on coupling prolonged exposure therapy, a first-line evidence-based cognitive behavioral therapy that directs changes within fear networks, with concurrent delivery of short bursts of vagus nerve stimulation (VNS), which enhance synaptic plasticity. METHODS We performed a first-in-human prospective open-label early feasibility study (EFS) using a next-generation miniaturized system to deliver VNS therapy in nine individuals with moderate to severe treatment-resistant PTSD. All individuals received a standard 12-session course of prolonged exposure therapy combined with VNS. Assessments were performed before, 1 week after, and 1, 3, and 6 months after the completion of therapy. CLINICALTRIALS gov registration: NCT04064762. RESULTS VNS therapy resulted in significant, clinically-meaningful improvements in multiple metrics of PTSD symptoms and severity compared to baseline (CAPS-5, PCL-5, and HADS all p < 0.001 after therapy). These benefits persisted at 6 months after the cessation of therapy, suggesting lasting improvements. All participants showed loss of PTSD diagnosis after completing treatment. No serious or unexpected device-related adverse events were observed. CONCLUSIONS These findings provide a demonstration of the safety and feasibility of VNS therapy for PTSD and highlight the potential of this approach. Collectively, these support the validation of VNS therapy for PTSD in a rigorous randomized controlled trial.
Collapse
Affiliation(s)
- M B Powers
- Baylor Scott & White Research Institute, Dallas, TX 75246 USA.
| | - Hays Sa
- Department of Bioengineering, Erik Jonsson School of Engineering and Computer Science, University of Texas at Dallas, Richardson, TX 75080 USA; Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA.
| | - Rosenfield D
- Department of Psychology, Southern Methodist University, Dallas, TX 75275, USA
| | - Porter Al
- Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA
| | - Gallaway Hl
- Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA
| | - Chauvette Gv
- Baylor Scott & White Research Institute, Dallas, TX 75246 USA
| | - Smits Jaj
- Department of Psychology and Institute for Mental Health Research, The University of Texas at Austin, Austin, TX 78712, USA
| | - A M Warren
- Baylor Scott & White Research Institute, Dallas, TX 75246 USA
| | - Douglas M
- Baylor Scott & White Research Institute, Dallas, TX 75246 USA
| | - R Naftalis
- Department of Surgery, Baylor Scott & White Health, Dallas, TX 75246 USA
| | - Wigginton Jg
- Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA
| | - Foreman M
- Department of Surgery, Baylor Scott & White Health, Dallas, TX 75246 USA
| | - Kilgard Mp
- Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA; Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080 USA
| | - Rennaker Rl
- Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX 75080 USA; Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080 USA
| |
Collapse
|
|
2
|
Cilli SL, Goldberg MA, Cosmo C, Arulpragasam AR, Zand Vakili A, Berlow YA, Philip NS. Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder and Generalized Anxiety Disorder. Curr Top Behav Neurosci 2024. [PMID: 39505816 DOI: 10.1007/7854_2024_540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
Abstract
Posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD) are debilitating psychiatric disorders. While treatments are often effective, many patients do not adequately respond or experience significant side effects. Transcranial magnetic stimulation (TMS) is an emerging approach for treating PTSD and GAD. Several randomized clinical trials have demonstrated that TMS over the dorsolateral prefrontal cortex may be efficacious in reducing psychiatric symptoms; however, results are inconsistent regarding whether any parameter or treatment paradigm is superior. Other RCTs have targeted novel brain regions using newer TMS modalities. Combining TMS with psychotherapy may augment response in patients with PTSD, yet results are inconclusive. Little research has been done on TMS in combination with psychotherapy for GAD, indicating a need for further investigation. Future studies may assess TMS parameter optimization for enhancing effectiveness and improving therapeutic response duration. Identifying response biomarkers through functional magnetic resonance imaging and electroencephalography may offer a means to predict and monitor clinical response as precision methods to improve treatment response.
Collapse
Affiliation(s)
- Samantha L Cilli
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Miriam A Goldberg
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Camila Cosmo
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Amanda R Arulpragasam
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Amin Zand Vakili
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Yosef A Berlow
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Noah S Philip
- Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA.
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
| |
Collapse
|
|
3
|
Tanner J, Orthlieb G, Helms Tillery S. Effect of touch on proprioception: non-invasive trigeminal nerve stimulation suggests general arousal rather than tactile-proprioceptive integration. Front Hum Neurosci 2024; 18:1429843. [PMID: 39469503 PMCID: PMC11513270 DOI: 10.3389/fnhum.2024.1429843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 09/09/2024] [Indexed: 10/30/2024] Open
Abstract
Introduction Proprioceptive error of estimated fingertip position in two-dimensional space is reduced with the addition of tactile stimulation applied at the fingertip. Tactile input does not disrupt the participants' estimation strategy, as the individual error vector maps maintain their overall structure. This relationship suggests integration of proprioception and tactile information improves proprioceptive estimation, which can also be improved with trained mental focus and attention. Task attention and arousal are physiologically regulated by the reticular activating system (RAS), a brainstem circuit including the locus coeruleus (LC). There is direct and indirect evidence that these structures can be modulated by non-invasive trigeminal nerve stimulation (nTNS), providing an opportunity to examine nTNS effect on the integrative relationship of proprioceptive and tactile information. Methods Fifteen right-handed participants performed a simple right-handed proprioceptive estimation task with tactile feedback (touch) and no tactile (hover) feedback. Participants repeated the task after nTNS administration. Stimulation was delivered for 10 min, and stimulation parameters were 3,000 Hz, 50 μs pulse width, with a mean of 7 mA. Error maps across the workspace are generated using polynomial models of the participants' target responses. Results Error maps did not demonstrate significant vector direction changes between conditions for any participant, indicating that nTNS does not disrupt spatial proprioception estimation strategies. A linear mixed model regression with nTNS epoch, tactile condition, and the interaction as factors demonstrated that nTNS reduced proprioceptive error under the hover condition only. Discussion We argue that nTNS does not disrupt spatial proprioceptive error maps but can improve proprioceptive estimation in the absence of tactile feedback. However, we observe no evidence that nTNS enhances tactile-proprioceptive integration as the touch condition does not exhibit significantly reduced error after nTNS.
Collapse
Affiliation(s)
- Justin Tanner
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, United States
| | | | | |
Collapse
|
|
4
|
Roeckner AR. Voice Hearing in Trauma-Related Psychopathology: Continued Exploration of Posttraumatic Stress Disorder Heterogeneity in Functional Neuroimaging Research. BIOLOGICAL PSYCHIATRY. COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2024; 9:973-974. [PMID: 39370231 DOI: 10.1016/j.bpsc.2024.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 10/08/2024]
Affiliation(s)
- Alyssa R Roeckner
- Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Austin, Texas.
| |
Collapse
|
|
5
|
Agathos J, Putica A, Steward T, Felmingham KL, O'Donnell ML, Davey C, Harrison BJ. Neuroimaging evidence of disturbed self-appraisal in posttraumatic stress disorder: A systematic review. Psychiatry Res Neuroimaging 2024; 344:111888. [PMID: 39236486 DOI: 10.1016/j.pscychresns.2024.111888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/23/2024] [Accepted: 08/28/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND The experience of self-hood in posttraumatic stress disorder (PTSD) is altered cognitively and somatically. Dysfunctional negative cognitions about the self are a central mechanism of PTSD symptomatology and treatment. However, while higher-order brain models of disturbances in self-appraisal (i.e., cognitive processes relating to evaluating the self) have been examined in other psychiatric disorders, it is unclear how normative brain function during self-appraisal is impaired in PTSD. METHODS This paper presents a PRISMA systematic review of functional neuroimaging studies (n = 5), to establish a neurobiological account of how self-appraisal processes are disturbed in PTSD. The review was prospectively registered with PROSPERO (CRD42023450509). RESULTS Self-appraisal in PTSD is linked to disrupted activity in core self-processing regions of the Default Mode Network (DMN); and regions involved in cognitive control and emotion regulation, salience and valuation. LIMITATIONS Because self-appraisal in PTSD is relatively under-studied, only a small number of studies could be included for review. Cross-study heterogeneity in analytic approaches and trauma-exposure history prohibited a quantitative meta-analysis. CONCLUSIONS This paper proposes a mechanistic account of how neural dysfunctions may manifest clinically in PTSD and inform targeted selection of appropriate treatment options. We present a research agenda for future work to advance the field.
Collapse
Affiliation(s)
- J Agathos
- Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry Street, Parkville, Victoria 3053, Australia.
| | - A Putica
- Department of Psychology, Counselling and Therapy, La Trobe University, Bundoora, Victoria, Australia
| | - T Steward
- Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry Street, Parkville, Victoria 3053, Australia; Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - K L Felmingham
- Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - M L O'Donnell
- Phoenix Australia Centre for Posttraumatic Mental Health, Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia
| | - C Davey
- Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry Street, Parkville, Victoria 3053, Australia
| | - B J Harrison
- Department of Psychiatry, The University of Melbourne, Level 3, 161 Barry Street, Parkville, Victoria 3053, Australia.
| |
Collapse
|
|
6
|
Callens L, Sienaert P. The Role of Electroconvulsive Therapy in Posttraumatic Stress Disorder: A Systematic Review. J ECT 2024:00124509-990000000-00208. [PMID: 39178058 DOI: 10.1097/yct.0000000000001063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/25/2024]
Abstract
ABSTRACT Posttraumatic stress disorder (PTSD) is associated with a high burden of disability and mortality. Despite standard treatments with antidepressants and/or psychotherapy, remission is often difficult to achieve. Electroconvulsive therapy (ECT) is an effective treatment for mood disorders but is currently not recognized as a treatment modality for PTSD. The literature about its potential role in the management of PTSD is growing. Thus, we aim to systematically review the available evidence for the role of ECT in PTSD.Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines, we performed a systematic literature search from 1958 to December 2023 using PubMed, Embase, Web of Science, Cochrane Central Register of Controlled trials databases, and the Clinicaltrials.gov-registry.Eighteen studies met our inclusion criteria: 1 meta-analysis, 2 randomized control trials, 2 prospective, 4 retrospective studies, 8 case reports, and 2 reviews.Accumulating evidence suggests that ECT might have a beneficial effect on the core symptoms of PTSD with comorbid conditions, such as depression or schizophrenia. Although in some studies, the effect on core PTSD symptoms was not related to an antidepressant effect of ECT, these findings need further replication. Nevertheless, in severe and intractable cases, ECT can be considered, especially in the presence of comorbid depression. Further research in patients without comorbidity is warranted.
Collapse
Affiliation(s)
- Laura Callens
- From the KU Leuven, Department of Neurosciences, Research Group Psychiatry, Neuropsychiatry, Academic Center for ECT and Neuromodulation (AcCENT), University Psychiatric Center KU Leuven, Kortenberg, Belgium
| | | |
Collapse
|
|
7
|
Brown R, Cherian K, Jones K, Wickham R, Gomez R, Sahlem G. Repetitive transcranial magnetic stimulation for post-traumatic stress disorder in adults. Cochrane Database Syst Rev 2024; 8:CD015040. [PMID: 39092744 PMCID: PMC11295260 DOI: 10.1002/14651858.cd015040.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
BACKGROUND The estimated lifetime prevalence of post-traumatic stress disorder (PTSD) in adults worldwide has been estimated at 3.9%. PTSD appears to contribute to alterations in neuronal network connectivity patterns. Current pharmacological and psychotherapeutic treatments for PTSD are associated with inadequate symptom improvement and high dropout rates. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapy involving induction of electrical currents in cortical brain tissue, may be an important treatment option for PTSD to improve remission rates and for people who cannot tolerate existing treatments. OBJECTIVES To assess the effects of repetitive transcranial magnetic stimulation (rTMS) on post-traumatic stress disorder (PTSD) in adults. SEARCH METHODS We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two clinical trials registers. We checked reference lists of relevant articles. The most recent search was January 2023. SELECTION CRITERIA We included randomized controlled trials (RCTs) assessing the efficacy and safety of rTMS versus sham rTMS for PTSD in adults from any treatment setting, including veterans. Eligible trials employed at least five rTMS treatment sessions with both active and sham conditions. We included trials with combination interventions, where a pharmacological agent or psychotherapy was combined with rTMS for both intervention and control groups. We included studies meeting the above criteria regardless of whether they reported any of our outcomes of interest. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed the risk of bias in accordance with Cochrane standards. Primary outcomes were PTSD severity immediately after treatment and serious adverse events during active treatment. Secondary outcomes were PTSD remission, PTSD response, PTSD severity at two follow-up time points after treatment, dropouts, and depression and anxiety severity immediately after treatment. MAIN RESULTS We included 13 RCTs in the review (12 published; 1 unpublished dissertation), with 577 participants. Eight studies included stand-alone rTMS treatment, four combined rTMS with an evidence-based psychotherapeutic treatment, and one investigated rTMS as an adjunctive to treatment-as-usual. Five studies were conducted in the USA, and some predominantly included white, male veterans. Active rTMS probably makes little to no difference to PTSD severity immediately following treatment (standardized mean difference (SMD) -0.14, 95% confidence interval (CI) -0.54 to 0.27; 3 studies, 99 participants; moderate-certainty evidence). We downgraded the certainty of evidence by one level for imprecision (sample size insufficient to detect a difference of medium effect size). We deemed one study as having a low risk of bias and the remaining two as having 'some concerns' for risk of bias. A sensitivity analysis of change-from-baseline scores enabled inclusion of a greater number of studies (6 studies, 252 participants). This analysis yielded a similar outcome to our main analysis but also indicated significant heterogeneity in efficacy across studies, including two studies with a high risk of bias. Reported rates of serious adverse events were low, with seven reported (active rTMS: 6; sham rTMS: 1). The evidence is very uncertain about the effect of active rTMS on serious adverse events (odds ratio (OR) 5.26, 95% CI 0.26 to 107.81; 5 studies, 251 participants; very low-certainty evidence [Active rTMS: 23/1000, sham rTMS: 4/1000]). We downgraded the evidence by one level for risk of bias and two levels for imprecision. We rated four of five studies as having a high risk of bias, and the fifth as 'some concerns' for bias. We were unable to assess PTSD remission immediately after treatment as none of the included studies reported this outcome. AUTHORS' CONCLUSIONS Based on moderate-certainty evidence, our review suggests that active rTMS probably makes little to no difference to PTSD severity immediately following treatment compared to sham stimulation. However, significant heterogeneity in efficacy was detected when we included a larger number of studies in sensitivity analysis. We observed considerable variety in participant and protocol characteristics across studies included in this review. For example, studies tended to be weighted towards inclusion of either male veterans or female civilians. Studies varied greatly in terms of the proportion of the sample with comorbid depression. Study protocols differed in treatment design and stimulation parameters (e.g. session number/duration, treatment course length, stimulation intensity/frequency, location of stimulation). These differences may affect efficacy, particularly when considering interactions with participant factors. Reported rates of serious adverse events were very low (< 1%) across active and sham conditions. It is uncertain whether rTMS increases the risk of serious adverse event occurrence, as our certainty of evidence was very low. Studies frequently lacked clear definitions for serious adverse events, as well as detail on tracking/assessment of data and information on the safety population. Increased reporting on these elements would likely aid the advancement of both research and clinical recommendations of rTMS for PTSD. Currently, there is insufficient evidence to meta-analyze PTSD remission, PTSD treatment response, and PTSD severity at different periods post-treatment. Further research into these outcomes could inform the clinical use of rTMS. Additionally, the relatively large contribution of data from trials that focused on white male veterans may limit the generalizability of our conclusions. This could be addressed by prioritizing recruitment of more diverse participant samples.
Collapse
Affiliation(s)
- Randi Brown
- Clinical Psychology, Palo Alto University, Palo Alto, CA, USA
| | - Kirsten Cherian
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Katherine Jones
- Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK
| | - Robert Wickham
- Department of Psychological Sciences, Northern Arizona University, Flagstaff, AZ, USA
| | - Rowena Gomez
- Clinical Psychology, Palo Alto University, Palo Alto, CA, USA
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Gregory Sahlem
- Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| |
Collapse
|
|
8
|
Liu H, Wang X, Gong T, Xu S, Zhang J, Yan L, Zeng Y, Yi M, Qian Y. Neuromodulation treatments for post-traumatic stress disorder: A systematic review and network meta-analysis covering efficacy, acceptability, and follow-up effects. J Anxiety Disord 2024; 106:102912. [PMID: 39094317 DOI: 10.1016/j.janxdis.2024.102912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/09/2024] [Accepted: 07/26/2024] [Indexed: 08/04/2024]
Abstract
Neuromodulation treatments are novel interventions for post-traumatic stress disorder (PTSD), but their comparative effects at treatment endpoint and follow-up and the influence of moderators remain unclear. We included randomized controlled trials (RCTs) that explored neuromodulation, both as monotherapy and in combination, for treating patients with PTSD. 21 RCTs with 981 PTSD patients were included. The neuromodulation treatment was classified into nine protocols, including subtypes of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), cervical vagal nerve stimulation (VNS), and trigeminal nerve stimulation (TNS). This Bayesian network meta-analysis demonstrated that (1) dual-tDCS (SMD = -1.30), high-frequency repetitive TMS (HF-rTMS) (SMD = -0.97), intermittent theta burst stimulation (iTBS) (SMD = -0.93), and low-frequency repetitive TMS (LF-rTMS) (SMD = -0.76) were associated with significant reductions in PTSD symptoms at the treatment endpoint, but these effects were not significant at follow-up; (2) no difference was found between any active treatment with sham controls; (3) regarding co-morbid additions, synchronized TMS (sTMS) was significantly associated with reductions of depression symptoms at treatment endpoint (SMD = -1.80) and dual-tDCS was associated with reductions in anxiety symptoms at follow-up (SMD = -1.70). Findings suggested dual-tDCS, HF-rTMS, iTBS, and LF-rTMS were effective for reducing PTSD symptoms, while their sustained efficacy was limited.
Collapse
Affiliation(s)
- Haoning Liu
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 51 Huayuan North Road, Haidian District, Beijing 100871, PR China
| | - Xinyi Wang
- Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, PR China
| | - Tingting Gong
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100083, PR China; Key Laboratory for Neuroscience, Ministry of Education / National Health Commission, Peking University, Beijing 100083, PR China
| | - Shi Xu
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100083, PR China; Key Laboratory for Neuroscience, Ministry of Education / National Health Commission, Peking University, Beijing 100083, PR China
| | - Jiachen Zhang
- Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, PR China
| | - Li Yan
- Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, PR China
| | - Yuyi Zeng
- Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, PR China
| | - Ming Yi
- Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing 100083, PR China; Key Laboratory for Neuroscience, Ministry of Education / National Health Commission, Peking University, Beijing 100083, PR China
| | - Ying Qian
- Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 51 Huayuan North Road, Haidian District, Beijing 100871, PR China.
| |
Collapse
|
|
9
|
Koek RJ, Avecillas-Chasin J, Krahl SE, Chen JW, Sultzer DL, Kulick AD, Mandelkern MA, Malpetti M, Gordon HL, Landry HN, Einstein EH, Langevin JP. Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results. J Psychiatr Res 2024; 175:131-139. [PMID: 38733927 PMCID: PMC11419692 DOI: 10.1016/j.jpsychires.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/23/2024] [Accepted: 05/02/2024] [Indexed: 05/13/2024]
Abstract
Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.
Collapse
Affiliation(s)
- Ralph J Koek
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, 760 Westwood Blvd., Room 58-229, Los Angeles, CA, USA, 90095-1759; Psychiatry Service, Mental Health and Behavioral Sciences, Sepulveda Ambulatory Care Center, VAGLAHS, 16111 Plummer St. (116A-11), North Hills, CA, USA, 91343.
| | - Josue Avecillas-Chasin
- Department of Neurosurgery University of Nebraska Medical Center College of Medicine, 42nd and Emile, Omaha, Nebraska USA, 68198.
| | - Scott E Krahl
- Department of Neurosurgery, University of California at Los Angeles (UCLA), 300 Stein Plaza Driveway Suite 420, Los Angeles, CA, 90095, USA; Research Service, VAGLAHS (Clinical Neurophysiology), 16111 Plummer St., Building 1, North Hills, CA, USA, 91343.
| | - James Wy Chen
- Department of Neurology, UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095, USA; Neurology Service (Epilepsy Center of Excellence), VAGLAHS, 11301 Wilshire Blvd, Los Angeles, CA, USA, 90073.
| | - David L Sultzer
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, 760 Westwood Blvd., Room 58-229, Los Angeles, CA, USA, 90095-1759; Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine Institute for Memory Impairments and Neurological Disorders, 3214 Biological Sciences III, Irvine, CA, USA, 92697-4545.
| | - Alexis D Kulick
- Psychology Service (Neuropsychology), Mental Health and Behavioral Sciences, VAGLAHS, 16111 Plummer St. (116A-11) North Hills, CA, USA, 91343.
| | - Mark A Mandelkern
- Imaging Department, VAGLAHS, 11301 Wilshire Blvd, Los Angeles, CA, USA, 90073.
| | - Maura Malpetti
- Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.
| | - Hailey L Gordon
- STEM Pathways at Boston University, 610 Commonwealth Avenue, Room 402, Boston, MA, 02215, USA.
| | | | - Evan H Einstein
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, 760 Westwood Blvd., Room 58-229, Los Angeles, CA, USA, 90095-1759
| | - Jean-Philippe Langevin
- Department of Neurosurgery, UCLA, 300 Stein Plaza Driveway Suite 420, Los Angeles, CA, 90095, USA; Southwest VA Epilepsy Center of Excellence, 11301 Wilshire Blvd, Bldg 500 (10H2), Los Angeles, CA, USA, 90073.
| |
Collapse
|
|
10
|
Rezaei M, Bagheri MMS. Clinical effects of anodal tDCS and identifying response markers in post-traumatic stress disorder (PTSD): An open-label study. Behav Brain Res 2024; 458:114751. [PMID: 37931705 DOI: 10.1016/j.bbr.2023.114751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/08/2023]
Abstract
Transcranial direct current stimulation (tDCS) is a promising treatment for post-traumatic stress disorder (PTSD). However, not all patients respond to this type of treatment. The first aim of present study was to examine efficacy of tDCS for PTSD, depression, anxiety, and anhedonia in patients with PTSD. The second aim of this study was to examine the demographic, clinical, and psychological factors that may predict response to tDCS. In this open-label study, 103 PTSD patients underwent 10 sessions of tDCS (2 mA, 20 min). The anodal and cathodal electrodes were placed over the left dorsolateral prefrontal cortex (DLPFC; F3) and right supra-orbital (FP2) Respectively. Clinical outcome measures included Posttraumatic the Stress Disorder Checklist for DSM-5 (PCL-5), the Beck Depression Inventory (BDI-II), the Beck Anxiety Inventory (BAI), and the Snaith-Hamilton Pleasure Scale (SHAPS). There was an overall significant improvement in symptoms of PTSD, depression, anxiety, and anhedonia from pre- to post-treatment. Results also revealed that non-responders had higher severity at baseline for depression, anxiety, and anhedonia. However, higher severity of depression and anhedonia at baseline predicted response status, with higher severity associated with greater likelihood of non-response. tDCS of the left dLPFC and right supra-orbital appears to have a positive effect in reducing PTSD and related symptoms. These initial results could have an important influence on the adoption of anodal tDCS over the left DLPFC for PTSD, by enabling the early identification of patients who respond to tDCS.
Collapse
Affiliation(s)
- Mehdi Rezaei
- Department of Psychology, Faculty of Educational Sciences and Psychology, University of Birjand, Birjand, Iran.
| | | |
Collapse
|
|
11
|
Rissardo JP, Vora NM, Tariq I, Mujtaba A, Caprara ALF. Deep Brain Stimulation for the Management of Refractory Neurological Disorders: A Comprehensive Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1991. [PMID: 38004040 PMCID: PMC10673515 DOI: 10.3390/medicina59111991] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/04/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023]
Abstract
In recent decades, deep brain stimulation (DBS) has been extensively studied due to its reversibility and significantly fewer side effects. DBS is mainly a symptomatic therapy, but the stimulation of subcortical areas by DBS is believed to affect the cytoarchitecture of the brain, leading to adaptability and neurogenesis. The neurological disorders most commonly studied with DBS were Parkinson's disease, essential tremor, obsessive-compulsive disorder, and major depressive disorder. The most precise approach to evaluating the location of the leads still relies on the stimulus-induced side effects reported by the patients. Moreover, the adequate voltage and DBS current field could correlate with the patient's symptoms. Implantable pulse generators are the main parts of the DBS, and their main characteristics, such as rechargeable capability, magnetic resonance imaging (MRI) safety, and device size, should always be discussed with patients. The safety of MRI will depend on several parameters: the part of the body where the device is implanted, the part of the body scanned, and the MRI-tesla magnetic field. It is worth mentioning that drug-resistant individuals may have different pathophysiological explanations for their resistance to medications, which could affect the efficacy of DBS therapy. Therefore, this could explain the significant difference in the outcomes of studies with DBS in individuals with drug-resistant neurological conditions.
Collapse
Affiliation(s)
| | - Nilofar Murtaza Vora
- Medicine Department, Terna Speciality Hospital and Research Centre, Navi Mumbai 400706, India;
| | - Irra Tariq
- Medicine Department, United Medical & Dental College, Karachi 75600, Pakistan;
| | - Amna Mujtaba
- Medicine Department, Karachi Medical & Dental College, Karachi 74700, Pakistan;
| | | |
Collapse
|
|
12
|
Yuan H, Liu B, Li F, Jin Y, Zheng S, Ma Z, Wu Z, Chen C, Zhang L, Gu Y, Gao X, Yang Q. Effects of intermittent theta-burst transcranial magnetic stimulation on post-traumatic stress disorder symptoms: A randomized controlled trial. Psychiatry Res 2023; 329:115533. [PMID: 37826976 DOI: 10.1016/j.psychres.2023.115533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/04/2023] [Accepted: 10/06/2023] [Indexed: 10/14/2023]
Abstract
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness, which can be alleviated by transcranial magnetic stimulation (TMS). Intermittent theta burst stimulation (iTBS), a newer form of repetitive transcranial magnetic stimulation (rTMS), offers the advantage of shorter treatment sessions compared to the standard 10 Hz rTMS treatment. In order to compare the two forms of TMS, we enrolled 75 participants aged between 18 and 55 years who presented with (PCL-C) scale score of at least 50. Participants were randomly assigned to groups in a ratio of 1:1:1, receiving either 10 Hz rTMS, iTBS, or sham-controlled iTBS. Participants in the two treatment groups underwent 15 therapies which consisted of 1800 pulses and targeted the right dorsolateral prefrontal cortex (DLPFC). The main outcomes included changes in scores on the PCL-C and the Post-Traumatic Growth Inventory (PTGI). After intervention, the PCL-C and PTGI scores in iTBS and rTMS groups were significantly different from those in sham-controlled iTBS group. No significant differences in PCL-C and PTGI were found between the two active treatment groups. ITBS, with a shorter treatment duration, can effectively improve the symptoms of PTSD, with no significant difference in effect from that of rTMS. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of iTBS in PTSD.
Collapse
Affiliation(s)
- Huiling Yuan
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China; Department of Psychiatry, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, China
| | - Bin Liu
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Fengzhan Li
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Yinchuan Jin
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Shi Zheng
- State key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China
| | - Zhujing Ma
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Zhongying Wu
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Chen Chen
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Liang Zhang
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Yanan Gu
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Xing Gao
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China
| | - Qun Yang
- Department of Military Medical Psychology, Air Force Medical University, Xi'an 710032, China.
| |
Collapse
|
|
13
|
Mercante B, Enrico P, Deriu F. Cognitive Functions following Trigeminal Neuromodulation. Biomedicines 2023; 11:2392. [PMID: 37760833 PMCID: PMC10525298 DOI: 10.3390/biomedicines11092392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/13/2023] [Accepted: 08/25/2023] [Indexed: 09/29/2023] Open
Abstract
Vast scientific effort in recent years have been focused on the search for effective and safe treatments for cognitive decline. In this regard, non-invasive neuromodulation has gained increasing attention for its reported effectiveness in promoting the recovery of multiple cognitive domains after central nervous system damage. In this short review, we discuss the available evidence supporting a possible cognitive effect of trigeminal nerve stimulation (TNS). In particular, we ask that, while TNS has been widely and successfully used in the treatment of various neuropsychiatric conditions, as far as research in the cognitive field is concerned, where does TNS stand? The trigeminal nerve is the largest cranial nerve, conveying the sensory information from the face to the trigeminal sensory nuclei, and from there to the thalamus and up to the somatosensory cortex. On these bases, a bottom-up mechanism has been proposed, positing that TNS-induced modulation of the brainstem noradrenergic system may affect the function of the brain networks involved in cognition. Nevertheless, despite the promising theories, to date, the use of TNS for cognitive empowering and/or cognitive decline treatment has several challenges ahead of it, mainly due to little uniformity of the stimulation protocols. However, as the field continues to grow, standardization of practice will allow for data comparisons across studies, leading to optimized protocols targeting specific brain circuitries, which may, in turn, influence cognition in a designed manner.
Collapse
Affiliation(s)
- Beniamina Mercante
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (B.M.); (P.E.)
| | - Paolo Enrico
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (B.M.); (P.E.)
| | - Franca Deriu
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (B.M.); (P.E.)
- AOU Sassari, Unit of Endocrinology, Nutritional and Metabolic Disorders, 07100 Sassari, Italy
| |
Collapse
|
|
14
|
Lieberman JM, Rabellino D, Densmore M, Frewen PA, Steyrl D, Scharnowski F, Théberge J, Neufeld RWJ, Schmahl C, Jetly R, Narikuzhy S, Lanius RA, Nicholson AA. Posterior cingulate cortex targeted real-time fMRI neurofeedback recalibrates functional connectivity with the amygdala, posterior insula, and default-mode network in PTSD. Brain Behav 2023; 13:e2883. [PMID: 36791212 PMCID: PMC10013955 DOI: 10.1002/brb3.2883] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Alterations within large-scale brain networks-namely, the default mode (DMN) and salience networks (SN)-are present among individuals with posttraumatic stress disorder (PTSD). Previous real-time functional magnetic resonance imaging (fMRI) and electroencephalography neurofeedback studies suggest that regulating posterior cingulate cortex (PCC; the primary hub of the posterior DMN) activity may reduce PTSD symptoms and recalibrate altered network dynamics. However, PCC connectivity to the DMN and SN during PCC-targeted fMRI neurofeedback remains unexamined and may help to elucidate neurophysiological mechanisms through which these symptom improvements may occur. METHODS Using a trauma/emotion provocation paradigm, we investigated psychophysiological interactions over a single session of neurofeedback among PTSD (n = 14) and healthy control (n = 15) participants. We compared PCC functional connectivity between regulate (in which participants downregulated PCC activity) and view (in which participants did not exert regulatory control) conditions across the whole-brain as well as in a priori specified regions-of-interest. RESULTS During regulate as compared to view conditions, only the PTSD group showed significant PCC connectivity with anterior DMN (dmPFC, vmPFC) and SN (posterior insula) regions, whereas both groups displayed PCC connectivity with other posterior DMN areas (precuneus/cuneus). Additionally, as compared with controls, the PTSD group showed significantly greater PCC connectivity with the SN (amygdala) during regulate as compared to view conditions. Moreover, linear regression analyses revealed that during regulate as compared to view conditions, PCC connectivity to DMN and SN regions was positively correlated to psychiatric symptoms across all participants. CONCLUSION In summary, observations of PCC connectivity to the DMN and SN provide emerging evidence of neural mechanisms underlying PCC-targeted fMRI neurofeedback among individuals with PTSD. This supports the use of PCC-targeted neurofeedback as a means by which to recalibrate PTSD-associated alterations in neural connectivity within the DMN and SN, which together, may help to facilitate improved emotion regulation abilities in PTSD.
Collapse
Affiliation(s)
- Jonathan M. Lieberman
- Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonOntarioCanada
- Imaging, Lawson Health Research InstituteLondonOntarioCanada
| | - Daniela Rabellino
- Imaging, Lawson Health Research InstituteLondonOntarioCanada
- Department of NeuroscienceWestern UniversityLondonOntarioCanada
| | - Maria Densmore
- Imaging, Lawson Health Research InstituteLondonOntarioCanada
- Department of PsychiatryWestern UniversityLondonOntarioCanada
| | - Paul A. Frewen
- Department of NeuroscienceWestern UniversityLondonOntarioCanada
- Department of PsychologyWestern UniversityLondonOntarioCanada
| | - David Steyrl
- Department of Cognition, Emotion, and Methods in PsychologyUniversity of ViennaViennaAustria
| | - Frank Scharnowski
- Department of Cognition, Emotion, and Methods in PsychologyUniversity of ViennaViennaAustria
| | - Jean Théberge
- Imaging, Lawson Health Research InstituteLondonOntarioCanada
- Department of PsychiatryWestern UniversityLondonOntarioCanada
- Department of Medical BiophysicsWestern UniversityLondonOntarioCanada
- Department of Diagnostic ImagingSt. Joseph's HealthcareLondonOntarioCanada
| | - Richard W. J. Neufeld
- Department of NeuroscienceWestern UniversityLondonOntarioCanada
- Department of PsychiatryWestern UniversityLondonOntarioCanada
- Department of PsychologyWestern UniversityLondonOntarioCanada
- Department of PsychologyUniversity of British Columbia, OkanaganKelownaBritish ColumbiaCanada
| | - Christian Schmahl
- Department of Psychosomatic Medicine and PsychotherapyCentral Institute of Mental Health MannheimHeidelberg UniversityHeidelbergGermany
| | - Rakesh Jetly
- The Institute of Mental Health ResearchUniversity of Ottawa, Royal Ottawa HospitalOntarioCanada
| | - Sandhya Narikuzhy
- Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonOntarioCanada
| | - Ruth A. Lanius
- Imaging, Lawson Health Research InstituteLondonOntarioCanada
- Department of NeuroscienceWestern UniversityLondonOntarioCanada
- Department of PsychiatryWestern UniversityLondonOntarioCanada
- Homewood Research InstituteGuelphOntarioCanada
| | - Andrew A. Nicholson
- Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonOntarioCanada
- Department of Cognition, Emotion, and Methods in PsychologyUniversity of ViennaViennaAustria
- Department of Medical BiophysicsWestern UniversityLondonOntarioCanada
- The Institute of Mental Health ResearchUniversity of Ottawa, Royal Ottawa HospitalOntarioCanada
- Homewood Research InstituteGuelphOntarioCanada
- Atlas Institute for Veterans and FamiliesOttawaOntarioCanada
- School of PsychologyUniversity of OttawaOttawaCanada
| |
Collapse
|
|
15
|
Ahnood A, Chambers A, Gelmi A, Yong KT, Kavehei O. Semiconducting electrodes for neural interfacing: a review. Chem Soc Rev 2023; 52:1491-1518. [PMID: 36734845 DOI: 10.1039/d2cs00830k] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In the past 50 years, the advent of electronic technology to directly interface with neural tissue has transformed the fields of medicine and biology. Devices that restore or even replace impaired bodily functions, such as deep brain stimulators and cochlear implants, have ushered in a new treatment era for previously intractable conditions. Meanwhile, electrodes for recording and stimulating neural activity have allowed researchers to unravel the vast complexities of the human nervous system. Recent advances in semiconducting materials have allowed effective interfaces between electrodes and neuronal tissue through novel devices and structures. Often these are unattainable using conventional metallic electrodes. These have translated into advances in research and treatment. The development of semiconducting materials opens new avenues in neural interfacing. This review considers this emerging class of electrodes and how it can facilitate electrical, optical, and chemical sensing and modulation with high spatial and temporal precision. Semiconducting electrodes have advanced electrically based neural interfacing technologies owing to their unique electrochemical and photo-electrochemical attributes. Key operation modalities, namely sensing and stimulation in electrical, biochemical, and optical domains, are discussed, highlighting their contrast to metallic electrodes from the application and characterization perspective.
Collapse
Affiliation(s)
- Arman Ahnood
- School of Engineering, RMIT University, VIC 3000, Australia
| | - Andre Chambers
- School of Physics, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Amy Gelmi
- School of Science, RMIT University, VIC 3000, Australia
| | - Ken-Tye Yong
- School of Biomedical Engineering, University of Sydney, Sydney, NSW 2006, Australia.,The University of Sydney Nano Institute, Sydney, NSW 2006, Australia.
| | - Omid Kavehei
- School of Biomedical Engineering, University of Sydney, Sydney, NSW 2006, Australia.,The University of Sydney Nano Institute, Sydney, NSW 2006, Australia.
| |
Collapse
|
|
16
|
Muacevic A, Adler JR. Application of Deep Brain Stimulation in Refractory Post-Traumatic Stress Disorder. Cureus 2023; 15:e33780. [PMID: 36819333 PMCID: PMC9928537 DOI: 10.7759/cureus.33780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/14/2023] [Indexed: 01/16/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) is a mental disorder that produces crippling anxiety and occurs in response to an extreme, traumatic stressor. Compared to the prevalence of PTSD in the general population, the prevalence of PTSD in at-risk populations (e.g., army veterans, those affected by environmental calamities, and others) can reach up to threefold. The conventional treatment of PTSD involves using SSRIs (serotonin reuptake inhibitors) and other anti-depressants along with psychotherapy such as debriefing and CBT (cognitive behavioral therapy). Due to increasing resistance to conventional treatment, more novel treatment options, such as stellate ganglion block shots and neuromodulation, are being explored. These neuromodulation techniques include transcranial magnetic stimulation (TMS), transcranial direct current stimulation (TDS), and deep brain stimulation (DBS). The rationale behind employing these techniques in refractory PTSD is the altered neurocircuitry seen in PTSD patients, which can be visualized on imaging. Studies involving the use of DBS for PTSD primarily target specific areas in the brain: the amygdala, the prefrontal cortex, the hippocampus, and the hypothalamus. This article aims to provide a brief overview of the various neuromodulation techniques currently employed in the management of treatment-resistant PTSD and an in-depth review of the available literature on animal models in which DBS for PTSD has been researched. We also shed light on the human clinical trials conducted for the same.
Collapse
|
|
17
|
Seligowski AV, Webber TK, Marvar PJ, Ressler KJ, Philip NS. Involvement of the brain-heart axis in the link between PTSD and cardiovascular disease. Depress Anxiety 2022; 39:663-674. [PMID: 35708302 PMCID: PMC9588548 DOI: 10.1002/da.23271] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/22/2022] [Accepted: 05/13/2022] [Indexed: 01/27/2023] Open
Abstract
Posttraumatic stress disorder (PTSD) has long been associated with a heightened risk of cardiovascular disease (CVD). A number of mechanisms have been implicated to underlie this brain-heart axis relationship, such as altered functioning of the autonomic nervous system and increased systemic inflammation. While neural alterations have repeatedly been observed in PTSD, they are rarely considered in the PTSD-CVD link. The brain-heart axis is a pathway connecting frontal and limbic brain regions to the brainstem and periphery via the autonomic nervous system and it may be a promising model for understanding CVD risk in PTSD given its overlap with PTSD neural deficits. We first provide a summary of the primary mechanisms implicated in the association between PTSD and CVD. We then review the brain-heart axis and its relevance to PTSD, as well as findings from PTSD trials demonstrating that a number of PTSD treatments have effects on areas of the brain-heart axis. Finally, we discuss sex considerations in the PTSD-CVD link. A critical next step in this study is to determine if PTSD treatments that affect the brain-heart axis (e.g., brain stimulation that improves autonomic function) also reduce the risk of CVD.
Collapse
Affiliation(s)
- Antonia V. Seligowski
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- McLean Hospital, Belmont, MA, USA
| | | | | | - Kerry J. Ressler
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- McLean Hospital, Belmont, MA, USA
| | - Noah S. Philip
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School, of Brown University, Providence, RI, USA
| |
Collapse
|
|
18
|
Concerto C, Lanza G, Fisicaro F, Pennisi M, Rodolico A, Torrisi G, Bella R, Aguglia E. Repetitive transcranial magnetic stimulation for post-traumatic stress disorder: Lights and shadows. World J Clin Cases 2022; 10:5929-5933. [PMID: 35979128 PMCID: PMC9258373 DOI: 10.12998/wjcc.v10.i17.5929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 01/27/2022] [Accepted: 05/12/2022] [Indexed: 02/06/2023] Open
Abstract
We have read with interest the publication that describes the available data related to the use of neuromodulation strategies for the treatment of post-traumatic stress disorder (PTSD). Despite treatment advances, however, a substantial proportion of PTSD patients receiving psychological and/or pharmacological treatment do not reach an adequate clinical response. In their paper, the authors draw attention to the current understanding of the use of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for PTSD. Most of the previous studies indeed applied both inhibitory (1 Hz) and excitatory (> 1 Hz, up to 20 Hz) rTMS to the right and/or left dorsolateral prefrontal cortex. Despite larger therapeutic effects observed when high-frequency stimulation was applied, the question of which side and frequency of stimulation is the most successful is still debated. The authors also reported on the after-effect of rTMS related to neuroplasticity and identified the intermittent theta burst stimulation as a technique of particular interest because of it showed the most effective improvement on PTSD symptoms. However, although numerous studies have highlighted the possible beneficial use of rTMS protocols for PTSD, the exact mechanism of action remains unclear. In their conclusions, the authors stated that rTMS has been demonstrated to be effective for the treatment of PTSD symptoms. Nevertheless, we believe that further research with homogeneous samples, standardized protocols, and objective outcome measures is needed to identify specific therapeutic targets and to better define significant changes when active and sham stimulation procedures are compared.
Collapse
Affiliation(s)
- Carmen Concerto
- Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Catania 95124, Italy
| | - Giuseppe Lanza
- Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
- Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina 94018, Italy
| | - Francesco Fisicaro
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Manuela Pennisi
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy
| | - Alessandro Rodolico
- Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Catania 95124, Italy
| | - Giulia Torrisi
- Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Catania 95124, Italy
| | - Rita Bella
- Department of Medical and Surgical Sciences and Advanced Technologies “G. F. Ingrassia”, University of Catania, Catania 95123, Italy
| | - Eugenio Aguglia
- Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Catania 95124, Italy
| |
Collapse
|
|
19
|
Du J, Diao H, Zhou X, Zhang C, Chen Y, Gao Y, Wang Y. Post-traumatic stress disorder: a psychiatric disorder requiring urgent attention. MEDICAL REVIEW (BERLIN, GERMANY) 2022; 2:219-243. [PMID: 37724188 PMCID: PMC10388753 DOI: 10.1515/mr-2022-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/21/2022] [Indexed: 09/20/2023]
Abstract
Post-traumatic stress disorder (PTSD) is a severe and heterogenous psychiatric disorder that was first defined as a mental disorder in 1980. Currently, the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and the International Classification of Diseases 11th Edition (ICD-11) offer the most widely accepted diagnostic guidelines for PTSD. In both diagnostic categories, experiencing a traumatic event (TE) is the necessary criterion for diagnosing PTSD. The TEs described in the DSM-5 include actual or threatened death, serious injury, sexual violence, and other extreme stressors, either directly or indirectly. More than 70% of adults worldwide are exposed to a TE at least once in their lifetime, and approximately 10% of individuals develop PTSD after experiencing a TE. The important features of PTSD are intrusion or re-experiencing fear memories, pervasive sense of threat, active avoidance, hyperarousal symptoms, and negative alterations of cognition and mood. Individuals with PTSD have high comorbidities with other psychiatric diseases, including major depressive disorder, generalized anxiety disorder, and substance use disorder. Multiple lines of evidence suggest that the pathophysiology of PTSD is complex, involving abnormal neural circuits, molecular mechanisms, and genetic mechanisms. A combination of both psychotherapy and pharmacotherapy is used to treat PTSD, but has limited efficacy in patients with refractory PTSD. Because of the high prevalence, heavy burden, and limited treatments, PTSD is a psychiatric disorder that requires urgent attention. In this review, we summarize and discuss the diagnosis, prevalence, TEs, pathophysiology, and treatments of PTSD and draw attention to its prevention.
Collapse
Affiliation(s)
- Jun Du
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Huapeng Diao
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Xiaojuan Zhou
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Chunkui Zhang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Yifei Chen
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Yan Gao
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Yizheng Wang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China
| |
Collapse
|
|
20
|
Assouline A, Mendelsohn A, Reshef A. Memory-directed acupuncture as a neuromodulatory treatment for PTSD: Theory, clinical model and case studies. Transl Psychiatry 2022; 12:110. [PMID: 35296636 PMCID: PMC8927413 DOI: 10.1038/s41398-022-01876-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 11/25/2022] Open
Abstract
Posttraumatic stress disorder (PTSD) poses an ongoing challenge to society, to health systems, and to the trauma victims themselves. Today PTSD is often considered an incurable chronic problem that lacks effective treatment. While PTSD is closely related to memory, it also affects many physiological systems. PTSD is usually treated with medications and psychotherapy with moderate success, leaving a substantial proportion of patients with enduring distress and disability. Therefore, a search for better treatment options is vital. In this paper, we propose a model in which a conversation-based technique is integrated with bodily manipulation through acupuncture. This approach first emerged in clinical experience showing intriguing results from treating PTSD patients using acupuncture as a main strategy. Its theoretical foundations derive from the clinic and rely on contemporary neuroscience's understanding of memory consolidation and reconsolidation processes. Research shows that acupuncture can have potentially positive effects at three levels: (a) achieving a balance between sympathetic and parasympathetic neural activity; (b) reducing activation in the limbic system, hence inducing a calming effect; (c) reshaping the functional connectivity map within important and relevant cortical regions that encompass the default-mode network. We suggest that coupling traumatic memory retrieval leading to reconsolidation, combined with acupuncture, offers considerable potential for positive clinical improvement in patients with PTSD. This may explain the positive results of the described case studies and can pave the path for future advances in research and treatment in this field.
Collapse
Affiliation(s)
- Amir Assouline
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
- Institute for Information Processing and Decision Making, University of Haifa, Haifa, Israel.
| | - Avi Mendelsohn
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel
- Institute for Information Processing and Decision Making, University of Haifa, Haifa, Israel
| | - Alon Reshef
- Ha'Emek Medical Center, Department of Psychiatry, Afula, Israel
| |
Collapse
|
|
21
|
Meeres J, Hariz M. Deep Brain Stimulation for Post-Traumatic Stress Disorder: A Review of the Experimental and Clinical Literature. Stereotact Funct Neurosurg 2022; 100:143-155. [PMID: 34979516 DOI: 10.1159/000521130] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/12/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Up to 30% of patients with post-traumatic stress disorder (PTSD), especially combat veterans, remain refractory to conventional treatment. For them, deep brain stimulation (DBS) has been suggested. Here, we review the literature on animal models of PTSD in which DBS has been used to treat PTSD-type behavior, and we review and discuss patient reports of DBS for PTSD. METHODS A broad search was performed to find experimental animal articles and clinical reports on PubMed, Ovid MEDLINE, Cochrane Library, and PsycINFO, using combinations and variations of search words pertinent to DBS and PTSD. RESULTS The search yielded 30 articles, 24 on DBS in rat models of PTSD, and 6 publications between 2016 and 2020 reporting on a total of 3 patients. DBS in rat models targeted 4 brain areas: medial prefrontal cortex (mPFC), ventral striatum, amygdala, and hippocampus. Clinical publications reported on 2 male combat veterans who received DBS in basolateral amygdala, and 1 female with PTSD due to domestic abuse, who received DBS of mPFC. All 3 patients benefitted to various extents from DBS, at follow-ups of 4 years, 6 months, and 7 months, respectively. CONCLUSIONS PTSD is the only potential clinical indication for DBS that shows extensive animal research prior to human applications. Nevertheless, DBS for PTSD remains highly investigational. Despite several years of government funding of DBS research in view of treating severe PTSD in combat veterans, ethical dilemmas, recruitment difficulties, and issues related to use of DBS in such a complex and heterogenous disorder remain prevalent.
Collapse
Affiliation(s)
- Jennifer Meeres
- Unit of Functional Neurosurgery, UCL Institute of Neurology, London, United Kingdom
| | - Marwan Hariz
- Unit of Functional Neurosurgery, UCL Institute of Neurology, London, United Kingdom.,Department of Clinical Neuroscience, Umeå University, Umeå, Sweden
| |
Collapse
|
|
22
|
Arulpragasam AR, van 't Wout-Frank M, Barredo J, Faucher CR, Greenberg BD, Philip NS. Low Intensity Focused Ultrasound for Non-invasive and Reversible Deep Brain Neuromodulation-A Paradigm Shift in Psychiatric Research. Front Psychiatry 2022; 13:825802. [PMID: 35280168 PMCID: PMC8907584 DOI: 10.3389/fpsyt.2022.825802] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/18/2022] [Indexed: 01/15/2023] Open
Abstract
This article describes an emerging non-invasive neuromodulatory technology, called low intensity focused ultrasound (LIFU). This technology is potentially paradigm shifting as it can deliver non-invasive and reversible deep brain neuromodulation through acoustic sonication, at millimeter precision. Low intensity focused ultrasound's spatial precision, yet non-invasive nature sets it apart from current technologies, such as transcranial magnetic or electrical stimulation and deep brain stimulation. Additionally, its reversible effects allow for the causal study of deep brain regions implicated in psychiatric illness. Studies to date have demonstrated that LIFU can safely modulate human brain activity at cortical and subcortical levels. Due to its novelty, most researchers and clinicians are not aware of the potential applications and promise of this technique, underscoring the need for foundational papers to introduce the community to LIFU. This mini-review and synthesis of recent advances examines several key papers on LIFU administered to humans, describes the population under study, parameters used, and relevant findings that may guide future research. We conclude with a concise overview of some of the more pressing questions to date, considerations when interpreting new data from an emerging field, and highlight the opportunities and challenges in this exciting new area of study.
Collapse
Affiliation(s)
- Amanda R Arulpragasam
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States.,Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States
| | - Mascha van 't Wout-Frank
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States.,Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States.,COBRE Center for Neuromodulation, Butler Hospital, Providence, RI, United States
| | - Jennifer Barredo
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States.,Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States.,COBRE Center for Neuromodulation, Butler Hospital, Providence, RI, United States
| | - Christiana R Faucher
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States
| | - Benjamin D Greenberg
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States.,Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States.,COBRE Center for Neuromodulation, Butler Hospital, Providence, RI, United States
| | - Noah S Philip
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, United States.,Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States.,COBRE Center for Neuromodulation, Butler Hospital, Providence, RI, United States
| |
Collapse
|
|
23
|
Nicholson AA, Rabellino D, Densmore M, Frewen PA, Steryl D, Scharnowski F, Théberge J, Neufeld RWJ, Schmahl C, Jetly R, Lanius RA. Differential mechanisms of posterior cingulate cortex downregulation and symptom decreases in posttraumatic stress disorder and healthy individuals using real-time fMRI neurofeedback. Brain Behav 2022; 12:e2441. [PMID: 34921746 PMCID: PMC8785646 DOI: 10.1002/brb3.2441] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/25/2021] [Accepted: 11/09/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Intrinsic connectivity networks, including the default mode network (DMN), are frequently disrupted in individuals with posttraumatic stress disorder (PTSD). The posterior cingulate cortex (PCC) is the main hub of the posterior DMN, where the therapeutic regulation of this region with real-time fMRI neurofeedback (NFB) has yet to be explored. METHODS We investigated PCC downregulation while processing trauma/stressful words over 3 NFB training runs and a transfer run without NFB (total n = 29, PTSD n = 14, healthy controls n = 15). We also examined the predictive accuracy of machine learning models in classifying PTSD versus healthy controls during NFB training. RESULTS Both the PTSD and healthy control groups demonstrated reduced reliving symptoms in response to trauma/stressful stimuli, where the PTSD group additionally showed reduced symptoms of distress. We found that both groups were able to downregulate the PCC with similar success over NFB training and in the transfer run, although downregulation was associated with unique within-group decreases in activation within the bilateral dmPFC, bilateral postcentral gyrus, right amygdala/hippocampus, cingulate cortex, and bilateral temporal pole/gyri. By contrast, downregulation was associated with increased activation in the right dlPFC among healthy controls as compared to PTSD. During PCC downregulation, right dlPFC activation was negatively correlated to PTSD symptom severity scores and difficulties in emotion regulation. Finally, machine learning algorithms were able to classify PTSD versus healthy participants based on brain activation during NFB training with 80% accuracy. CONCLUSIONS This is the first study to investigate PCC downregulation with real-time fMRI NFB in both PTSD and healthy controls. Our results reveal acute decreases in symptoms over training and provide converging evidence for EEG-NFB targeting brain networks linked to the PCC.
Collapse
Affiliation(s)
- Andrew A Nicholson
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.,Department of Cognition, Emotion, and Methods in Psychology, University of Vienna, Vienna, Austria
| | - Daniela Rabellino
- Department of Neuroscience, Western University, London, Ontario, Canada.,Imaging, Lawson Health Research Institute, London, Ontario, Canada
| | - Maria Densmore
- Imaging, Lawson Health Research Institute, London, Ontario, Canada.,Department of Psychiatry, Western University, London, Ontario, Canada
| | - Paul A Frewen
- Department of Neuroscience, Western University, London, Ontario, Canada.,Department of Psychology, Western University, London, Ontario, Canada
| | - David Steryl
- Department of Cognition, Emotion, and Methods in Psychology, University of Vienna, Vienna, Austria
| | - Frank Scharnowski
- Department of Cognition, Emotion, and Methods in Psychology, University of Vienna, Vienna, Austria
| | - Jean Théberge
- Imaging, Lawson Health Research Institute, London, Ontario, Canada.,Department of Medical Biophysics, Western University, London, Ontario, Canada.,Department of Psychiatry, Western University, London, Ontario, Canada.,Department of Diagnostic Imaging, St. Joseph's Healthcare, London, Ontario, Canada
| | - Richard W J Neufeld
- Department of Neuroscience, Western University, London, Ontario, Canada.,Department of Psychology, Western University, London, Ontario, Canada.,Department of Psychiatry, Western University, London, Ontario, Canada.,Department of Psychology, University of British Columbia, Okanagan, Kelowna, British Columbia, Canada
| | - Christian Schmahl
- Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Heidelberg University, Heidelberg, Germany
| | - Rakesh Jetly
- Canadian Forces, Health Services, Ottawa, Ontario, Canada
| | - Ruth A Lanius
- Department of Neuroscience, Western University, London, Ontario, Canada.,Imaging, Lawson Health Research Institute, London, Ontario, Canada.,Department of Psychiatry, Western University, London, Ontario, Canada
| |
Collapse
|
|
24
|
Petrosino NJ, Cosmo C, Berlow YA, Zandvakili A, van ’t Wout-Frank M, Philip NS. Transcranial magnetic stimulation for post-traumatic stress disorder. Ther Adv Psychopharmacol 2021; 11:20451253211049921. [PMID: 34733479 PMCID: PMC8558793 DOI: 10.1177/20451253211049921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/09/2021] [Indexed: 01/14/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder. While current treatment options are effective for some, many individuals fail to respond to first-line psychotherapies and pharmacotherapy. Transcranial magnetic stimulation (TMS) has emerged over the past several decades as a noninvasive neuromodulatory intervention for psychiatric disorders including depression, with mounting evidence for its safety, tolerability, and efficacy in treating PTSD. While several meta-analyses of TMS for PTSD have been published to date showing large effect sizes on PTSD overall, there is marked variability between studies, making it difficult to draw simple conclusions about how best to treat patients. The following review summarizes over 20 years of the existing literature on TMS as a PTSD treatment, and includes nine randomized controlled trials and many other prospective studies of TMS monotherapy, as well as five randomized controlled trials investigating TMS combined with psychotherapy. While the majority of studies utilize repetitive TMS targeted to the right dorsolateral prefrontal cortex (DLPFC) at low frequency (1 Hz) or high frequency (10 or 20 Hz), others have used alternative frequencies, targeted other regions (most commonly the left DLPFC), or trialed different stimulation protocols utilizing newer TMS modalities such as synchronized TMS and theta-burst TMS (TBS). Although it is encouraging that positive outcomes have been shown, there is a paucity of studies directly comparing available approaches. Biomarkers, such as functional imaging and electroencephalography, were seldomly incorporated yet remain crucial for advancing our knowledge of how to predict and monitor treatment response and for understanding mechanism of action of TMS in this population. Effects on PTSD are often sustained for up to 2-3 months, but more long-term studies are needed in order to understand and predict duration of response. In short, while TMS appears safe and effective for PTSD, important steps are needed to operationalize optimal approaches for patients suffering from this disorder.
Collapse
Affiliation(s)
- Nicholas J. Petrosino
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Camila Cosmo
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Yosef A. Berlow
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Amin Zandvakili
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Mascha van ’t Wout-Frank
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| | - Noah S. Philip
- VA RR&D Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, 830 Chalkstone Avenue, Providence, RI 02908, USA
- Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA
| |
Collapse
|
|
25
|
The Molecular Biology of Susceptibility to Post-Traumatic Stress Disorder: Highlights of Epigenetics and Epigenomics. Int J Mol Sci 2021; 22:ijms221910743. [PMID: 34639084 PMCID: PMC8509551 DOI: 10.3390/ijms221910743] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022] Open
Abstract
Exposure to trauma is one of the most important and prevalent risk factors for mental and physical ill-health. Excessive or prolonged stress exposure increases the risk of a wide variety of mental and physical symptoms. However, people differ strikingly in their susceptibility to develop signs and symptoms of mental illness after traumatic stress. Post-traumatic stress disorder (PTSD) is a debilitating disorder affecting approximately 8% of the world’s population during their lifetime, and typically develops after exposure to a traumatic event. Despite that exposure to potentially traumatizing events occurs in a large proportion of the general population, about 80–90% of trauma-exposed individuals do not develop PTSD, suggesting an inter-individual difference in vulnerability to PTSD. While the biological mechanisms underlying this differential susceptibility are unknown, epigenetic changes have been proposed to underlie the relationship between exposure to traumatic stress and the susceptibility to develop PTSD. Epigenetic mechanisms refer to environmentally sensitive modifications to DNA and RNA molecules that regulate gene transcription without altering the genetic sequence itself. In this review, we provide an overview of various molecular biological, biochemical and physiological alterations in PTSD, focusing on changes at the genomic and epigenomic level. Finally, we will discuss how current knowledge may aid us in early detection and improved management of PTSD patients.
Collapse
|
|
26
|
Georgiev D, Akram H, Jahanshahi M. Deep brain stimulation for psychiatric disorders: role of imaging in identifying/confirming DBS targets, predicting, and optimizing outcome and unravelling mechanisms of action. PSYCHORADIOLOGY 2021; 1:118-151. [PMID: 38665808 PMCID: PMC10917192 DOI: 10.1093/psyrad/kkab012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 04/28/2024]
Abstract
Following the established application of deep brain stimulation (DBS) in the treatment of movement disorders, new non-neurological indications have emerged, such as for obsessive-compulsive disorders, major depressive disorder, dementia, Gilles de la Tourette Syndrome, anorexia nervosa, and addictions. As DBS is a network modulation surgical treatment, the development of DBS for both neurological and psychiatric disorders has been partly driven by advances in neuroimaging, which has helped explain the brain networks implicated. Advances in magnetic resonance imaging connectivity and electrophysiology have led to the development of the concept of modulating widely distributed, complex brain networks. Moreover, the increasing number of targets for treating psychiatric disorders have indicated that there may be a convergence of the effect of stimulating different targets for the same disorder, and the effect of stimulating the same target for different disorders. The aim of this paper is to review the imaging studies of DBS for psychiatric disorders. Imaging, and particularly connectivity analysis, offers exceptional opportunities to better understand and even predict the clinical outcomes of DBS, especially where there is a lack of objective biomarkers that are essential to properly guide DBS pre- and post-operatively. In future, imaging might also prove useful to individualize DBS treatment. Finally, one of the most important aspects of imaging in DBS is that it allows us to better understand the brain through observing the changes of the functional connectome under neuromodulation, which may in turn help explain the mechanisms of action of DBS that remain elusive.
Collapse
Affiliation(s)
- Dejan Georgiev
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
- Department of Neurology, University Medical Centre Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia
- Artificial Intelligence Laboratory, Faculty of Computer and Information Science, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
| | - Harith Akram
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | - Marjan Jahanshahi
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK
- The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, University of Electronic Science and Technology of China, Chengdu, 611731, China
| |
Collapse
|
|
27
|
Miuli A, Sepede G, Stigliano G, Mosca A, Di Carlo F, d’Andrea G, Lalli A, Spano MC, Pettorruso M, Martinotti G, di Giannantonio M. Hypomanic/manic switch after transcranial magnetic stimulation in mood disorders: A systematic review and meta-analysis. World J Psychiatry 2021; 11:477-490. [PMID: 34513609 PMCID: PMC8394688 DOI: 10.5498/wjp.v11.i8.477] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/24/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nowadays there is an increasing use of transcranial magnetic stimulation (TMS) both in neurological and psychiatric fields. After Food and Drug Administration approval of TMS for the therapy of treatment-resistant depression, TMS has been widely used in the context of mood disorders (MD). However, growing reports regarding the possibility of developing hypomanic/manic switch (HMS) have generated concern regarding its use in MDs.
AIM To investigate the actual risk of developing HMS due to TMS in the treatment of MD.
METHODS We led our research on PubMed, Scopus and Web of Science on March 22, 2020, in accordance to the PRISMA guidelines for systematic review. Only double blind/single blind studies, written in English and focused on the TMS treatment of MD, were included. A meta-analysis of repetitive TMS protocol studies including HMS was conducted using RevMan 5.4 software. The assessment of Risk of Bias was done using Cochrane risk of bias tool. This protocol was registered on PROSPERO with the CRD42020175811 code.
RESULTS Twenty-five studies were included in our meta-analysis: Twenty-one double blind randomized controlled trials (RCT) and four single blind-RCT (no. of subjects involved in active stimulation = 576; no. of subjects involved in sham protocol = 487). The most frequently treated pathology was major depressive episode/major depressive disorder, followed by resistant depression, bipolar depression and other MD. The majority of the studies used a repetitive TMS protocol, and the left dorsolateral prefrontal cortex was the main target area. Side effects were reported in eight studies and HMS (described as greater energy, insomnia, irritability, anxiety, suicidal attempt) in four studies. When comparing active TMS vs sham treatment, the risk of developing HMS was not significantly different between conditions.
CONCLUSION Applying the most usual protocols and the appropriate precautionary measures, TMS seems not to be related to HMS development.
Collapse
Affiliation(s)
- Andrea Miuli
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Gianna Sepede
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Gianfranco Stigliano
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Alessio Mosca
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Francesco Di Carlo
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Giacomo d’Andrea
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Aliseo Lalli
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Maria Chiara Spano
- Department of Psychiatry Affective Neuropsychiatry, Sahlgrenska University Hospital, Göteborg 40530, Sweden
| | - Mauro Pettorruso
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| | - Giovanni Martinotti
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
- Department of Pharmacy, Clinical Science, University of Hertfordshire, Herts AL10 9AB, Italy
| | - Massimo di Giannantonio
- Department of Neuroscience, Imaging and Clinical Sciences, “G. d'Annunzio” University of Chieti, Chieti 66100, Italy
| |
Collapse
|
|
28
|
van 't Wout-Frank M, Shea MT, Sorensen DO, Faucher CR, Greenberg BD, Philip NS. A Secondary Analysis on Effects of Theta Burst Transcranial Magnetic Stimulation to Reduce Anger in Veterans With Posttraumatic Stress Disorder. Neuromodulation 2021; 24:870-878. [PMID: 32945055 PMCID: PMC8453662 DOI: 10.1111/ner.13256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/08/2020] [Accepted: 07/17/2020] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Anger is an important clinical feature of posttraumatic stress disorder (PTSD) that can hamper recovery. We recently reported that intermittent theta burst stimulation (iTBS) demonstrated preliminary efficacy to reduce symptoms of posttraumatic stress disorder and major depression; here, we performed a secondary analysis testing whether iTBS reduced symptoms of anger over the course of iTBS treatment and compared to sham stimulation. MATERIALS AND METHODS Fifty veterans with chronic PTSD received ten daily sessions of sham-controlled, double-blind iTBS (1800 pulses/session, once per weekday) targeting the right dorsolateral prefrontal cortex (intent-to-treat = 25 per group). Participants who completed the double-blind phase were offered another ten sessions of unblinded iTBS. Participants completed the Dimensions of Anger Reactions scale at pre-iTBS baseline, treatment midpoints, and endpoints of the blinded and unblinded phases, and at one-month after the last stimulation session. Correlations between anger, PTSD, depression, and sleep were also explored. RESULTS After the first week, during the double-blind phase, participants randomized to active stimulation reported significantly reduced anger compared to sham stimulation (p = 0.04). Participants initially randomized to sham appeared to catch-up to the point they no longer differed from those initially randomized to active iTBS when they received iTBS during the unblinded phase (p = 0.14). Anger reduction was maintained at one-month after iTBS in participants initially randomized to active stimulation (i.e., total of four weeks of iTBS). CONCLUSIONS This secondary analysis suggests that iTBS might reduce anger in veterans with PTSD. Future studies focused on more granular level anger outcomes and effects of number of stimulation sessions are needed.
Collapse
Affiliation(s)
- Mascha van 't Wout-Frank
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| | - Mary Tracie Shea
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| | - David O Sorensen
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| | - Christiana R Faucher
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| | - Benjamin D Greenberg
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| | - Noah S Philip
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA
| |
Collapse
|
|
29
|
Belsher BE, Beech EH, Reddy MK, Smolenski DJ, Rauch SAM, Kelber M, Issa F, Lewis C, Bisson JI. Advances in repetitive transcranial magnetic stimulation for posttraumatic stress disorder: A systematic review. J Psychiatr Res 2021; 138:598-606. [PMID: 33992983 DOI: 10.1016/j.jpsychires.2021.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/01/2021] [Accepted: 05/01/2021] [Indexed: 01/18/2023]
Abstract
Repetitive transcranial magnetic stimulation (rTMS) as a treatment for posttraumatic stress disorder (PTSD) has gained interest over the past two decades. However, it has yet to be recommended in major treatment guidelines. We conducted a systematic review of randomized controlled trials to examine the efficacy of rTMS for PTSD. Thirteen studies with 549 participants were included in this review. We compared the effects of (1) rTMS versus sham, and (2) high-frequency (HF) versus low-frequency (LF) rTMS, on posttreatment PTSD scores and other secondary outcomes. We calculated the standardized mean differences (SMD) to determine the direction of effects, and unstandardized mean differences to estimate the magnitude of efficacy. At post-treatment, rTMS was superior to sham comparison in reducing PTSD (SMD = -1.13, 95% CI: -2.10 to -0.15) and depression severity (SMD = -0.83, 95% CI: -1.30 to -0.36). The quality of evidence, however, was rated very low due to small samples sizes, treatment heterogeneity, inconsistent results, and an imprecise pooled effect. HF rTMS was associated with slightly improved, albeit imprecise, outcomes compared to LF rTMS on PTSD (SMD = -0.19, 95% CI: -1.39 to 1.00) and depression (SMD = -1.09, 95% CI: -1.65 to -0.52) severity. Further research is required to advance the evidence on this treatment.
Collapse
Affiliation(s)
- Bradley E Belsher
- Carl T Hayden Veterans Medical Center, 650 E Indian School Rd, Phoenix, AZ, 85012, USA; Uniformed Services University of the Health Sciences, 4310 Jones Bridge Road, Bethesda, MD, 20814, USA.
| | - Erin H Beech
- Psychological Health Center of Excellence, Defense Health Agency, 1335 East West Highway, Silver Spring, MD, 20910, USA
| | - Madhavi K Reddy
- Psychological Health Center of Excellence, Defense Health Agency, 1335 East West Highway, Silver Spring, MD, 20910, USA
| | - Derek J Smolenski
- Psychological Health Center of Excellence, Defense Health Agency, 1335 East West Highway, Silver Spring, MD, 20910, USA
| | - Sheila A M Rauch
- Atlanta VA Healthcare System, 1670 Clairmont Road, Decatur, GA, 300233, USA; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park, 3rd Floor, Atlanta, GA, 30329, USA
| | - Marija Kelber
- Psychological Health Center of Excellence, Defense Health Agency, 1335 East West Highway, Silver Spring, MD, 20910, USA
| | - Fuad Issa
- Psychological Health Center of Excellence, Defense Health Agency, 1335 East West Highway, Silver Spring, MD, 20910, USA
| | - Catrin Lewis
- Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Jonathan I Bisson
- Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| |
Collapse
|
|
30
|
van Rooij SJ, Sippel LM, McDonald WM, Holtzheimer PE. Defining focal brain stimulation targets for PTSD using neuroimaging. Depress Anxiety 2021; 38:10.1002/da.23159. [PMID: 33876868 PMCID: PMC8526638 DOI: 10.1002/da.23159] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/17/2021] [Accepted: 04/02/2021] [Indexed: 02/02/2023] Open
Abstract
INTRODUCTION Focal brain stimulation has potential as a treatment for posttraumatic stress disorder (PTSD). In this review, we aim to inform selection of focal brain stimulation targets for treating PTSD by examining studies of the functional neuroanatomy of PTSD and treatment response. We first briefly review data on brain stimulation interventions for PTSD. Although published data suggest good efficacy overall, the neurobiological rationale for each stimulation target is not always clear. METHODS Therefore, we assess pre- and post-treatment (predominantly psychotherapy) functional neuroimaging studies in PTSD to determine which brain changes seem critical to treatment response. Results of these studies are presented within a previously proposed functional neural systems model of PTSD. RESULTS While not completely consistent, research suggests that downregulating the fear learning and threat and salience detection circuits (i.e., amygdala, dorsal anterior cingulate cortex and insula) and upregulating the emotion regulation and executive function and contextual processing circuits (i.e., prefrontal cortical regions and hippocampus) may mediate PTSD treatment response. CONCLUSION This literature review provides some justification for current focal brain stimulation targets. However, the examination of treatment effects on neural networks is limited, and studies that include the stimulation targets are lacking. Further, additional targets, such as the cingulate, medial prefrontal cortex, and inferior parietal lobe, may also be worth investigation, especially when considering how to achieve network level changes. Additional research combining PTSD treatment with functional neuroimaging will help move the field forward by identifying and validating novel targets, providing better rationale for specific treatment parameters and personalizing treatment for PTSD.
Collapse
Affiliation(s)
- Sanne J.H. van Rooij
- Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA
| | - Lauren M. Sippel
- National Center for PTSD, U.S. Department of Veterans Affairs, White River Junction, VT
- Geisel School of Medicine at Dartmouth, Hanover, NH
| | - William M. McDonald
- Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Atlanta, GA
| | - Paul E. Holtzheimer
- National Center for PTSD, U.S. Department of Veterans Affairs, White River Junction, VT
- Geisel School of Medicine at Dartmouth, Hanover, NH
| |
Collapse
|
|
31
|
Weems CF, Russell JD, Herringa RJ, Carrion VG. Translating the neuroscience of adverse childhood experiences to inform policy and foster population-level resilience. ACTA ACUST UNITED AC 2021; 76:188-202. [PMID: 33734788 DOI: 10.1037/amp0000780] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Imaging methods have elucidated several neurobiological correlates of traumatic and adverse experiences in childhood. This knowledge base may foster the development of programs and policies that aim to build resilience and adaptation in children and youth facing adversity. Translation of this research requires both effective and accurate communication of the science. This review begins with a discussion of integrating the language used to describe and identify childhood adversity and their outcomes to clarify the translation of neurodevelopmental findings. An integrative term, Traumatic and Adverse Childhood Experiences (TRACEs+) is proposed, alongside a revised adverse childhood experiences (ACEs) pyramid that emphasizes that a diversity of adverse experiences may lead to a common outcome and that a diversity of outcomes may result from a common adverse experience. This term facilitates linkages between the ACEs literature and the emerging neurodevelopmental knowledge surrounding the effect of traumatic adverse childhood experiences on youth in terms of the knowns and unknowns about neural connectivity in youth samples. How neuroscience findings may lead directly or indirectly to specific techniques or targets for intervention and the reciprocal nature of these relationships is addressed. Potential implications of the neuroscience for policy and intervention at multiple levels are illustrated using existing policy programs that may be informed by (and inform) neuroscience. The need for transdisciplinary models to continue to move the science to action closes the article. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Collapse
Affiliation(s)
- Carl F Weems
- Department of Human Development and Family Studies, Iowa State University
| | - Justin D Russell
- Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison
| | - Ryan J Herringa
- Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison
| | | |
Collapse
|
|
32
|
Bozzay ML, Primack JM, Swearingen HR, Barredo J, Philip NS. Combined transcranial magnetic stimulation and brief cognitive behavioral therapy for suicide: study protocol for a randomized controlled trial in veterans. Trials 2020; 21:924. [PMID: 33183345 PMCID: PMC7663863 DOI: 10.1186/s13063-020-04870-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 11/04/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND At least 17 veterans die every day from suicide. Although existing treatments such as brief cognitive behavioral therapy (BCBT) have been found to reduce suicide attempts in military personnel, a number of patients go on to attempt suicide after completing therapy. Thus, finding ways to enhance treatment efficacy to reduce suicide is critical. Repetitive transcranial magnetic stimulation (TMS) is a noninvasive technique that can be used to stimulate brain regions that are impaired in suicidal patients, that has been successfully used to augment treatments for psychiatric disorders implicated in suicide. The goal of this study is to test whether augmenting BCBT with TMS in suicidal veterans reduces rates of suicidal ideation, attempts, and other deleterious treatment outcomes. METHODS One hundred thirty veterans with a suicide plan or suicidal behavior in the prior 2 weeks will be recruited from inpatient and outpatient settings at the Providence VA Medical Center in the USA. Veterans will be randomly assigned to receive 30 daily sessions of active or sham TMS in concert with a 12-week BCBT protocol in a parallel group design. Veterans will complete interviews and questionnaires related to psychiatric symptoms, suicidal ideation and behavior, treatment utilization, and functioning during a baseline assessment prior to treatment, at treatment endpoint, and 6- and 12-month follow-ups. Primary analyses will use mixed effect regressions to examine effects of treatment condition on suicidal behaviors, improvements in psychosocial functioning, and psychiatric hospitalization. Similar models as well as exploratory latent growth curve analyses will examine mediators and moderators of treatment effects. DISCUSSION This protocol provides a framework for designing multilayered treatment studies for suicide. When completed, this study will be the first clinical trial evaluating the efficacy of augmenting BCBT for suicide with TMS. The results of this trial will have implications for treatment of suicide ideation and behaviors and implementation of augmented treatment designs. If positive, results from this study can be rapidly implemented across the VA system and will have a direct and meaningful impact on veteran suicide. TRIAL REGISTRATION This study was registered prior to participant enrollment with ClinicalTrials.gov NCT03952468 . Registered on May 16, 2019. TRIAL SPONSOR CONTACT Robert O'Brien (VA Health Services R&D), robert.obrien7@va.gov.
Collapse
Affiliation(s)
- Melanie L. Bozzay
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI 02912 USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, RI 02908 USA
| | - Jennifer M. Primack
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI 02912 USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, RI 02908 USA
| | - Hannah R. Swearingen
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, RI 02908 USA
| | - Jennifer Barredo
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI 02912 USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, RI 02908 USA
| | - Noah S. Philip
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI 02912 USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, RI 02908 USA
| |
Collapse
|
|
33
|
Use of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric and Neurocognitive Symptoms Associated With Concussion in Military Populations. J Head Trauma Rehabil 2020; 35:388-400. [PMID: 33165152 DOI: 10.1097/htr.0000000000000628] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Since the year 2000, over 342 000 military service members have experienced a concussion, often associated with chronic neuropsychiatric and neurocognitive symptoms. Repetitive transcranial magnetic stimulation (rTMS) protocols have been developed for many of these symptoms in the general population. OBJECTIVE To conduct a scoping review of the literature on rTMS for neuropsychological and neurocognitive symptoms following concussion. METHODS PubMed and Google Scholar search engines identified 9 articles, written in English, corresponding to the search terms TBI or concussion; and TMS or rTMS; and depression, PTSD, or cognition. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric or neurocognitive primary outcome measures, or described samples where 80% or more of the cohort did not have a TBI were excluded. RESULTS There were no reports of seizures nor difference in the frequency or quality of other adverse events as compared with the broader rTMS literature, supporting the safety of rTMS in this population. Support for the efficacy of rTMS for the treatment of neuropsychiatric and neurocognitive symptoms, in this population, is limited. CONCLUSIONS Large-scale, innovative, neuroscience-informed protocols are recommended to elucidate the potential utility of rTMS for the complex neuropsychiatric and neurocognitive symptoms associated with military concussions.
Collapse
|
|
34
|
Nicholson AA, Ros T, Densmore M, Frewen PA, Neufeld RWJ, Théberge J, Jetly R, Lanius RA. A randomized, controlled trial of alpha-rhythm EEG neurofeedback in posttraumatic stress disorder: A preliminary investigation showing evidence of decreased PTSD symptoms and restored default mode and salience network connectivity using fMRI. Neuroimage Clin 2020; 28:102490. [PMID: 33395981 PMCID: PMC7708928 DOI: 10.1016/j.nicl.2020.102490] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/20/2020] [Accepted: 10/27/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The default-mode network (DMN) and salience network (SN) have been shown to display altered connectivity in posttraumatic stress disorder (PTSD). Restoring aberrant connectivity within these networks with electroencephalogram neurofeedback (EEG-NFB) has been shown previously to be associated with acute decreases in symptoms. Here, we conducted a double-blind, sham-controlled randomized trial of alpha-rhythm EEG-NFB in participants with PTSD (n = 36) over 20-weeks. Our aim was to provide mechanistic evidence underlying clinical improvements by examining changes in network connectivity via fMRI. METHODS We randomly assigned participants with a primary diagnosis of PTSD to either the experimental group (n = 18) or sham-control group (n = 18). We collected resting-state fMRI scans pre- and post-NFB intervention, for both the experimental and sham-control PTSD groups. We further compared baseline brain connectivity measures pre-NFB to age-matched healthy controls (n = 36). RESULTS With regard to the primary outcome measure of PTSD severity, we found a significant main effect of time in the absence of a group × time interaction. Nevertheless, we found significantly decreased PTSD severity scores in the experimental NFB group only, when comparing post-NFB (dz = 0.71) and 3-month follow-up scores (dz = 0.77) to baseline measures. Interestingly, we found evidence to suggest a shift towards normalization of DMN and SN connectivity post-NFB in the experimental group only. Both decreases in PTSD severity and NFB performance were correlated to DMN and SN connectivity post-NFB in the experimental group. Critically, remission rates of PTSD were significant higher in the experimental group (61.1%) as compared to the sham-control group (33.3%). CONCLUSION The current study shows mechanistic evidence for therapeutic changes in DMN and SN connectivity that are known to be associated with PTSD psychopathology with no patient dropouts. This preliminary investigation merits further research to demonstrate fully the clinical efficacy of EEG-NFB as an adjunctive therapy for PTSD.
Collapse
Affiliation(s)
- Andrew A Nicholson
- Department of Cognition, Emotion, and Methods in Psychology, University of Vienna, Austria
| | - Tomas Ros
- Departments of Neuroscience and Psychiatry, University of Geneva, Campus Biotech, Geneva, Switzerland
| | - Maria Densmore
- Departments of Neuroscience, Western University, London, ON, Canada; Imaging, Lawson Health Research Institute, London, ON, Canada
| | - Paul A Frewen
- Departments of Neuroscience, Western University, London, ON, Canada; Departments of Psychology, Western University, London, ON, Canada
| | - Richard W J Neufeld
- Departments of Neuroscience, Western University, London, ON, Canada; Departments of Psychiatry, Western University, London, ON, Canada; Departments of Psychology, Western University, London, ON, Canada
| | - Jean Théberge
- Departments of Psychiatry, Western University, London, ON, Canada; Departments of Psychology, Western University, London, ON, Canada; Departments of Medical Imaging, Western University, London, ON, Canada; Imaging, Lawson Health Research Institute, London, ON, Canada; Department of Diagnostic Imaging, St. Joseph's Healthcare, London, ON, Canada
| | - Rakesh Jetly
- Canadian Forces, Health Services, Ottawa, Ontario, Canada
| | - Ruth A Lanius
- Departments of Neuroscience, Western University, London, ON, Canada; Departments of Psychiatry, Western University, London, ON, Canada; Imaging, Lawson Health Research Institute, London, ON, Canada.
| |
Collapse
|
|
35
|
Gouveia FV, Davidson B, Meng Y, Gidyk DC, Rabin JS, Ng E, Abrahao A, Lipsman N, Giacobbe P, Hamani C. Treating Post-traumatic Stress Disorder with Neuromodulation Therapies: Transcranial Magnetic Stimulation, Transcranial Direct Current Stimulation, and Deep Brain Stimulation. Neurotherapeutics 2020; 17:1747-1756. [PMID: 32468235 PMCID: PMC7851279 DOI: 10.1007/s13311-020-00871-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness. While standard treatment with pharmacotherapy and psychotherapy may be effective, approximately 20 to 30% of patients remain symptomatic. These individuals experience depression, anxiety, and elevated rates of suicide. For treatment-resistant patients, there is a growing interest in the use of neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). We conducted a systematic review on the use of neuromodulation strategies for PTSD and pooled 13 randomized clinical trials (RCTs), 11 case series, and 6 case reports for analysis. Overall, most studies reported favorable outcomes in alleviating both PTSD and depressive symptoms. Although several RCTs described significant differences when active and sham stimulations were compared, others found marginal or nonsignificant differences between groups. Also positive were studies comparing PTSD symptoms before and after treatment. The side effect profile with all 3 modalities was found to be low, with mostly mild adverse events being reported. Despite these encouraging data, several aspects remain unknown. Given that PTSD is a highly heterogeneous condition that can be accompanied by distinct psychiatric diagnoses, defining a unique treatment for this patient population can be quite challenging. There has also been considerable variation across trials regarding stimulation parameters, symptomatic response, and the role of adjunctive psychotherapy. Future studies are needed to address these issues.
Collapse
Affiliation(s)
| | - Benjamin Davidson
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Ying Meng
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | | | - Jennifer S Rabin
- Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Enoch Ng
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Agessandro Abrahao
- Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Nir Lipsman
- Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Peter Giacobbe
- Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada
- Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
| | - Clement Hamani
- Sunnybrook Research Institute, 2075 Bayview Av, S126, Toronto, ON, M4N3M5, Canada.
- Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada.
- Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada.
| |
Collapse
|
|
36
|
Effects of repetitive transcranial magnetic stimulation in subjects with sleep disorders. Sleep Med 2020; 71:113-121. [PMID: 32173186 DOI: 10.1016/j.sleep.2020.01.028] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 01/06/2020] [Accepted: 01/31/2020] [Indexed: 01/08/2023]
|
|
37
|
Mapping PTSD symptoms to brain networks: a machine learning study. Transl Psychiatry 2020; 10:195. [PMID: 32555146 PMCID: PMC7303205 DOI: 10.1038/s41398-020-00879-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022] Open
Abstract
Posttraumatic Stress Disorder (PTSD) is a prevalent and debilitating condition with complex and variable presentation. While PTSD symptom domains (intrusion, avoidance, cognition/mood, and arousal/reactivity) correlate highly, the relative importance of these symptom subsets often differs across patients. In this study, we used machine learning to derive how PTSD symptom subsets differ based upon brain functional connectivity. We acquired resting-state magnetic resonance imaging in a sample (N = 50) of PTSD patients and characterized clinical features using the PTSD Checklist for DSM-5 (PCL-5). We compared connectivity among 100 cortical and subcortical regions within the default mode, salience, executive, and affective networks. We then used principal component analysis and least-angle regression (LARS) to identify relationships between symptom domain severity and brain networks. We found connectivity predicted PTSD symptom profiles. The goodness of fit (R2) for total PCL-5 score was 0.29 and the R2 for intrusion, avoidance, cognition/mood, and arousal/reactivity symptoms was 0.33, 0.23, -0.01, and 0.06, respectively. The model performed significantly better than chance in predicting total PCL-5 score (p = 0.030) as well as intrusion and avoidance scores (p = 0.002 and p = 0.034). It was not able to predict cognition and arousal scores (p = 0.412 and p = 0.164). While this work requires replication, these findings demonstrate that this computational approach can directly link PTSD symptom domains with neural network connectivity patterns. This line of research provides an important step toward data-driven diagnostic assessments in PTSD, and the use of computational methods to identify individual patterns of network pathology that can be leveraged toward individualized treatment.
Collapse
|
|
38
|
Bozzay ML, Primack J, Barredo J, Philip NS. Transcranial magnetic stimulation to reduce suicidality - A review and naturalistic outcomes. J Psychiatr Res 2020; 125:106-112. [PMID: 32251917 PMCID: PMC7197489 DOI: 10.1016/j.jpsychires.2020.03.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/14/2020] [Accepted: 03/26/2020] [Indexed: 02/07/2023]
Abstract
Although there is growing interest in the use of repetitive Transcranial Magnetic Stimulation (TMS) as a treatment for suicidality, efficacy data in this area, and knowledge of potential treatment mechanisms, remains limited. The first objective of this study was to systematically review clinical trial data examining the effectiveness of TMS as a treatment for suicidal ideation. Our secondary objective was to investigate the extent to which changes in suicidality are independent of improvements in depression in a clinical sample of veterans who received TMS treatment. In Study 1, we searched the Pubmed and biRxiv databases from inception until July 2019 to identify studies that examined the efficacy of TMS for suicidal thoughts and/or behaviors. Data regarding sample characteristics, treatment parameters, and results were synthesized from six randomized controlled trials and five unblinded trials (total n = 593). Our systematic review indicated that while TMS was consistently associated with reduced depression, its impact on suicidality is unclear. Interpretation of results related to suicidality were complicated by study design elements and modest sample sizes. In Study 2, we conducted a retrospective analysis of 43 patients who received care for depression in a neuromodulation clinic at a Veteran's Affairs hospital. Results found significant decreases in suicidal ideation, and depressive symptom change did not always account for improvements in ideation. Taken together, our literature review and clinic study indicate preliminary promise of TMS for suicide, and underscore the need for more fine-grained, suicide-specific TMS research.
Collapse
Affiliation(s)
- Melanie L Bozzay
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence RI USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence RI USA
| | - Jennifer Primack
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence RI USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence RI USA
- Address correspondence to: Noah S. Philip, M.D. ; Telephone: + 1 (401) 273-7100 x2369. Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, Rhode Island 02908, United States
| | - Jennifer Barredo
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence RI USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence RI USA
- Address correspondence to: Noah S. Philip, M.D. ; Telephone: + 1 (401) 273-7100 x2369. Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, Rhode Island 02908, United States
| | - Noah S. Philip
- Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence RI USA
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence RI USA
- Address correspondence to: Noah S. Philip, M.D. ; Telephone: + 1 (401) 273-7100 x2369. Providence VA Medical Center, 830 Chalkstone Boulevard, Providence, Rhode Island 02908, United States
| |
Collapse
|
|
39
|
Petrosino NJ, Wout-Frank MV', Aiken E, Swearingen HR, Barredo J, Zandvakili A, Philip NS. One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder. Neuropsychopharmacology 2020; 45:940-946. [PMID: 31794974 PMCID: PMC7162862 DOI: 10.1038/s41386-019-0584-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/18/2019] [Accepted: 11/26/2019] [Indexed: 11/30/2022]
Abstract
Theta burst transcranial magnetic stimulation (TBS) is a potential new treatment for post-traumatic stress disorder (PTSD). We previously reported active intermittent TBS (iTBS) was associated with superior clinical outcomes for up to 1-month, in a sample of fifty veterans with PTSD, using a crossover design. In that study, participants randomized to the active group received a total of 4-weeks of active iTBS, or 2-weeks if randomized to sham. Results were superior with greater exposure to active iTBS, which raised the question of whether observed effects persisted over the longer-term. This study reviewed naturalistic outcomes up to 1-year from study endpoint, to test the hypothesis that greater exposure to active iTBS would be associated with superior outcomes. The primary outcome measure was clinical relapse, defined as any serious adverse event (e.g., suicide, psychiatric hospitalization, etc.,) or need for retreatment with repetitive transcranial magnetic stimulation (rTMS). Forty-six (92%) of the initial study's intent-to-treat participants were included. Mean age was 51.0 ± 12.3 years and seven (15.2%) were female. The group originally randomized to active iTBS (4-weeks active iTBS) demonstrated superior outcomes at one year compared to those originally randomized to sham (2-weeks active iTBS); log-rank ChiSq = 5.871, df = 1, p = 0.015; OR = 3.50, 95% CI = 1.04-11.79. Mean days to relapse were 296.0 ± 22.1 in the 4-week group, and 182.0 ± 31.9 in the 2-week group. When used, rTMS retreatment was generally effective. Exploratory neuroimaging revealed default mode network connectivity was predictive of 1-year outcomes (corrected p < 0.05). In summary, greater accumulated exposure to active iTBS demonstrated clinically meaningful improvements in the year following stimulation, and default mode connectivity could be used to predict longer-term outcomes.
Collapse
Affiliation(s)
- Nicholas J Petrosino
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Mascha van 't Wout-Frank
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Emily Aiken
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Hannah R Swearingen
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Jennifer Barredo
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Amin Zandvakili
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Noah S Philip
- From the VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, and The Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02903, USA.
| |
Collapse
|
|
40
|
Freire RC, Cabrera-Abreu C, Milev R. Neurostimulation in Anxiety Disorders, Post-traumatic Stress Disorder, and Obsessive-Compulsive Disorder. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1191:331-346. [PMID: 32002936 DOI: 10.1007/978-981-32-9705-0_18] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Many pharmacological treatments were proved effective in the treatment of panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD); still many patients do not achieve remission with these treatments. Neurostimulation techniques have been studied as promising alternatives or augmentation treatments to pharmacological and psychological therapies. The most studied neurostimulation method for anxiety disorders, PTSD, and OCD was repetitive transcranial magnetic stimulation (rTMS). This neurostimulation technique had the highest level of evidence for GAD. There were also randomized sham-controlled trials indicating that rTMS may be effective in the treatment of PTSD and OCD, but there were conflicting findings regarding these two disorders. There is indication that rTMS may be effective in the treatment of panic disorder, but the level of evidence is low. Deep brain stimulation (DBS) was most studied for treatment of OCD, but the randomized sham-controlled trials had mixed findings. Preliminary findings indicate that DBS could be affective for PTSD. There is weak evidence indicating that electroconvulsive therapy, transcranial direct current stimulation, vagus nerve stimulation, and trigeminal nerve stimulation could be effective in the treatment of anxiety disorders, PTSD, and OCD. Regarding these disorders, there is no support in the current literature for the use of neurostimulation in clinical practice. Large high-quality studies are warranted.
Collapse
Affiliation(s)
- Rafael Christophe Freire
- Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
- Department of Psychiatry, Queen's University, Kingston, ON, Canada.
| | - Casimiro Cabrera-Abreu
- Department of Psychiatry, Queen's University and Providence Care Hospital, Kingston, ON, Canada
| | - Roumen Milev
- Department of Psychiatry, Queen's University, Kingston, ON, Canada
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
| |
Collapse
|
|
41
|
Barredo J, Bellone JA, Edwards M, Carpenter LL, Correia S, Philip NS. White matter integrity and functional predictors of response to repetitive transcranial magnetic stimulation for posttraumatic stress disorder and major depression. Depress Anxiety 2019; 36:1047-1057. [PMID: 31475432 PMCID: PMC8015421 DOI: 10.1002/da.22952] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 07/02/2019] [Accepted: 07/27/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Recent evidence suggests that therapeutic repetitive transcranial magnetic stimulation (TMS) is an effective treatment for pharmacoresistant posttraumatic stress disorder (PTSD) and comorbid major depressive disorder (MDD). We recently demonstrated that response to 5 Hz TMS administered to the dorsolateral prefrontal cortex was predicted by functional connectivity of the medial prefrontal (MPFC) and subgenual anterior cingulate cortex (sgACC). This functionally-defined circuit is a novel target for treatment optimization research, however, our limited knowledge of the structural pathways that underlie this functional predisposition is a barrier to target engagement research. METHODS To investigate underlying structural elements of our previous functional connectivity findings, we submitted pre-TMS diffusion-weighted imaging data from 20 patients with PTSD and MDD to anatomically constrained tract-based probabilistic tractography (FreeSurfer's TRActs Constrained by UnderLying Anatomy). Averaged pathway fractional anisotropy (FA) was extracted from four frontal white matter tracts: the forceps minor, cingulum, anterior thalamic radiations (ATRs), and uncinate fasciculi. Tract FA statistics were treated as explanatory variables in backward regressions testing the relationship between tract integrity and functional connectivity coefficients from MPFC and sgACC predictors of symptom improvement after TMS. RESULTS FA in the ATRs was consistently associated with symptom improvement in PTSD and MDD (Bonferroni-corrected p < .05). CONCLUSION We found that structural characteristics of the ATR account for significant variance in individual-level functional predictors of post-TMS improvement. TMS optimization studies should target this circuit either in stand-alone or successive TMS stimulation protocols.
Collapse
Affiliation(s)
- Jennifer Barredo
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University,Center for Neurorestoration and Neurotechnology, Providence VA Medical Center,Corresponding author: Jennifer Barredo PhD, 830 Chalkstone Ave, Providence RI 02908;
| | - John A. Bellone
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University,Center for Neurorestoration and Neurotechnology, Providence VA Medical Center
| | - Melissa Edwards
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University
| | - Linda L. Carpenter
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University,Butler Hospital Neuromodulation Research Facility
| | - Stephen Correia
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University,Center for Neurorestoration and Neurotechnology, Providence VA Medical Center,Butler Hospital Neuromodulation Research Facility
| | - Noah S. Philip
- Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University,Center for Neurorestoration and Neurotechnology, Providence VA Medical Center,Butler Hospital Neuromodulation Research Facility
| |
Collapse
|
|
42
|
Lee DJ, Lozano CS, Dallapiazza RF, Lozano AM. Current and future directions of deep brain stimulation for neurological and psychiatric disorders. J Neurosurg 2019; 131:333-342. [PMID: 31370011 DOI: 10.3171/2019.4.jns181761] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 04/18/2019] [Indexed: 11/06/2022]
Abstract
Deep brain stimulation (DBS) has evolved considerably over the past 4 decades. Although it has primarily been used to treat movement disorders such as Parkinson's disease, essential tremor, and dystonia, recently it has been approved to treat obsessive-compulsive disorder and epilepsy. Novel potential indications in both neurological and psychiatric disorders are undergoing active study. There have been significant advances in DBS technology, including preoperative and intraoperative imaging, surgical approaches and techniques, and device improvements. In addition to providing significant clinical benefits and improving quality of life, DBS has also increased the understanding of human electrophysiology and network interactions. Despite the value of DBS, future developments should be aimed at developing less invasive techniques and attaining not just symptom improvement but curative disease modification.
Collapse
Affiliation(s)
- Darrin J Lee
- 1Department of Neurological Surgery, University of Southern California, Los Angeles, California
| | - Christopher S Lozano
- 2Department of Neurological Surgery, University of Toronto, Ontario, Canada; and
| | | | - Andres M Lozano
- 2Department of Neurological Surgery, University of Toronto, Ontario, Canada; and
| |
Collapse
|
|
43
|
Pivac N. Theranostic approach to PTSD. Prog Neuropsychopharmacol Biol Psychiatry 2019; 92:260-262. [PMID: 30707987 DOI: 10.1016/j.pnpbp.2019.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Nela Pivac
- Rudjer Boskovic Institute, Division of Molecular Medicine, Laboratory for Molecular Neuropsychiatry, Bijenicka cesta 54, 10000 Zagreb, Croatia.
| |
Collapse
|
|
44
|
Philip NS, Aiken EE, Kelley ME, Burch W, Waterman L, Holtzheimer PE. Synchronized transcranial magnetic stimulation for posttraumatic stress disorder and comorbid major depression. Brain Stimul 2019; 12:1335-1337. [PMID: 31204205 DOI: 10.1016/j.brs.2019.06.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 06/05/2019] [Indexed: 12/14/2022] Open
Affiliation(s)
- Noah S Philip
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA.
| | - Emily E Aiken
- VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, USA
| | - Mary E Kelley
- Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA, USA
| | - William Burch
- White River Junction VA Medical Center, White River Junction, VT, USA
| | - Laurie Waterman
- White River Junction VA Medical Center, White River Junction, VT, USA
| | - Paul E Holtzheimer
- National Center for Posttraumatic Stress Disorder, USA; Departments of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth, USA
| |
Collapse
|
|
45
|
Su AS, Zhang JW, Zou J. The anxiolytic-like effects of puerarin on an animal model of PTSD. Biomed Pharmacother 2019; 115:108978. [PMID: 31102911 DOI: 10.1016/j.biopha.2019.108978] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 05/05/2019] [Accepted: 05/08/2019] [Indexed: 12/27/2022] Open
Abstract
Post traumatic stress disorder (PTSD) is a mental illness that affected numerous people. The anti-PTSD-like effects of puerarin is unknown, although the antidepressant- and anxiolytic- like effects of puerarin have been reported. The PTSD behavioral deficits in rats were induced by single prolonged stress (SPS), mainly including the reduced time/entries in the open arms and the elevated time/entries in the closed arms in elevated plus maze test, increased freezing duration in contextual fear paradigm and lowered time/entries in the central zone in open field test. However, the behavioral deficits were attenuated by puerarin (50 and 100 mg/kg) without affecting the locomotor activity. For the evaluation of mechanism, the decreased levels of progesterone, allopregnanolone, and the increased levels of corticosterone, corticotropin releasing hormone, and adrenocorticotropic hormone in the brain or serum were induced by SPS, which is blocked by puerarin. In summary, the anti-PTSD-like effects of puerarin were associated with biosynthesis of neurosteroids and normalized levels of stress hormones in HPA axis.
Collapse
Affiliation(s)
- Ai-Shan Su
- GCP Center, Nangfang Hospital of Southern Medical University, Guangzhou, 501515, China
| | - Jun-Wei Zhang
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510140, China
| | - Jing Zou
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, Sichuan, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China.
| |
Collapse
|