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  1. Article: Cingulate-mediated depressive symptoms in neurologic disease and therapeutics.

    Riva-Posse, Patricio / Holtzheimer, Paul E / Mayberg, Helen S

    Handbook of clinical neurology

    2020  Volume 166, Page(s) 371–379

    Abstract: The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially ... ...

    Abstract The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially showing volumetric changes, followed by the insights that functional imaging and physiology contributed to neuroscience and psychiatry, the distinct areas of the cingulate subdivisions were seen to have unique contributions. The subcallosal cingulate, with its functional responsivity to mood states and to antidepressant therapies, has been identified as a central node within the mood regulation network. In this chapter, detailed descriptions of the anatomic and functional changes that are seen in depression will be discussed. Finally, a focus on the development of deep brain stimulation in the subcallosal cingulate area will be used to emphasize the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed to treat depression.
    MeSH term(s) Animals ; Deep Brain Stimulation/methods ; Depression/pathology ; Depression/physiopathology ; Depression/therapy ; Gyrus Cinguli/pathology ; Gyrus Cinguli/physiopathology ; Humans
    Language English
    Publishing date 2020-01-08
    Publishing country Netherlands
    Document type Journal Article ; Review
    ISSN 0072-9752
    ISSN 0072-9752
    DOI 10.1016/B978-0-444-64196-0.00021-2
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  2. Article ; Online: Defining Treatment-Resistant Posttraumatic Stress Disorder: A Framework for Future Research.

    Sippel, Lauren M / Holtzheimer, Paul E / Friedman, Matthew J / Schnurr, Paula P

    Biological psychiatry

    2018  Volume 84, Issue 5, Page(s) e37–e41

    MeSH term(s) Biomedical Research ; Humans ; Practice Guidelines as Topic ; Stress Disorders, Post-Traumatic/classification ; Stress Disorders, Post-Traumatic/diagnosis ; Stress Disorders, Post-Traumatic/therapy ; Treatment Outcome
    Language English
    Publishing date 2018-04-10
    Publishing country United States
    Document type Letter
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2018.03.011
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    Zs.A 720: Show issues Location:
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  3. Article ; Online: Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

    Cha, Jungho / Choi, Ki Sueng / Rajendra, Justin K / McGrath, Callie L / Riva-Posse, Patricio / Holtzheimer, Paul E / Figee, Martijn / Kopell, Brian H / Mayberg, Helen S

    Molecular psychiatry

    2023  

    Abstract: Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed ... ...

    Abstract Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.
    Language English
    Publishing date 2023-11-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-023-02306-6
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    Zs.A 4812: Show issues Location:
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  4. Article ; Online: The Management of Posttraumatic Stress Disorder and Acute Stress Disorder: Synopsis of the 2023 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

    Schnurr, Paula P / Hamblen, Jessica L / Wolf, Jonathan / Coller, Rachael / Collie, Claire / Fuller, Matthew A / Holtzheimer, Paul E / Kelly, Ursula / Lang, Ariel J / McGraw, Kate / Morganstein, Joshua C / Norman, Sonya B / Papke, Katie / Petrakis, Ismene / Riggs, David / Sall, James A / Shiner, Brian / Wiechers, Ilse / Kelber, Marija S

    Annals of internal medicine

    2024  Volume 177, Issue 3, Page(s) 363–374

    Abstract: Description: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article ... ...

    Abstract Description: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against.
    Methods: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed.
    Recommendations: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life.
    MeSH term(s) Humans ; United States ; Stress Disorders, Post-Traumatic/therapy ; Stress Disorders, Traumatic, Acute ; Veterans/psychology ; Quality of Life ; Psychotherapy ; United States Department of Veterans Affairs
    Language English
    Publishing date 2024-02-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 336-0
    ISSN 1539-3704 ; 0003-4819
    ISSN (online) 1539-3704
    ISSN 0003-4819
    DOI 10.7326/M23-2757
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  5. Article ; Online: Neurocognitive mechanisms of poor social connection in posttraumatic stress disorder: Evidence for abnormalities in social working memory.

    Sippel, Lauren M / Holtzheimer, Paul E / Huckins, Jeremy F / Collier, Eleanor / Feilong, Ma / Wheatley, Thalia / Meyer, Meghan L

    Depression and anxiety

    2021  Volume 38, Issue 6, Page(s) 615–625

    Abstract: ... We examined recruitment of the default network and behavioral responses during social working memory (SWM; i.e ... e.g., loneliness, social network size).: Results: Compared to trauma-exposed controls ... individuals with PTSD reported smaller social networks (p = .032) and greater loneliness (p = .038 ...

    Abstract Background: Poor social connection is a central feature of posttraumatic stress disorder (PTSD), but little is known about the neurocognitive processes associated with social difficulties in this population. We examined recruitment of the default network and behavioral responses during social working memory (SWM; i.e., maintaining and manipulating social information on a moment-to-moment basis) in relation to PTSD and social connection.
    Methods: Participants with PTSD (n = 31) and a trauma-exposed control group (n = 21) underwent functional magnetic resonance imaging while completing a task in which they reasoned about two or four people's relationships in working memory (social condition) and alphabetized two or four people's names in working memory (nonsocial condition). Participants also completed measures of social connection (e.g., loneliness, social network size).
    Results: Compared to trauma-exposed controls, individuals with PTSD reported smaller social networks (p = .032) and greater loneliness (p = .038). Individuals with PTSD showed a selective deficit in SWM accuracy (p = .029) and hyperactivation in the default network, particularly in the dorsomedial subsystem, on trials with four relationships to consider. Moreover, default network hyperactivation in the PTSD group (vs. trauma-exposed group) differentially related to social network size and loneliness (p's < .05). Participants with PTSD also showed less resting state functional connectivity within the dorsomedial subsystem than controls (p = .002), suggesting differences in the functional integrity of a subsystem key to SWM.
    Conclusions: SWM abnormalities in the default network may be a basic mechanism underlying poorer social connection in PTSD.
    MeSH term(s) Humans ; Loneliness ; Magnetic Resonance Imaging ; Memory, Short-Term ; Stress Disorders, Post-Traumatic/diagnostic imaging
    Language English
    Publishing date 2021-02-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1378635-0
    ISSN 1520-6394 ; 1091-4269
    ISSN (online) 1520-6394
    ISSN 1091-4269
    DOI 10.1002/da.23139
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    Zs.A 3823: Show issues Location:
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  6. Article ; Online: Prefrontal transcranial magnetic stimulation for depression in US military veterans - A naturalistic cohort study in the veterans health administration.

    Madore, Michelle R / Kozel, F Andrew / Williams, Leanne M / Green, L Chauncey / George, Mark S / Holtzheimer, Paul E / Yesavage, Jerome A / Philip, Noah S

    Journal of affective disorders

    2021  Volume 297, Page(s) 671–678

    Abstract: ... level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral ... all p<.001) reductions in MDD and PTSD. Of the 340 veterans who received an adequate dose, MDD response ...

    Abstract Background: Repetitive transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD), however, the evidence in veterans has been mixed. To this end, VA implemented a nationwide TMS program that included evaluating clinical outcomes within a naturalistic design. TMS was hypothesized to be safe and provide clinically meaningful reductions in MDD and posttraumatic stress disorder (PTSD) symptoms.
    Methods: Inclusion criteria were MDD diagnosis and standard clinical TMS eligibility. Of the 770 patients enrolled between October 2017 and March 2020, 68.4% (n = 521) met threshold-level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral prefrontal cortex, 120% motor threshold, 10 Hz, 3000 pulses/treatment). Adequate dose was operationally defined as 30 sessions. MDD and PTSD symptoms were measured using the 9-item patient health questionnaire (PHQ-9) and PTSD checklist for DSM-5 (PCL-5), respectively.
    Results: Of the 770 who received at least one session, TMS was associated with clinically meaningful (Cohen's d>1.0) and statistically significant (all p<.001) reductions in MDD and PTSD. Of the 340 veterans who received an adequate dose, MDD response and remission rates were 41.4% and 20%, respectively. In veterans with comorbid PTSD, 65.3% demonstrated clinically meaningful reduction and 46.1% no longer met PTSD threshold criteria after TMS. Side effects were consistent with the known safety profile of TMS.
    Limitations: Include those inherent to retrospective observational cohort study in Veterans.
    Conclusions: These multisite, large-scale data supports the effectiveness and safety of TMS for veterans with MDD and PTSD using standard clinical approaches.
    MeSH term(s) Cohort Studies ; Depression ; Depressive Disorder, Major/therapy ; Dorsolateral Prefrontal Cortex ; Humans ; Prefrontal Cortex ; Retrospective Studies ; Stress Disorders, Post-Traumatic/therapy ; Transcranial Magnetic Stimulation ; Treatment Outcome ; Veterans ; Veterans Health
    Language English
    Publishing date 2021-10-20
    Publishing country Netherlands
    Document type Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 135449-8
    ISSN 1573-2517 ; 0165-0327
    ISSN (online) 1573-2517
    ISSN 0165-0327
    DOI 10.1016/j.jad.2021.10.025
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    Zs.A 1485: Show issues Location:
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  7. Article ; Online: Effects of Left Versus Right Dorsolateral Prefrontal Cortex Repetitive Transcranial Magnetic Stimulation on Affective Flexibility in Healthy Women: A Pilot Study.

    Lantrip, Crystal / Delaloye, Sibylle / Baird, Lauren / Dreyer-Oren, Sarah / Brady, Robert E / Roth, Robert M / Gunning, Faith / Holtzheimer, Paul

    Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology

    2019  Volume 32, Issue 2, Page(s) 69–75

    Abstract: ... nonaffective switch costs, the interaction effect in the two-way ANOVA was not significant (F1,19=3.053, P=0 ... nonaffective switch costs significantly improved immediately after left rTMS (t1,19=2.664, P=0.015) but not ...

    Abstract Objective: To determine the antidepressant mechanism of action for repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) in healthy women. Our primary hypothesis was that a single session of left DLPFC rTMS, compared with a session of right DLPFC rTMS, would result in better (reduced) negative nonaffective switch costs in healthy women.
    Background: The antidepressant mechanism of action for rTMS is not clear. It is possible that rTMS to the DLPFC improves emotion regulation, which could be a part of its antidepressant mechanism.
    Methods: Twenty-five healthy women were randomized to receive left high-frequency (HF) rTMS versus right HF rTMS in one session and then contralateral stimulation during a second session. Emotion regulation was assessed via switch costs for reappraisal of negatively valenced information on an affective flexibility task.
    Results: For negative nonaffective switch costs, the interaction effect in the two-way ANOVA was not significant (F1,19=3.053, P=0.097). Given that left HF rTMS is the approved treatment for depression, post hoc t tests were completed with particular interest in the left-side findings. These tests confirmed that negative nonaffective switch costs significantly improved immediately after left rTMS (t1,19=2.664, P=0.015) but not right rTMS.
    Conclusions: These findings suggest that left DLPFC HF rTMS may lead to antidepressant effects by improving the regulation of emotion.
    MeSH term(s) Adult ; Affect/physiology ; Emotions/physiology ; Female ; Functional Laterality/physiology ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Photic Stimulation/methods ; Pilot Projects ; Prefrontal Cortex/physiology ; Transcranial Magnetic Stimulation/methods ; Young Adult
    Language English
    Publishing date 2019-06-17
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108112-8
    ISSN 1543-3641 ; 1543-3633
    ISSN (online) 1543-3641
    ISSN 1543-3633
    DOI 10.1097/WNN.0000000000000190
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    Zs.A 2439: Show issues Location:
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  8. Article ; Online: Rapid Antidepressant Effects of Deep Brain Stimulation and Their Relation to Surgical Protocol.

    Riva-Posse, Patricio / Crowell, Andrea L / Wright, Kathryn / Waters, Allison C / Choi, KiSueng / Garlow, Steven J / Holtzheimer, Paul E / Gross, Robert E / Mayberg, Helen S

    Biological psychiatry

    2020  Volume 88, Issue 8, Page(s) e37–e39

    MeSH term(s) Antidepressive Agents/therapeutic use ; Deep Brain Stimulation ; Depression
    Chemical Substances Antidepressive Agents
    Language English
    Publishing date 2020-05-14
    Publishing country United States
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2020.03.017
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  9. Article ; Online: Novel targets for antidepressant therapies.

    Holtzheimer, Paul E / Nemeroff, Charles B

    Current psychiatry reports

    2008  Volume 10, Issue 6, Page(s) 465–473

    Abstract: ... corticotropin-releasing factor-1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, N ...

    Abstract Most depressed patients fail to achieve remission despite adequate antidepressant monotherapy, and a substantial minority show minimal improvement despite optimal and aggressive therapy. However, major advances have taken place in elucidating the neurobiology of depression, and several novel targets for antidepressant therapy have emerged. Three primary approaches are currently being taken: 1) optimizing the pharmacologic modulation of monoaminergic neurotransmission, 2) developing medications that target neurotransmitter systems other than the monoamines, and 3) directly modulating neuronal activity via focal brain stimulation. We review novel therapeutic targets for developing improved antidepressant therapies, including triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, dopamine receptor agonists, corticotropin-releasing factor-1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, N-methyl-D-aspartate receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Developments in therapeutic focal brain stimulation include vagus nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, and deep brain stimulation.
    MeSH term(s) Antidepressive Agents/adverse effects ; Antidepressive Agents/therapeutic use ; Antipsychotic Agents/adverse effects ; Antipsychotic Agents/therapeutic use ; Biogenic Monoamines/metabolism ; Brain/drug effects ; Brain/physiopathology ; Deep Brain Stimulation ; Depressive Disorder, Major/physiopathology ; Depressive Disorder, Major/therapy ; Drug Therapy, Combination ; Drugs, Investigational/adverse effects ; Drugs, Investigational/therapeutic use ; Electroconvulsive Therapy ; Humans ; Receptors, Neurotransmitter/drug effects ; Transcranial Magnetic Stimulation ; Vagus Nerve Stimulation
    Chemical Substances Antidepressive Agents ; Antipsychotic Agents ; Biogenic Monoamines ; Drugs, Investigational ; Receptors, Neurotransmitter
    Language English
    Publishing date 2008-10-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2055376-6
    ISSN 1535-1645 ; 1523-3812
    ISSN (online) 1535-1645
    ISSN 1523-3812
    DOI 10.1007/s11920-008-0075-5
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  10. Article: Causal Factors of Anxiety and Depression in College Students: Longitudinal Ecological Momentary Assessment and Causal Analysis Using Peter and Clark Momentary Conditional Independence.

    Huckins, Jeremy F / DaSilva, Alex W / Hedlund, Elin L / Murphy, Eilis I / Rogers, Courtney / Wang, Weichen / Obuchi, Mikio / Holtzheimer, Paul E / Wagner, Dylan D / Campbell, Andrew T

    JMIR mental health

    2020  Volume 7, Issue 6, Page(s) e16684

    Abstract: ... All reported results are significant at P<.001 unless otherwise stated. Depression was causally influenced ...

    Abstract Background: Across college campuses, the prevalence of clinically relevant depression or anxiety is affecting more than 27% of the college population at some point between entry to college and graduation. Stress and self-esteem have both been hypothesized to contribute to depression and anxiety levels. Although contemporaneous relationships between these variables have been well-defined, the causal relationship between these mental health factors is not well understood, as frequent sampling can be invasive, and many of the current causal techniques are not well suited to investigate correlated variables.
    Objective: This study aims to characterize the causal and contemporaneous networks between these critical mental health factors in a cohort of first-year college students and then determine if observed results replicate in a second, distinct cohort.
    Methods: Ecological momentary assessments of depression, anxiety, stress, and self-esteem were obtained weekly from two cohorts of first-year college students for 40 weeks (1 academic year). We used the Peter and Clark Momentary Conditional Independence algorithm to identify the contemporaneous (t) and causal (t-1) network structures between these mental health metrics.
    Results: All reported results are significant at P<.001 unless otherwise stated. Depression was causally influenced by self-esteem (t-1 r
    Conclusions: This paper is an initial attempt to describe the contemporaneous and causal relationships among these four mental health metrics in college students. We replicated previous research identifying concurrent relationships between these variables and extended them by identifying causal links among these metrics. These results provide support for the vulnerability model of depression and anxiety. Understanding how causal factors impact the evolution of these mental states over time may provide key information for targeted treatment or, perhaps more importantly, preventative interventions for individuals at risk for depression and anxiety.
    Language English
    Publishing date 2020-06-10
    Publishing country Canada
    Document type Journal Article
    ISSN 2368-7959
    ISSN 2368-7959
    DOI 10.2196/16684
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