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1.
Res Sq ; 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38562753

ABSTRACT

Neuromodulation trials for PTSD have yielded mixed results, and the optimal neuroanatomical target remains unclear. We analyzed three datasets to study brain circuitry causally linked to PTSD in military Veterans. After penetrating traumatic brain injury (n=193), lesions that reduced probability of PTSD were preferentially connected to a circuit including the medial prefrontal cortex (mPFC), amygdala, and anterolateral temporal lobe (cross-validation p=0.01). In Veterans without lesions (n=180), PTSD was specifically associated with connectivity within this circuit (p<0.01). Connectivity change within this circuit correlated with PTSD improvement after transcranial magnetic stimulation (TMS) (n=20) (p<0.01), even though the circuit was not directly targeted. Finally, we directly targeted this circuit with fMRI-guided accelerated TMS, leading to rapid resolution of symptoms in a patient with severe lifelong PTSD. All results were independent of depression severity. This lesion-based PTSD circuit may serve as a neuromodulation target for Veterans with PTSD.

2.
Transl Psychiatry ; 14(1): 5, 2024 Jan 06.
Article in English | MEDLINE | ID: mdl-38184652

ABSTRACT

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30-45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.


Subject(s)
Depressive Disorder, Major , Humans , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/therapy , Glutamic Acid , Transcranial Magnetic Stimulation , Depression , Biomarkers
3.
BMJ Open ; 13(8): e070654, 2023 08 16.
Article in English | MEDLINE | ID: mdl-37586858

ABSTRACT

INTRODUCTION: This study's overarching goal is to examine the relationship between brain circuits and suicidal thoughts and behaviours (STBs) in a transdiagnostic sample of US military veterans. Because STBs have been linked with maladaptive decision-making and disorders linked to impulsivity, this investigation focuses on valence and inhibitory control circuits. METHODS AND ANALYSIS: In this prospective, observational study, we will collect functional MRI (fMRI), cognitive and clinical data from 136 veterans (target sample size) recruited from the Providence VA Health System (PVAHS): 68 with STBs and 68 matched controls. Behavioural data will be collected using standardised measures of STBs, psychiatric symptoms, cognition, functioning and medical history. Neuroimaging data will include structural, task and resting fMRI. We will conduct follow-up interviews and assessments at 6, 12 and 24 months post-enrolment. Primary analyses will compare data from veterans with and without STBs and will also evaluate whether activation and connectivity within circuits of valence and inhibition covary with historical and prospective patterns of suicidal ideation and behaviour. ETHICS AND DISSEMINATION: The PVAHS Institutional Review Board approved this study (2018-051). Written informed consent will be obtained from all participants. Findings from this study will be published in peer-reviewed journals and presented at local, regional, national and international conferences.Nauder Namaky, Ph.D.* nauder_namaky@brown.edu.


Subject(s)
Suicidal Ideation , Veterans , Humans , Impulsive Behavior , Neuroimaging , Observational Studies as Topic , Prospective Studies
4.
Neuroimage Clin ; 35: 103049, 2022.
Article in English | MEDLINE | ID: mdl-35738081

ABSTRACT

INTRODUCTION: Repetitive Transcranial magnetic stimulation (rTMS) is an FDA approved treatment for major depressive disorder (MDD). However, neural mechanisms contributing to rTMS effects on depressive symptoms, cognition, and behavior are unclear. Proton magnetic resonance spectroscopy (MRS), a noninvasive neuroimaging technique measuring concentrations of biochemical compounds within the brain in vivo, may provide mechanistic insights. METHODS: This systematic review summarized published MRS findings from rTMS treatment trials to address potential neurometabolic mechanisms of its antidepressant action. Using PubMed, Google Scholar, Web of Science, and JSTOR, we identified twelve empirical studies that evaluated changes in MRS metabolites in a within-subjects, pre- vs. post-rTMS treatment design in patients with MDD. RESULTS: rTMS protocols ranged from four days to eight weeks duration, were applied at high frequency to the left dorsolateral prefrontal cortex (DLPFC) in most studies, and were conducted in patients aged 13-to-70. Most studies utilized MRS point resolved spectroscopy acquisitions at 3 Tesla in the bilateral anterior cingulate cortex and DLPFC. Symptom improvements were correlated with rTMS-related increases in the concentration of glutamatergic compounds (glutamate, Glu, and glutamine, Gln), GABA, and N-acetylated compounds (NAA), with some results trend-level. CONCLUSIONS: This is the first in-depth systematic review of metabolic effects of rTMS in individuals with MDD. The extant literature suggests rTMS stimulation does not produce changes in neurometabolites independent of clinical response; increases in frontal lobe glutamatergic compounds, N-acetylated compounds and GABA following high frequency left DLPFC rTMS therapy were generally associated with clinical improvement. Glu, Gln, GABA, and NAA may mediate rTMS treatment effects on MDD symptomatology through intracellular mechanisms.


Subject(s)
Depressive Disorder, Major , Neocortex , Depression , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/metabolism , Depressive Disorder, Major/therapy , Glutamic Acid/metabolism , Glutamine/metabolism , Humans , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/metabolism , Transcranial Magnetic Stimulation/methods , Treatment Outcome , gamma-Aminobutyric Acid/metabolism
5.
Front Psychiatry ; 13: 825802, 2022.
Article in English | MEDLINE | ID: mdl-35280168

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.

6.
Neuromodulation ; 25(8): 1431-1442, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35088729

ABSTRACT

OBJECTIVES: Mechanical Affective Touch Therapy (MATT) is a safe, novel form of noninvasive peripheral nerve stimulation. Although mechanical stimulation activates nerves, we know little about its impact on psychiatric symptoms and their underlying cortical mechanisms. We examined the effects of open-label MATT on resting state functional connectivity (RSFC) and its relationship with anxiety and affective symptomatology (clinical results in separate report). MATERIALS AND METHODS: A total of 22 adults with an Axis I anxiety disorder were recruited from the community. After two initial sessions assisted by research staff, participants self-administered 20-minute sessions of MATT at home at least twice daily for four weeks. Self-report measures of mood and anxiety severity were collected at baseline, two weeks, and four weeks. Resting state functional magnetic resonance imaging was collected before the initial MATT session (n = 20), immediately after the first session (n = 18), and following four weeks of MATT (n = 14). Seed-based whole-brain functional connectivity analyses identified brain connectivity patterns correlated with responsiveness to MATT. Seeds were based on Neurosynth meta-analytic maps for "anxiety" and "pain" given MATT's hypothesized role in anxiety symptom amelioration and potential mechanism of action through C-tactile afferents, which play an important role in detecting pain and its affective components. Connectivity results were corrected for multiple comparisons (voxel p < 0.005, cluster p-FDR < 0.05). RESULTS: Baseline RSFC is predictive of symptom improvement with chronic MATT. Acute increases in insula connectivity were observed between mid-cingulate cortex and postcentral motor regions following the first MATT session. Chronic MATT was associated with increased connectivity between pain and anxiety regions of interest (ROIs) and posterior default mode network (DMN) regions involved in memory and self-reflection; the connectivity changes correlated with decreases in stress and depression symptoms. CONCLUSIONS: MATT is associated with alterations in RSFC in the DMN of anxiety disorder patients both acutely and after long-term administration, and baseline RSFC is predictive of post-treatment symptom improvement.


Subject(s)
Rest , Touch , Adult , Humans , Rest/physiology , Anxiety Disorders/diagnostic imaging , Anxiety Disorders/therapy , Brain Mapping , Magnetic Resonance Imaging/methods , Brain
7.
Mil Psychol ; 34(3): 315-325, 2022.
Article in English | MEDLINE | ID: mdl-38536269

ABSTRACT

Rates of Veteran suicide continue to be unacceptably high. Suicidal ideation and behavior are contextually and situationally based, limiting the ability of traditional prevention and assessment strategies to prevent acute crises. The Mobile Application for the Prevention of Suicide (MAPS) is a novel, smartphone-based intervention strategy that utilizes ecological momentary assessment to identify suicide risk in the moment and delivers treatment strategies in real-time. The app is personalized to each patient, utilizes empirically intervention strategies, and is delivered adjunctively to Veterans Affairs (VA) treatment as usual. This article outlines the MAPS intervention and presents results of an open trial to assess its feasibility and acceptability. Eight Veterans were recruited from aVeterans Affairs Medical Center (VAMC) psychiatric inpatient unit following hospitalization for either a suicide ideation or attempt. Veterans received MAPS for 2 weeks post-hospitalization. Veterans reported high levels of satisfaction with MAPS and all opted to extend their use of MAPS beyond the 2-week trial period. MAPS may be a useful adjunctive to treatment as usual for high-risk Veterans by allowing patients and their providers to better track suicide risk and deploy intervention strategies when risk is detected.

8.
Biol Psychiatry ; 89(11): 1073-1083, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33820628

ABSTRACT

Despite significant advances in psychiatric and psychological treatment over the last 30 years, suicide deaths have increased. Unfortunately, neuroscience insights have yielded few translational interventions that specifically target suicidal thoughts and behaviors. In our view, this is attributable to two factors. The first factor is our limited integration of neurocircuitry models with contemporary suicide theory. The second challenge is inherent to the variable nature of suicide risk over time. Few interventional neuroscience studies evaluate how temporal fluctuations in risk affect treatment, despite evidence that temporality is a key component distinguishing suicide phenotypes. To wit, individual variability in risk trajectories may provide different treatment targets to engage as a patient moves between suicidal ideation and attempt. Here, we first review contemporary ideation-to-action theories of suicide from a neurobiological perspective, focusing on valence and executive function circuits and the key role of state-induced (e.g., within stressful contexts) functional modulation on longitudinal risk trajectories. We then describe neural correlates of suicide reduction following various interventions, ranging from circuit specific (i.e., transcranial magnetic stimulation) to broader pharmacological (i.e., ketamine, lithium) to psychological (i.e., brief cognitive therapy). We then introduce novel strategies for tracking risk in naturalistic settings and real time using ecological momentary interventions. We provide a critical integration of the literature focusing on the intersection between targets and temporality, and we conclude by proposing novel research designs integrating real-time and biologically based interventions to generate novel strategies for future suicide reduction research.


Subject(s)
Cognitive Behavioral Therapy , Neurosciences , Suicide , Humans , Suicidal Ideation , Transcranial Magnetic Stimulation
9.
Neuromodulation ; 24(5): 930-937, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33650209

ABSTRACT

OBJECTIVES: Repetitive transcranial magnetic stimulation (TMS) is a promising treatment for suicidality, but it is underlying neural mechanisms remain poorly understood. Our prior findings indicated that frontostriatal functional connectivity correlates with the severity of suicidal thoughts and behaviors. In this secondary analysis of data from an open label trial, we evaluated whether changes in frontostriatal functional connectivity would accompany suicidality reductions following TMS. We also explored the relationship between frontostriatal connectivity change and underlying white matter (WM) organization. MATERIALS AND METHODS: We conducted seed-based functional connectivity analysis on participants (N = 25) with comorbid post-traumatic stress disorder and depression who received eight weeks of 5 Hz TMS to left dorsolateral prefrontal cortex. We measured clinical symptoms with the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and the PTSD Checklist for DSM-5 (PCL-5). We derived suicidality from IDS-SR item 18. Magnetic resonance imaging data were collected before TMS, and at treatment end point. These data were entered into analyses of covariance, evaluating the effect of suicidality change across treatment on striatal and thalamic functional connectivity. Changes in other PTSD and depression symptoms were included as covariates and results were corrected for multiple comparisons. Diffusion connectometry in a participant subsample (N = 17) explored the relationship between frontal WM integrity at treatment baseline and subsequent functional connectivity changes correlated with differences in suicidality. RESULTS: Suicidal ideation decreased in 65% of participants. Reductions in suicidality and functional connectivity between the dorsal striatum and frontopolar cortex were correlated (p-False Discover Rate-corrected < 0.001), after covariance for clinical symptom change. All other results were nonsignificant. Our connectometry results indicated that the integrity of frontostriatal WM may circumscribe functional connectivity response to TMS for suicide. CONCLUSIONS: Targeted reduction of fronto-striatal connectivity with TMS may be a promising treatment for suicidality. Future research can build on this multimodal approach to advance individualized stimulation approaches in high-risk patients.


Subject(s)
Stress Disorders, Post-Traumatic , Suicide , Humans , Magnetic Resonance Imaging , Prefrontal Cortex/diagnostic imaging , Transcranial Magnetic Stimulation
10.
Trials ; 21(1): 924, 2020 Nov 12.
Article in English | MEDLINE | ID: mdl-33183345

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.


Subject(s)
Cognitive Behavioral Therapy , Veterans , Humans , Randomized Controlled Trials as Topic , Suicidal Ideation , Suicide, Attempted , Transcranial Magnetic Stimulation
11.
Transl Psychiatry ; 10(1): 195, 2020 06 18.
Article in English | MEDLINE | ID: mdl-32555146

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.


Subject(s)
Stress Disorders, Post-Traumatic , Brain/diagnostic imaging , Brain Mapping , Diagnostic and Statistical Manual of Mental Disorders , Humans , Machine Learning , Magnetic Resonance Imaging , Stress Disorders, Post-Traumatic/diagnostic imaging
13.
J Psychiatr Res ; 125: 106-112, 2020 06.
Article in English | MEDLINE | ID: mdl-32251917

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.


Subject(s)
Suicide Prevention , Transcranial Magnetic Stimulation , Humans , Retrospective Studies , Suicidal Ideation
14.
Neuropsychopharmacology ; 45(6): 940-946, 2020 05.
Article in English | MEDLINE | ID: mdl-31794974

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.


Subject(s)
Stress Disorders, Post-Traumatic , Veterans , Adult , Cross-Over Studies , Female , Humans , Male , Middle Aged , Stress Disorders, Post-Traumatic/therapy , Theta Rhythm , Transcranial Magnetic Stimulation
15.
Depress Anxiety ; 36(11): 1047-1057, 2019 11.
Article in English | MEDLINE | ID: mdl-31475432

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.


Subject(s)
Depressive Disorder, Major/therapy , Stress Disorders, Post-Traumatic/therapy , Transcranial Magnetic Stimulation/methods , White Matter/physiology , Anisotropy , Comorbidity , Corpus Callosum , Depressive Disorder, Major/complications , Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Major/physiopathology , Diffusion Magnetic Resonance Imaging , Female , Gyrus Cinguli , Humans , Male , Middle Aged , Nerve Net , Prefrontal Cortex , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/diagnostic imaging , Stress Disorders, Post-Traumatic/physiopathology , Treatment Outcome , White Matter/diagnostic imaging
16.
Am J Psychiatry ; 176(11): 939-948, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31230462

ABSTRACT

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder associated with disruption in social and occupational function. Transcranial magnetic stimulation (TMS) represents a novel approach to PTSD, and intermittent theta-burst stimulation (iTBS) is a new, more rapid administration protocol with data supporting efficacy in depression. The authors conducted a sham-controlled study of iTBS for PTSD. METHODS: Fifty veterans with PTSD received 10 days of sham-controlled iTBS (1,800 pulses/day), followed by 10 unblinded sessions. Primary outcome measures included acceptability (retention rates), changes in PTSD symptoms (clinician- and self-rated), quality of life, social and occupational function, and depression, obtained at the end of 2 weeks; analysis of variance was used to compare active with sham stimulation. Secondary outcomes were evaluated 1 month after treatment, using mixed-model analyses. Resting-state functional MRI was acquired at pretreatment baseline on an eligible subset of participants (N=26) to identify response predictors. RESULTS: Retention was high, side effects were consistent with standard TMS, and blinding was successful. At 2 weeks, active iTBS was significantly associated with improved social and occupational function (Cohen's d=0.39); depression was improved with iTBS compared with the sham treatment (d=-0.45), but the difference fell short of significance, and moderate nonsignificant effect sizes were observed on self-reported PTSD symptoms (d=-0.34). One-month outcomes, which incorporated data from the unblinded phase of the study, indicated superiority of active iTBS on clinician- and self-rated PTSD symptoms (d=-0.74 and -0.63, respectively), depression (d=-0.47), and social and occupational function (d=0.93) (all significant). Neuroimaging indicated that clinical improvement was significantly predicted by stronger (greater positive) connectivity within the default mode network and by anticorrelated (greater negative) cross-network connectivity. CONCLUSIONS: iTBS appears to be a promising new treatment for PTSD. Most clinical improvements from stimulation occurred early, which suggests a need for further investigation of optimal iTBS time course and duration. Consistent with previous neuroimaging studies of TMS, default mode network connectivity played an important role in response prediction.


Subject(s)
Stress Disorders, Post-Traumatic/therapy , Theta Rhythm , Transcranial Magnetic Stimulation/methods , Depression/complications , Depression/therapy , Double-Blind Method , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Patient Acceptance of Health Care/statistics & numerical data , Quality of Life , Social Behavior , Stress Disorders, Post-Traumatic/complications , Transcranial Magnetic Stimulation/adverse effects , Treatment Outcome
17.
Front Psychiatry ; 10: 44, 2019.
Article in English | MEDLINE | ID: mdl-30809160

ABSTRACT

In depression, brain and behavioral correlates of decision-making differ between individuals with and without suicidal thoughts and behaviors. Though promising, it remains unknown if these potential biomarkers of suicidality will generalize to other high-risk clinical populations. To preliminarily assess whether brain structure or function tracked suicidality in individuals with posttraumatic stress disorder (PTSD), we measured resting-state functional connectivity and cortical thickness in two functional networks involved in decision-making, a ventral fronto-striatal reward network and a lateral frontal cognitive control network. Neuroimaging data and self-reported suicidality ratings, and suicide-related hospitalization data were obtained from 50 outpatients with PTSD and also from 15 healthy controls, and all were subjected to seed-based resting-state functional connectivity and cortical thickness analyses using a priori seeds from reward and cognitive control networks. First, general linear models (GLM) were used to evaluate whether ROI-to-ROI functional connectivity was predictive of self-reported suicidality after false discovery rate (FDR)-correction for multiple comparisons and covariance of age and depression symptoms. Next, regional cortical thickness statistics were included as predictors of ROI-to-ROI functional connectivity in follow-up GLMs evaluating structure-function relationships. Functional connectivity between reward regions was positively correlated with suicidality (p-FDR ≤ 0.05). Functional connectivity of the lateral pars orbitalis to anterior cingulate/paracingulate control regions also tracked suicidality (p-FDR ≤ 0.05). Furthermore, cortical thickness in anterior cingulate/paracingulate was associated with functional correlates of suicidality in the control network (p-FDR < 0.05). These results provide a preliminary demonstration that biomarkers of suicidality in decision-making networks observed in depression may generalize to PTSD and highlight the promise of these circuits as transdiagnostic biomarkers of suicidality.

18.
Brain Connect ; 8(9): 549-557, 2018 11.
Article in English | MEDLINE | ID: mdl-30398386

ABSTRACT

Posttraumatic stress disorder (PTSD) is associated with disrupted functional connectivity in multiple neural networks. Multinetwork models of PTSD hypothesize that aberrant regional connectivity emerges from broad network-level disruptions. However, few studies have tested how characteristics of network-level organization influence regional functional connectivity in PTSD. This gap in knowledge impacts both our understanding of the pathophysiology of the disorder and the development of network-targeted PTSD treatments. We acquired resting-state imaging from a naturalistic sample of patients with PTSD (n = 42) and healthy controls (n = 42). Group differences in functional connectivity were identified using region of interest analyses and estimations of within- and between neural network activity; PTSD patients demonstrated reduced amygdala-orbitofrontal connectivity and increased default mode network (DMN) connectivity compared with controls. We then used convergence-a novel measure representing the capacity for functional integration-to test whether differences in functional architecture underlie connectivity signatures of PTSD. This approach found that reduced frontoparietal network (FPN) convergence was associated with reduced amygdala-orbitofrontal connectivity. Furthermore, in controls only, increased DMN convergence was associated with reduced DMN-to-salience network connectivity, and increased FPN convergence was associated with reduced FPN-to-ventral attention network connectivity. These results suggest that FPN functional architecture may underlie insufficiencies in top-down control in PTSD, with results broadly supporting the notion that networks' functional architecture influences the breakdown of normative functional relationships in PTSD. This work also indicates the potential of convergence to be applied to clinical populations in future research studies.


Subject(s)
Brain/physiopathology , Nerve Net/physiopathology , Stress Disorders, Post-Traumatic/physiopathology , Adult , Amygdala/physiology , Amygdala/physiopathology , Attention/physiology , Brain Mapping/methods , Connectome , Female , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neural Pathways/physiopathology , Prefrontal Cortex/physiopathology , Rest/physiology
19.
Article in English | MEDLINE | ID: mdl-29486862

ABSTRACT

Research into therapeutic transcranial magnetic stimulation (TMS) for major depression has dramatically increased in the last decade. Understanding the mechanism of action of TMS is crucial to improve efficacy and develop the next generation of therapeutic stimulation. Early imaging research provided initial data supportive of widely held assumptions about hypothesized inhibitory or excitatory consequences of stimulation. Early work also indicated that while TMS modulated brain activity under the stimulation site, effects at deeper regions, in particular, the subgenual anterior cingulate cortex, were associated with clinical improvement. Concordant with earlier findings, functional connectivity studies also demonstrated that clinical improvements were related to changes distal, rather than proximal, to the site of stimulation. Moreover, recent work suggests that TMS modulates and potentially normalizes functional relationships between neural networks. An important observation that emerged from this review is that similar patterns of connectivity changes are observed across studies regardless of TMS parameters. Though promising, we stress that these imaging findings must be evaluated cautiously given the widespread reliance on modest sample sizes and little implementation of statistical validation. Additional limitations included use of imaging before and after a course of TMS, which provided little insight into changes that might occur during the weeks of stimulation. Furthermore, as studies to date have focused on depression, it is unclear whether our observations were related to mechanisms of action of TMS for depression or represented broader patterns of functional brain changes associated with clinical improvement.


Subject(s)
Brain/diagnostic imaging , Depressive Disorder, Major/therapy , Neuroimaging/methods , Transcranial Magnetic Stimulation/methods , Brain Mapping , Depressive Disorder, Major/diagnostic imaging , Humans
20.
Biol Psychiatry ; 83(3): 263-272, 2018 02 01.
Article in English | MEDLINE | ID: mdl-28886760

ABSTRACT

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) therapy can modulate pathological neural network functional connectivity in major depressive disorder (MDD). Posttraumatic stress disorder is often comorbid with MDD, and symptoms of both disorders can be alleviated with TMS therapy. This is the first study to evaluate TMS-associated changes in connectivity in patients with comorbid posttraumatic stress disorder and MDD. METHODS: Resting-state functional connectivity magnetic resonance imaging was acquired before and after TMS therapy in 33 adult outpatients in a prospective open trial. TMS at 5 Hz was delivered, in up to 40 daily sessions, to the left dorsolateral prefrontal cortex. Analyses used a priori seeds relevant to TMS, posttraumatic stress disorder, or MDD (subgenual anterior cingulate cortex [sgACC], left dorsolateral prefrontal cortex, hippocampus, and basolateral amygdala) to identify imaging predictors of response and to evaluate clinically relevant changes in connectivity after TMS, followed by leave-one-out cross-validation. Imaging results were explored using data-driven multivoxel pattern activation. RESULTS: More negative pretreatment connectivity between the sgACC and the default mode network predicted clinical improvement, as did more positive amygdala-to-ventromedial prefrontal cortex connectivity. After TMS, symptom reduction was associated with reduced connectivity between the sgACC and the default mode network, left dorsolateral prefrontal cortex, and insula, and reduced connectivity between the hippocampus and the salience network. Multivoxel pattern activation confirmed seed-based predictors and correlates of treatment outcomes. CONCLUSIONS: These results highlight the central role of the sgACC, default mode network, and salience network as predictors of TMS response and suggest their involvement in mechanisms of action. Furthermore, this work indicates that there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders.


Subject(s)
Cerebral Cortex/physiopathology , Connectome/methods , Depressive Disorder, Major/physiopathology , Nerve Net/physiopathology , Stress Disorders, Post-Traumatic/physiopathology , Transcranial Magnetic Stimulation/methods , Adult , Depressive Disorder, Major/therapy , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Stress Disorders, Post-Traumatic/therapy , Treatment Outcome
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