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1. Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report

Author

Charles R. Conway, Scott T. Aaronson, Harold A. Sackeim, Walter Duffy, Mary Stedman, João Quevedo, Rebecca M. Allen, Patricio Riva-Posse, Matthew A. Berger, Gustavo Alva, Mohd Azfar Malik, David L. Dunner, Ivan Cichowicz, Heather Luing, John Zajecka, Ziad Nahas, Brian J. Mickey, Anita S. Kablinger, Christopher L. Kriedt, Mark T. Bunker, Ying-Chieh (Lisa) Lee, Olivia Shy, Shannon Majewski, Bryan Olin, Quyen Tran, and A. John Rush

Subjects
Electroconvulsive therapy, Esketamine, RECOVER trial, Transcranial magnetic stimulation (TMS), Treatment-resistant depression (TRD), Vagus nerve stimulation (VNS), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. Objective: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. Methods: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). Results: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. Conclusions: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. Trial registration: ClinicalTrials.gov Identifier NCT03887715.

Published
2024
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2. Effects of TMS on anhedonia and suicidal ideation in treatment-resistant depression: Outcomes from the University of Minnesota Interventional Psychiatry Program

Author

A. Irem Sonmez, Ryan Webler, Alyssa M. Krueger, Clara Godoy-Henderson, Christi Sullivan, Saydra Wilson, Sarah Olsen, Sabine Schmid, Alexander Herman, Alik Widge, Carol Peterson, Ziad Nahas, and C. Sophia Albott

Subjects
Transcranial magnetic stimulation (TMS), Treatment-resistant depression (TRD), Anhedonia, Suicidal ideation, Mental healing, RZ400-408, Psychiatry, RC435-571
Abstract

Background: A developing literature suggests that transcranial magnetic stimulation (TMS) can target anhedonia and suicidal ideation (SI), core symptoms of treatment-resistant depression (TRD). This present naturalistic study extends the existing literature by investigating the connection between changes in anhedonia and suicidal ideation (SI) related to transcranial magnetic stimulation (TMS), independent of any overall changes in depression. Methods: Pre and post treatment PHQ-9 and IDS-SR data were collected from 181 TRD patients who received dorsolateral prefrontal cortex ( dlPFC) TMS using the Figure-8 or H1-coil. Changes in overall depression symptoms, anhedonia, and SI were analyzed using chi square tests, repeated measure ANOVAS, and linear regression for repeated measures. Results: TMS yielded changes in overall depression symptoms (PHQ-9 Cohen’s d = 1.02; IDS-SR Cohen’s d = 1.05), with 23.9 % and 41.7 % of patients experiencing response as measured by IDS-SR and PHQ-9, respectively. TMS treatment was also associated with large changes in both anhedonia (d = 1.03) and SI (d = 0.88), which were similar in magnitude to changes in all other depression symptoms (d = 0.97). Importantly, changes in anhedonia predicted changes in SI, even after controlling for baseline depression severity and change in other depression symptoms. Limitations: The lack of a control arm and a neuroimaging measure temper mechanistic conclusion. Conclusion: Our results reinforce the effectiveness of TMS in TRD and provide new evidence that anhedonia and SI may belong to a broader symptom cluster potentially undergirded by a shared circuitry accessible to dlPFC TMS.

Published
2024
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3. Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping–Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms

Author

Ryan D. Webler, Cristian Morales Carrasco, Samuel E. Cooper, Mo Chen, Christopher O. Hunt, Sierra Hennessy, Lancy Cao, Carol Lam, Allen Chiu, Cash Differding, Erin Todd, Timothy J. Hendrickson, Desmond J. Oathes, Alik S. Widge, Robert J.M. Hermosillo, Steven M. Nelson, Damien A. Fair, Shmuel M. Lissek, and Ziad Nahas

Subjects
Fear conditioning, Fear generalization, Hippocampal network–targeted TMS, Hippocampus, Precision functional mapping, TMS, Psychiatry, RC435-571
Abstract

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network–targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: β = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: β = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Published
2024
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4. DLPFC stimulation alters working memory related activations and performance: An interleaved TMS-fMRI study

Author

Ryan D. Webler, James Fox, Lisa M. McTeague, Philip C. Burton, Logan Dowdle, Edward Baron Short, Jeffrey J. Borckardt, Xingbao Li, Mark S. George, and Ziad Nahas

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Findings from correlative neuroimaging studies link increased frontoparietal network (FPN) activation and default mode network (DMN) deactivation to enhanced high cognitive demand processing. To causally investigate FPN-DMN contributions to high cognitive demand processing, the current interleaved TMS-fMRI study simultaneously manipulated and indexed neural activity while tracking cognitive performance during high and low cognitive load conditions. Methods: Twenty participants completed an n-back task consisting of four conditions (0-back, 0-backTMS, 2-back, 2-backTMS) while undergoing interleaved TMS-fMRI. During TMS concurrent with n-back blocks, TMS single pulses were delivered to the left DLPFC at 100% motor-threshold every 2.4s. Results: TMS delivered during high cognitive load strengthened cognitive processing. FPN node activations and DMN node deactivations were increased in the high versus low cognitive load TMS condition. Contrary to our hypothesis, TMS did not increase high load related activation in FPN nodes. However, as hypothesized, increased DMN node deactivations emerged as a function of TMS during high load (right angular gyrus) and from interactions between cognitive load and TMS (right middle temporal gyrus). Load and TMS combined to dampen activation within the DMN at trend level (p = .058). Deactivation in a dorsomedial DMN node was associated with TMS driven improvements in high load cognitive processing. Conclusions: Exogenous perturbation of the DLPFC via single pulse TMS amplified DMN node deactivations and enhanced high cognitive demand processing. Neurobehavioral findings linking these effects hint at a promising, albeit preliminary, cognitive control substrate requiring replication in higher-powered studies that use control stimulation.

Published
2022
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6. Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: A prefrontal interleaved TMS fMRI study

Author

Ryan D. Webler, Carmen Hamady, Chris Molnar, Kevin Johnson, Leo Bonilha, Berry S. Anderson, Claartje Bruin, Daryl E. Bohning, Mark S. George, and Ziad Nahas

Subjects
Interleaved TMS fMRI, Prefrontal cortex, Schizophrenia, Functional connectivity, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: Prefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia. Objective: /Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity. Methods: We enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10 Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition. Results: Of the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p = 0.0157; max z-score = 4.7) and neighboring BA46 (p = 0.019; max z-score = 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p = 0.02; max z-score = 3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p = 0.004). Conclusions: Subjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia.

Published
2020
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9. Sustained Activation of the Anterior Thalamic Neurons with Low Doses of Kainic Acid Boosts Hippocampal Neurogenesis

Author

Farah Chamaa, Batoul Darwish, Rami Arnaout, Ziad Nahas, Elie D. Al-Chaer, Nayef E. Saadé, and Wassim Abou-Kheir

Subjects
kainic acid stimulation, neurogenesis, hippocampus, stem/progenitor cells, anterior nucleus, dexamethasone, Cytology, QH573-671
Abstract

Adult hippocampal neurogenesis is prone to modulation by several intrinsic and extrinsic factors. The anterior nucleus (AN) of the thalamus has extensive connections with the hippocampus, and stimulation of this region may play a role in altering neurogenesis. We have previously shown that electrical stimulation of the AN can substantially boost hippocampal neurogenesis in adult rats. Here, we performed selective unilateral chemical excitation of the cell bodies of the AN as it offers a more specific and sustained stimulation when compared to electrical stimulation. Our aim is to investigate the long-term effects of KA stimulation of the AN on baseline hippocampal proliferation of neural stem cells and neurogenesis. Continuous micro-perfusion of very low doses of kainic acid (KA) was administered into the right AN for seven days. Afterwards, adult male rats received 5′-bromo-2′-deoxyuridine (BrdU) injections (200 mg/kg, i.p) and were euthanized at either one week or four weeks post micro-perfusion. Open field and Y-maze tests were performed before euthanasia. The KA stimulation of the AN evoked sustained hippocampal neurogenesis that was associated with improved spatial memory in the Y-maze test. Administering dexamethasone prior to and simultaneously with the KA stimulation decreased both the hippocampal neurogenesis and the improved spatial recognition memory previously seen in the Y-maze test. These results suggest that hippocampal neurogenesis may be a downstream effect of stimulation in general, and of excitation of the cell bodies of the AN in particular, and that stimulation of that area improves spatial memory in rats.

Published
2022
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10. A narrative review on invasive brain stimulation for treatment-resistant depression

Author

Manoj P. Dandekar, Alexandre P. Diaz, Ziaur Rahman, Ritele H. Silva, Ziad Nahas, Scott Aaronson, Sudhakar Selvaraj, Albert J. Fenoy, Marsal Sanches, Jair C. Soares, Patricio Riva-Posse, and Joao Quevedo

Subjects
Treatment-resistant depression, deep brain stimulation, vagus nerve stimulation, epidural cortical stimulation subcallosal cingulate gyrus, medial forebrain bundle, Psychiatry, RC435-571
Abstract

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Published
2021
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11. The relationship between clinical insight and cognitive and affective empathy in schizophrenia

Author

Mia Atoui, Fatima El Jamil, Joseph El Khoury, Mark Doumit, Nathalie Syriani, Munir Khani, and Ziad Nahas

Subjects
Cognitive empathy, Affective empathy, Clinical insight, Perspective taking, Personal distress, Empathic concern, Fantasy, Symptomatology, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Schizophrenia is often associated with poor clinical insight (unawareness of mental illness and its symptoms) and deficits in empathy, which are important for social functioning. Cognitive empathy has been linked to clinical insight while affective empathy and its role in insight and pathology have received mixed evidence. Methods: Instruments assessing symptomatology (Positive and Negative Syndrome Scale; PANSS), clinical insight (Scales to assess awareness of mental disorders; SUMD), and cognitive and affective empathy were administered to 22 participants with first episode and chronic schizophrenia and 21 healthy controls. Self-report, parent-report, and performance based measures were used to assess cognitive and affective empathy (The interpersonal reactivity index; IRI/Reading the Mind in the Eyes Test/Faux Pas) to reduce bias and parse shared variance. Results: Age of onset, gender, and symptomatology emerged as significant predictors of poor clinical insight. Additionally, the fantasy subscale of the IRI as reported by parents emerged as a positive predictor while the personal distress (parent report) subscale emerged as a negative predictor of awareness into mental illness. There were significant differences on performance-based measures of empathy between the control and schizophrenia groups. Conclusion: Findings suggest that affective empathy is relatively intact across phases of illness whereas cognitive empathy abilities are compromised and could be targets for psychotherapy intervention.

Published
2018
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12. Personalizing Dual-Target Cortical Stimulation with Bayesian Parameter Optimization Successfully Treats Central Post-Stroke Pain: A Case Report

Author

Evan M. Dastin-van Rijn, Seth D. König, Danielle Carlson, Vasudha Goel, Andrew Grande, Donald R. Nixdorf, Sarah Benish, Alik S. Widge, Ziad Nahas, Michael C. Park, Tay I. Netoff, Alexander B. Herman, and David P. Darrow

Subjects
cortical stimulation, stroke, chronic pain, electrophysiology, optimization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Central pain disorders, such as central post-stroke pain, remain clinically challenging to treat, despite many decades of pharmacological advances and the evolution of neuromodulation. For treatment refractory cases, previous studies have highlighted some benefits of cortical stimulation. Recent advances in new targets for pain and the optimization of neuromodulation encouraged our group to develop a dual cortical target approach paired with Bayesian optimization to provide a personalized treatment. Here, we present a case report of a woman who developed left-sided facial pain after multiple thalamic strokes. All previous pharmacologic and interventional treatments failed to mitigate the pain, leaving her incapacitated due to pain and medication side effects. She subsequently underwent a single burr hole for placement of motor cortex (M1) and dorsolateral prefrontal cortex (dlPFC) paddles for stimulation with externalization. By using Bayesian optimization to find optimal stimulation parameters and stimulation sites, we were able to reduce pain from an 8.5/10 to a 0/10 during a 5-day inpatient stay, with pain staying at or below a 2/10 one-month post-procedure. We found optimal treatment to be simultaneous stimulation of M1 and dlPFC without any evidence of seizure induction. In addition, we found no worsening in cognitive performance during a working memory task with dlPFC stimulation. This personalized approach using Bayesian optimization may provide a new foundation for treating central pain and other functional disorders through systematic evaluation of stimulation parameters.

Published
2021
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13. Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus

Author

Farah Chamaa, Hisham F. Bahmad, Ahmad-Kareem Makkawi, Reda M. Chalhoub, Elie D. Al-Chaer, George B. Bikhazi, Ziad Nahas, and Wassim Abou-Kheir

Subjects
nitrous oxide, anesthetics, depression, neurogenesis, dentate gyrus, hippocampus, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2). Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.

Published
2018
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14. Fifteen Minutes of Left Prefrontal Repetitive Transcranial Magnetic Stimulation Acutely Increases Thermal Pain Thresholds in Healthy Adults

Author

Jeffrey J Borckardt, Arthur R Smith, Scott T Reeves, Mitchell Weinstein, F Andrew Kozel, Ziad Nahas, Neal Shelley, R Kyle Branham, K Jackson Thomas, and Mark S George

Subjects
Medicine (General), R5-920
Abstract

BACKGROUND: Transcranial magnetic stimulation (TMS) of the motor cortex appears to alter pain perception in healthy adults and in patients with chronic neuropathic pain. There is, however, emerging brain imaging evidence that the left prefrontal cortex is involved in pain inhibition in humans.

Published
2007
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15. A review of the new minimally invasive brain stimulation techniques in psychiatry

Author

Jeong-Ho Chae, Xingbao Li, Ziad Nahas, F. Andrew Kozel, and Mark S. George

Subjects
Minimally invasive brain stimulation (MIBS), Transcranial magnetic stimulation (TMS), Vagus nerve stimulation (VNS), Deep brain stimulation (DBS), Psychiatry, RC435-571
Abstract

New knowledge about the specific brain regions involved in neuropsychiatric disorders is rapidly evolving due to recent advances in functional neuroimaging techniques. The ability to stimulate the brain in awake alert adults without neurosurgery is a real advance that neuroscientists have long dreamed for. Several novel and minimally invasive techniques to stimulate the brain have recently developed. Among these newer somatic interventions, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS) show promise as therapeutic tools in the treatment of neuropsychiatric disorders. This article reviews the history, methodology, and the future of these minimally invasive brain stimulation (MIBS) techniques and their emerging research and therapeutic applications in psychiatry

Published
2001
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16. Inverse Effects of Oxytocin on Attributing Mental Activity to Others in Depressed and Healthy Subjects: A Double-Blind Placebo Controlled fMRI Study.

Author

David Pincus, Samet Kose, Ashley Arana, Kevin Johnson, Paul Morgan, Jeffrey Borckardt, Tal Herbsman, Fran Hardaway, Mark George, Jaak Panksepp, and Ziad Nahas

Subjects
Depression, Oxytocin, Theory of Mind, fMRI, mentalization, Psychiatry, RC435-571
Abstract

Background: Oxytocin is a stress-attenuating and pro-social neuropeptide. To date, no study has looked at the effects of oxytocin in modulating brain activity in depressed individuals nor attempted to correlate this activity with attribution of mental activity in others. Method: We enrolled 10 unmedicated depressed adults and 10 matched healthy controls in a crossover, double blind placebo controlled fmri 40 i.u. intra-nasal oxytocin study (20 i.u. per nostril). Each subject performed Reading the Mind in the Eyes task (RMET) before and after inhalation of oxytocin or placebo control for a total of 80 scans. Results: Before oxytocin administration, RMET engaged medial and lateral prefrontal cortex, amygdala, insula and associative areas. Depressed subjects showed increased anterior ventral activation for the RMET minus gender identification contrast whereas matched controls showed increased dorsal and frontal activity. Compared to placebo, oxytocin in depressed subjects showed increased activity in the superior middle frontal gyrus and insula, while controls exhibited more activity in ventral regions. Oxytocin also led to inverse effects in reaction times on attribution task between groups, with controls getting faster and depressed individuals slower to respond. Conclusion: Depression is associated with increased paralimbic activity during emotional mental attribution of others, appearing to be distinctly modulated by oxytocin when compared to healthy controls. Further studies are needed to explore long-term exposure to pro-social neuropeptides on mood in depressed populations and assess their clinical relevance.

Published
2010
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21. Causally probing the role of the human hippocampus in fear discrimination: A precision functional mapping guided TMS study in individuals with post-traumatic stress symptoms

Author

Ryan D Webler, Cristian Carrasco, Samuel Cooper, Mo Chen, Christopher Hunt, Sierra Hennessy, Lancy Cao, Carol Lam, Allen Chiu, Cash Differding, Erin Todd, Timothy Hendrickson, Desmond Oathes, Alik Widge, Robert Hermosillo, Steve Nelson, Damien Fair, Shmuel Lissek, and Ziad Nahas

Abstract

Fear overgeneralization is a potential pathogenic mechanism of anxiety-related disorders. A dominant model posits that overgeneralization occurs when the hippocampus fails to distinctly encode benign stimuli with insufficient similarity to previously encountered fear cues, triggering excessive retrieval of stored fear representations. This model has cross-species support but has not been causally tested in humans. A developing literature demonstrates that hippocampal network targeted transcranial magnetic stimulation (HNT-TMS) can strengthen hippocampal-dependent memory encoding. Building on this literature, we hypothesized that HNT-TMS would strengthen encoding of perceptually similar stimuli and thereby reduce retrieval errors (i.e., sharpen discrimination) in participants with post-traumatic stress symptoms. We predicted that this effect would emerge for fear stimuli as measured by the Farmer Task and neutral stimuli as measured by the Mnemonic Similarity Task. Continuous theta-burst stimulation (cTBS) was delivered to individualized left posterior-parietal targets derived via precision functional mapping, seed-based connectivity, and electric-field modeling methods. A vertex control target was also stimulated in a within-subject design (final N = 25). Multilevel models did not reveal significant interactions between stimulation target and fear or neutral stimulus discrimination. However, HNT-TMS strengthened fear discrimination in participants with lower sensitization, indexed by responsivity to a control stimulus perceptually unrelated to the CS+. Sensitization reflects indiscriminate fear responding unrelated to CS + similarity and is not expected to engage the hippocampal CS + matching function. Our findings therefore indicate that HNT-TMS may selectively sharpen fear discrimination when the hippocampal CS + matching function is more strongly engaged.

Published
2023
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22. Causally mapping human threat extinction relevant circuits with depolarizing brain stimulation methods

Author

Ryan D. Webler, Desmond J. Oathes, Sanne J.H. van Rooij, Jonathan C. Gewirtz, Ziad Nahas, Shmuel M. Lissek, and Alik S. Widge

Subjects
Behavioral Neuroscience, Neuropsychology and Physiological Psychology, Cognitive Neuroscience, Article
Abstract

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.

Published
2022

23. Personalizing Dual-Target Cortical Stimulation with Bayesian Parameter Optimization Successfully Treats Central Post-Stroke Pain: A Case Report

Author

Evan M. Dastin-van Rijn, Seth D. König, Danielle Carlson, Vasudha Goel, Andrew Grande, Donald R. Nixdorf, Sarah Benish, Alik S. Widge, Ziad Nahas, Michael C. Park, Tay I. Netoff, Alexander B. Herman, and David P. Darrow

Subjects
General Neuroscience, Case Report, Neurosciences. Biological psychiatry. Neuropsychiatry, chronic pain, electrophysiology, stroke, optimization, cortical stimulation, RC321-571
Abstract

Central pain disorders, such as central post-stroke pain, remain clinically challenging to treat, despite many decades of pharmacological advances and the evolution of neuromodulation. For treatment refractory cases, previous studies have highlighted some benefits of cortical stimulation. Recent advances in new targets for pain and the optimization of neuromodulation encouraged our group to develop a dual cortical target approach paired with Bayesian optimization to provide a personalized treatment. Here, we present a case report of a woman who developed left-sided facial pain after multiple thalamic strokes. All previous pharmacologic and interventional treatments failed to mitigate the pain, leaving her incapacitated due to pain and medication side effects. She subsequently underwent a single burr hole for placement of motor cortex (M1) and dorsolateral prefrontal cortex (dlPFC) paddles for stimulation with externalization. By using Bayesian optimization to find optimal stimulation parameters and stimulation sites, we were able to reduce pain from an 8.5/10 to a 0/10 during a 5-day inpatient stay, with pain staying at or below a 2/10 one-month post-procedure. We found optimal treatment to be simultaneous stimulation of M1 and dlPFC without any evidence of seizure induction. In addition, we found no worsening in cognitive performance during a working memory task with dlPFC stimulation. This personalized approach using Bayesian optimization may provide a new foundation for treating central pain and other functional disorders through systematic evaluation of stimulation parameters.

Published
2022

25. Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: A prefrontal interleaved TMS fMRI study

Author

Carmen Hamady, Chris Molnar, Berry Anderson, Mark S. George, Ziad Nahas, Daryl E. Bohning, Leo Bonilha, Kevin A. Johnson, Ryan D. Webler, and Claartje Bruin

Subjects
Adult, Male, medicine.medical_treatment, Biophysics, Prefrontal Cortex, behavioral disciplines and activities, 050105 experimental psychology, lcsh:RC321-571, Interleaved TMS fMRI, Functional connectivity, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Cortex (anatomy), medicine, Humans, 0501 psychology and cognitive sciences, Prefrontal cortex, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Brain Mapping, Resting state fMRI, medicine.diagnostic_test, business.industry, General Neuroscience, 05 social sciences, Motor Cortex, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Transcranial Magnetic Stimulation, Transcranial magnetic stimulation, medicine.anatomical_structure, Schizophrenia, Cortical Excitability, Female, Neurology (clinical), Nerve Net, Functional magnetic resonance imaging, business, Neuroscience, 030217 neurology & neurosurgery, Motor cortex
Abstract

Background Prefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia. Objective /Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity. Methods We enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition. Results Of the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p=0.0157; max z-score=4.7) and neighboring BA46 (p=0.019; max z-score=4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p=0.02; max z-score=3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p=0.004). Conclusions Subjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia.

Published
2020

26. Psychotherapy through a Sufi Islamic lens: A dialectic of transcendence and acceptance

Author

Craig N. Shealy, Ziad Nahas, and Ghena Ismail

Subjects
Complementary and Manual Therapy, Dialectic, Mindfulness, Psychoanalysis, Transcendence (philosophy), Philosophy, media_common.quotation_subject, Lens (geology), Islam, Psychiatry and Mental health, Clinical Psychology, Complementary and alternative medicine, Spirituality, Meditation, media_common
Published
2021

27. DLPFC stimulation alters working memory related activations and performance: An interleaved TMS-fMRI study

Author

Ryan D. Webler, James Fox, Lisa M. McTeague, Philip C. Burton, Logan Dowdle, Edward Baron Short, Jeffrey J. Borckardt, Xingbao Li, Mark S. George, and Ziad Nahas

Subjects
Brain Mapping, Dorsolateral Prefrontal Cortex, Memory, Short-Term, General Neuroscience, Biophysics, Brain, Humans, Neurology (clinical), Magnetic Resonance Imaging
Abstract

Findings from correlative neuroimaging studies link increased frontoparietal network (FPN) activation and default mode network (DMN) deactivation to enhanced high cognitive demand processing. To causally investigate FPN-DMN contributions to high cognitive demand processing, the current interleaved TMS-fMRI study simultaneously manipulated and indexed neural activity while tracking cognitive performance during high and low cognitive load conditions.Twenty participants completed an n-back task consisting of four conditions (0-back, 0-backTMS, 2-back, 2-backTMS) while undergoing interleaved TMS-fMRI. During TMS concurrent with n-back blocks, TMS single pulses were delivered to the left DLPFC at 100% motor-threshold every 2.4s.TMS delivered during high cognitive load strengthened cognitive processing. FPN node activations and DMN node deactivations were increased in the high versus low cognitive load TMS condition. Contrary to our hypothesis, TMS did not increase high load related activation in FPN nodes. However, as hypothesized, increased DMN node deactivations emerged as a function of TMS during high load (right angular gyrus) and from interactions between cognitive load and TMS (right middle temporal gyrus). Load and TMS combined to dampen activation within the DMN at trend level (p = .058). Deactivation in a dorsomedial DMN node was associated with TMS driven improvements in high load cognitive processing.Exogenous perturbation of the DLPFC via single pulse TMS amplified DMN node deactivations and enhanced high cognitive demand processing. Neurobehavioral findings linking these effects hint at a promising, albeit preliminary, cognitive control substrate requiring replication in higher-powered studies that use control stimulation.

Published
2021

28. Association between substance use disorders and self‐ and other‐directed aggression: An integrated model approach

Author

Salim M. Adib, Ziad Nahas, Elias Ghossoub, Hani Tamim, Fadi T. Maalouf, and Ghada El-Hajj Fuleihan

Subjects
Adult, Male, medicine.medical_specialty, Substance-Related Disorders, Population, Suicide, Attempted, 050109 social psychology, Alcohol use disorder, Violence, Odds, Arts and Humanities (miscellaneous), Risk Factors, Epidemiology, Developmental and Educational Psychology, medicine, Humans, 0501 psychology and cognitive sciences, Association (psychology), education, General Psychology, education.field_of_study, Aggression, business.industry, 05 social sciences, Regression analysis, Odds ratio, Middle Aged, medicine.disease, Alcoholism, Female, medicine.symptom, business, 050104 developmental & child psychology, Clinical psychology
Abstract

Our study's objective is to determine whether substance use disorders' association with aggression differs according to the type of substance and/or the form of aggression, within the same population. We used data from the National Survey on Drug Use and Health across 2008-2014, with a pooled sample of 270,227 adult respondents. We used regression models to estimate the odds ratios for those having alcohol and/or drug use disorder(s) perpetrating (a) each form of aggression compared with no aggression and (b) other-directed compared with self-directed aggression. Alcohol use disorder alone and drug use disorder(s) alone were both associated with significantly increased odds of committing self-directed, other-directed, and combined aggression. Individuals with drug use disorder(s) alone were more likely to commit other-directed than self-directed aggression (adjusted odds ratio = 1.46, 95% CI = 1.04-2.05). Individuals with alcohol use disorder alone were not likely to commit one over the other (adjusted odds ratio = 1.20, 95% CI = 0.90-1.61). In conclusion, the integrated model of aggression based on the stress-diathesis model is a relevant framework to study risk factors for aggression. Further research is needed to identify longitudinal predictors of directionality of aggression.

Published
2019

29. Long-Term Efficacy of Repeated Daily Prefrontal Transcranial Magnetic Stimulation (TMS) In Treatmnt-Resistant Depression

Author

Ziad Nahas, Sarah H. Lisanby, Martina Pavlicova, Antonio Mantovani, Mark S. George, Paul E. Holtzheimer, Chandra Wajdik, David H. Avery, Harold A. Sackeim, and William M. McDonald

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Influential Publications, Prefrontal Cortex, Acute effect, behavioral disciplines and activities, Article, Depressive Disorder, Treatment-Resistant, Pharmacotherapy, Double-Blind Method, Rating scale, medicine, Secondary Prevention, Humans, In patient, Depression (differential diagnoses), Psychiatric Status Rating Scales, Middle Aged, Transcranial Magnetic Stimulation, Transcranial magnetic stimulation, Treatment Outcome, Physical therapy, Antidepressant, Female, Psychology, Follow-Up Studies
Abstract

A few studies have examined the durability of transcranial magnetic stimulation (TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up.Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome.Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission (HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month.While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS.

Published
2020

30. A Blind Module Identification Approach for Predicting Effective Connectivity Within Brain Dynamical Subnetworks

Author

Ziad Nahas and Fadi N. Karameh

Subjects
Blind deconvolution, Computer science, Models, Neurological, Electroencephalography, Unobservable, 050105 experimental psychology, 03 medical and health sciences, 0302 clinical medicine, Seizures, medicine, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Subnetwork, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, 05 social sciences, Brain, Pattern recognition, Kalman filter, Nonlinear system, Identification (information), Nonlinear Dynamics, Neurology, Key (cryptography), Neurology (clinical), Artificial intelligence, Nerve Net, Anatomy, business, Algorithms, 030217 neurology & neurosurgery
Abstract

Model-based network discovery measures, such as the brain effective connectivity, require fitting of generative process models to measurements obtained from key areas across the network. For distributed dynamic phenomena, such as generalized seizures and slow-wave sleep, studying effective connectivity from real-time recordings is significantly complicated since (i) outputs from only a subnetwork can be practically measured, and (ii) exogenous subnetwork inputs are unobservable. Model fitting, therefore, constitutes a challenging blind module identification or model inversion problem for finding both the parameters and the many unknown inputs of the subnetwork. We herein propose a novel estimation framework for identifying nonlinear dynamic subnetworks in the case of slowly-varying, otherwise unknown local inputs. Starting with approximate predictions obtained using Cubature Kalman filtering, residuals of local output predictions are utilized to improve upon local input estimates. The algorithm performance is tested on both simulated and clinical EEG of induced seizures under electroconvulsive therapy (ECT). For the simulated network, the algorithm significantly boosted the estimation accuracy for inputs and connections from noisy EEG. For the clinical data, the algorithm predicted increased subnetwork inputs during the pre-stimulus anesthesia condition. Importantly, it predicted an increased frontocentral connectivity during the generalized seizure that is commensurate with electrode placement and that corroborates the clinical hypothesis of increased frontal focality of therapeutic ECT seizures. The proposed framework can be extended to account for several input configurations and can in principle be applied to study effective connectivity within brain subnetworks defined at the microscale (cortical lamina interaction) or at the macroscale (sensory integration).

Published
2018

31. Covid effects on clinical outcomes of TMS treatment: a naturalistic study

Author

Alexander B. Herman, A.Irem Sonmez, C. Sophia Albott, Christina Warner, Alik S. Widge, Sarah Olsen, Christi Sullivan, Saydra Wilson, and Ziad Nahas

Subjects
Naturalistic observation, General Neuroscience, Biophysics, Neurosciences. Biological psychiatry. Neuropsychiatry, Neurology (clinical), Psychology, Article, RC321-571, Clinical psychology
Published
2021

32. A two-site, open-label, non-randomized update, suggests focal electrically administered seizure therapy (FEAST) may have a reduced time to re-orientation compared to right unilateral ultra-brief pulse electroconvulsive therapy (UBP-RUL ECT)

Author

James B. Fox, C. Mazingue, Ziad Nahas, Mark S. George, Peter B. Rosenquist, H.A. Sackeim, Edward Baron Short, William V. McCall, G. Sahlem, and Andrew J. Manett

Subjects
medicine.medical_specialty, business.industry, General Neuroscience, medicine.medical_treatment, Biophysics, Brief pulse, lcsh:RC321-571, Physical medicine and rehabilitation, Electroconvulsive therapy, Orientation (mental), medicine, Neurology (clinical), Open label, business, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Published
2019

34. A closer look at patterns and characteristics of suicide in Lebanon: A first nationwide report of cases from 2008 to 2018

Author

Lea Zeinoun, Michel Daher, Maya Bizri, Alexandra M. Mihailescu, Rabih El Chammay, Ziad Nahas, and Mia Atoui

Subjects
Male, medicine.medical_specialty, media_common.quotation_subject, 03 medical and health sciences, 0302 clinical medicine, Epidemiology, Ethnicity, Prevalence, medicine, Per capita, Humans, Lebanon, General Psychology, media_common, Middle East, Public health, Taboo, General Medicine, 030227 psychiatry, Suicide, Psychiatry and Mental health, Geography, Annual percentage rate, Nationality, Female, Male to female, 030217 neurology & neurosurgery, Demography
Abstract

Suicide is a leading preventable cause of mortality worldwide. Suicide rates in Lebanon are unknown, as reported numbers are extrapolated and modeled over neighboring countries with poor quality of vital registration data.Numbers of death by suicide were obtained from the Internal Security Forces records from January 2008 through December 2018. Records from 2011 through 2018 specified the gender of the individual, the means of the suicide, the date and place of suicide. As of March 2014, nationality of the individual was recorded.The total recorded number of completed suicides over 11 years is 1366 with an annual rate ranging between 1.87 and 2.4 per 100,000 capita. The male to female ratio was 2:1. Death by firearms (41.4 %) was the most common means used, followed by hanging (26.5 %), jumping from a height (13.6 %), and poisoning (13.5 %). Males were more likely to use firearms while females were more likely to use hanging or jumping from a height (p 0.001), the latter being a common finding in non-Lebanese nationals (Ethiopian). Suicides were most common in Mount Lebanon and least common in Nabatieh governates, while their distribution across seasons was similar.In Lebanon, like most of the Middle Eastern countries, suicide is a social and religious taboo. Our study shows a sizable prevalence of suicide rates, particularly after national efforts to improve awareness and reporting. Suicide means and vulnerable populations should be at the heart of targeted prevention strategies.

Published
2021

35. Concurrent Benzodiazepine Use and TMS Clinical Outcomes

Author

Alik S. Widge, Irem Somez, C. Sophia Albott, Ziad Nahas, Christi Sullivan, Sarah Olsen, Dawson Cooper, Alexander B. Herman, and Saydra Wilson

Subjects
Benzodiazepine, business.industry, medicine.drug_class, Anesthesia, Medicine, business, Biological Psychiatry
Published
2021

36. Long-term stimulation of the anteromedial thalamus increases hippocampal neurogenesis and spatial reference memory in adult rats

Author

Wassim Abou-Kheir, Batoul Darwish, Farah Chamaa, Elie D. Al-Chaer, Nayef E. Saadé, and Ziad Nahas

Subjects
Male, medicine.medical_specialty, Deep brain stimulation, Deep Brain Stimulation, Neurogenesis, medicine.medical_treatment, Thalamus, Hippocampus, Stimulation, Hippocampal formation, Rats, Sprague-Dawley, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Neural Stem Cells, Internal medicine, medicine, Animals, Progenitor cell, Spatial Memory, 030304 developmental biology, 0303 health sciences, business.industry, Dentate gyrus, Rats, Endocrinology, Anterior Thalamic Nuclei, Dentate Gyrus, business, 030217 neurology & neurosurgery
Abstract

Deep brain stimulation (DBS) has shown positive clinical results in neurodegenerative diseases. Previous work from our group showed that a single session of DBS to the anteromedial thalamic nucleus (AMN) in awake rats, increased proliferation of stem/progenitor cells in the dentate gyrus (DG) of the hippocampus. We thought to examine the effect of single versus multiple sessions of DBS to the AMN in modulating adult hippocampal neurogenesis. Rats received unilateral single session, multiple sessions or no electrical stimulation (sham) in the right AMN. Rats received 5’-bromo-2’-deoxyuridine (BrdU) injections and were followed over a period of 1 week or 4 weeks. Single session of electrical stimulation induced a 1.9-fold increase in the number of proliferating BrdU positive cells after one week from stimulation and a 1.8-fold increase at four weeks post stimulation, both in the ipsilateral DG. As for multiple sessions of stimulation, they induced a 3- fold increase that extended to the contralateral DG after 4 weeks from stimulation. Spatial reference memory was tested in the Y-maze test by examining novel arm exploration. Both single and multiple sessions of stimulation prompted an increase in novel arm exploration at week 4, while only the multiple sessions of stimulation had this effect starting from week 1. This study demonstrates that sustained activation of the AMN boosts neurogenesis and improves spatial reference memory.

Published
2021

37. Evaluation of Lebanon’s National Helpline for Emotional Support and Suicide Prevention: Reduction of Emotional Distress among Callers

Author

Ziad Nahas, Mia Atoui, Lila Z Khederlarian, Serene F Yordi, Farah Yehia, Rabih El Chammay, and Pia Zeinoun

Subjects
medicine.medical_specialty, Data collection, Social Psychology, Suicide prevention, Psychiatry and Mental health, Clinical Psychology, Distress, Emotional distress, medicine, Sexual orientation, Sustenance, Pshychiatric Mental Health, medicine.symptom, Risk factor, Psychiatry, Psychology, Suicidal ideation
Abstract

Helplines provide time-limited help and orientation to callers who are suicidal or experiencing self-reported emotional distress, but there is no evidence regarding the efficacy of helplines in low-to-middle income countries like Lebanon. The Embrace Lifeline is Lebanon’s national and only helpline for emotional support and suicide prevention, operating since 2018. We accessed anonymous data of 4657 calls received between February 2018 and February 2020. We analysed caller characteristics and predictors of distress and evaluated the immediate outcome of calls by examining the difference in caller distress from beginning to end of call, using a repeated-measures design. The helpline received calls from a majority Lebanese sample that was diverse in terms of age, location, education, employment status and sexual orientation. We found a significant and large (d = 1.94 and 1.99, respectively) decrease in subjective levels of distress among those calling for emotional distress only, and those with additional suicide-related behaviour. The most distressed callers were likely to be female, in a relationship (as opposed to not), and experiencing at least one risk factor, and while everyone showed improved distressed, those with at least one risk factor showed the most decrease. The helpline is effectively reducing distress and suicidal ideation, across a wide sample of callers. Future studies need to investigate long-term sustenance and circumvent limitations related to data collection capture.

Published
2021

38. Expanded Safety and Efficacy Data for a New Method of Performing Electroconvulsive Therapy

Author

Ziad Nahas, Gregory L. Sahlem, Suzanne Kerns, Harold A. Sackeim, James B. Fox, Mark S. George, E. Baron Short, Matthew Schmidt, Jon Snipes, William H. DeVries, and Carol Burns

Subjects
Adult, Male, medicine.medical_specialty, Bipolar Disorder, cognitive adverse effects, medicine.medical_treatment, efficacy, Neuroscience (miscellaneous), behavioral disciplines and activities, Original Studies, electroconvulsive therapy, 03 medical and health sciences, 0302 clinical medicine, Electroconvulsive therapy, Seizures, medicine, Humans, Anesthesia, Bipolar disorder, Psychiatry, Adverse effect, Electrodes, Aged, Psychiatric Status Rating Scales, Depressive Disorder, business.industry, Neuropsychology, Hamilton Rating Scale for Depression, ECT, Cognition, Middle Aged, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Treatment Outcome, FEAST, depression, Cohort, Antidepressant, Female, Cognition Disorders, business, human activities, 030217 neurology & neurosurgery
Abstract

Objective Electroconvulsive therapy (ECT) is the most rapid and effective antidepressant treatment but with concerns about cognitive adverse effects. A new form of ECT, focal electrically administered seizure therapy (FEAST), was designed to increase the focality of stimulation and better match stimulus parameters with neurophysiology. We recently reported on the safety and feasibility of FEAST in a cohort (n = 17) of depressed patients. We now report on the safety, feasibility, preliminary efficacy, and cognitive effects of FEAST in a new cohort. Methods Open-label FEAST was administered to 20 depressed adults (6 men; 3 with bipolar disorder; age 49.1 ± 10.6 years). Clinical and cognitive assessments were obtained at baseline and end of course. Time to orientation recovery was assessed at each treatment. Nonresponders switched to conventional ECT. Results Participants tolerated the treatment well with no dropouts. Five patients (25%) transitioned from FEAST to conventional ECT due to inadequate response. After FEAST (mean, 9.3 ± 3.5 sessions; range, 4–14), there was a 58.1% ± 36.0% improvement in Hamilton Rating Scale for Depression scores compared with that in the baseline (P < 0.0001); 13 (65%) of 20 patients met response criteria, and 11 (55%) of 20 met remission criteria. Patients achieved reorientation (4 of 5 items) in 4.4 ± 3.0 minutes (median, 4.5 minutes), timed from eyes opening. There was no deterioration in neuropsychological measures. Conclusions These findings provide further support for the safety and efficacy of FEAST. The remission and response rates were in the range found using conventional ECT, and the time to reorientation may be quicker. However, without a randomized comparison group, conclusions are tentative.

Published
2016

39. Thalamic Stimulation in Awake Rats Induces Neurogenesis in the Hippocampal Formation

Author

Farah Chamaa, Wafaa Sweidan, Nayef E. Saadé, Wassim Abou-Kheir, and Ziad Nahas

Subjects
Male, 0301 basic medicine, Deep brain stimulation, Neurogenesis, medicine.medical_treatment, Thalamus, Biophysics, Hippocampus, Stimulation, Hippocampal formation, lcsh:RC321-571, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Dentate gyrus, Wakefulness, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, biology, General Neuroscience, Thalamic stimulation, Rats, 030104 developmental biology, biology.protein, Female, Neurology (clinical), NeuN, Psychology, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background Deep brain stimulation (DBS) provides clinical benefits for a variety of movement disorders and lately emerged as a potential treatment for cognitive and mood disorders. Modulation of adult hippocampal neurogenesis may play a role in mediating its effects. Objective To investigate the effects of unilateral anteromedial thalamic nucleus (AMN) stimulation on adult hippocampal neurogenesis in awake and unrestrained rats. Methods Four groups of adult Sprague–Dawley male and female rats received unilateral stimulation (n = 6 each) or sham surgery (n = 4 each) in the right AMN; another group of males (n = 4) was stimulated in the right ventral posterolateral thalamic nucleus (VPL). A naive group of males and females (n = 4 each) was also included. Rats received 4 injections (50 mg/kg/injection) of 5′-bromo-2′-deoxyuridine (BrdU) 3 days post-surgery and were euthanized 24 h later. The fractionator method was used together with confocal microscopy to count BrdU, GFAP and NeuN positive cells in the dentate gyrus (DG) and hilar zone of the hippocampus. Results Focal neurogenesis was induced in the ipsilateral DG after AMN but not VPL stimulation. Stimulation-induced effects were sex-independent and translated into a 76% increase in proliferation of neural stem/progenitor cells. Increased neurogenesis was most prominent at the caudal region of the DG, while no effect was detected in the hilar and the subventricular zones. Conclusions The exclusive hippocampal neurogenic response to AMN stimulation suggests an involvement of the Papez circuitry in mediating DBS effects and in the treatment of cognitive and behavioral disorders.

Published
2016

40. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013

Author

Yong Zhao, Hadi Danawi, Bach Xuan Tran, Gene Bukhman, Vasiliki Stathopoulou, Taavi Tillmann, Nelson Alvis-Guzman, Yongmei Li, Jerry Puthenpurakal Abraham, Sudan Prasad Neupane, Jack Caravanos, Ben Schöttker, Rafael Lozano, Damian G Hoy, Yoshihiro Kokubo, Nicholas J K Breitborde, Sergey Soshnikov, Yukito Shinohara, Randall V. Martin, Michael Brainin, Fernando Perez-Ruiz, Yingfeng Zheng, Santosh Mishra, Julio Cesar Montañez Hernandez, Michael Phillips, Belinda J. Gabbe, Hebe N. Gouda, Ziad A. Memish, Rupert R A Bourne, Guoqing Hu, Emmanuel A. Ameh, Abigail McLain, Michelle L. Bell, Christopher Margono, Marissa Iannarone, Wilkister N. Moturi, Donald H. Silberberg, Carl Abelardo T. Antonio, Nataliya Foigt, Anand Dayama, Yanping Wang, Amanda J. Mason-Jones, Bolajoko O. Olusanya, Monica S. Vavilala, Katherine B Gibney, David Tanne, Sidibe S Kany Roseline, Marcella Montico, Abhishek Singh, Sarah Derrett, Alireza Esteghamati, Seok Jun Yoon, Corine Karema, Rakhi Dandona, David M. Pereira, Kazem Rahimi, Gitanjali M. Singh, Vivekanand Jha, John Hornberger, Anne M. Riederer, Kathryn H. Jacobsen, Andrea Pedroza, Lily Alexander, Fiona M. Blyth, Tommi Vasankari, Kyle J Foreman, Rana J. Asghar, Tilahun Nigatu Haregu, Yousef Khader, Rafael Alfonso-Cristancho, Suzanne Barker-Collo, Lydia S. Atkins, Simerjot K. Jassal, Mohammad Ali Sahraian, Peter Scarborough, Hans W. Hoek, E. Ray Dorsey, Muluken Dessalegn, David C. Schwebel, Gavin Shaddick, Thomas D. Fleming, Mohammad Tavakkoli, Dorairaj Prabhakaran, Mohammad H. Forouzanfar, Christopher C. Mapoma, Jost B. Jonas, Erin C Mullany, Gene F. Kwan, Johanna M. Geleijnse, Antonio Luiz Pinho Ribeiro, Roberto Tchio Talongwa, Tolesa Bekele, Jed D. Blore, Gunn Marit Aasvang, Philimon Gona, Miguel Angel Alegretti, Babak Eshrati, Mitsuru Mukaigawara, Richard F. Gillum, Odgerel Chimed-Ochir, Ubai Alsharif, Richard C. Franklin, Felix Masiye, Richard T. Burnett, Sanjay Krishnaswami, Martin McKee, John J Huang, Lucía Cuevas-Nasu, Wagner Marcenes, Walid Ammar, Knud Juel, Joseph R. Zunt, Martha M Téllez Rojo, Mamta Swaroop, Noela M Prasad, Azmeraw T. Amare, Tim Driscoll, Michael Kravchenko, Heresh Amini, Amir Sapkota, Theo Vos, Charlotte Watts, Dennis Odai Laryea, D. Alex Quistberg, Justin Beardsley, Cheng Huang, Adnan M. Durrani, Sarah V Thackway, Rita Van Dingenen, Manami Inoue, Martha Híjar, Honglei Chen, Amany H. Refaat, Yichong Li, Vineet K. Chadha, Wenzhi Wang, Louisa Degenhardt, Kingsley N. Ukwaja, Nayu Ikeda, James D. Wilkinson, Linh N Bui, Maria Hagströmer, Gonghuan Yang, Ann Kristin Knudsen, David J. Margolis, Soewarta Kosen, Hans Kromhout, Atsushi Goto, Man Mohan Mehndiratta, Thomas N. Williams, Michael Soljak, Yun Jin Kim, Hideaki Toyoshima, Jeyaraj D Pandian, Borja del Pozo-Cruz, Soufiane Boufous, Ivy Shiue, Anders Larsson, Guilherme V. Polanczyk, John Powles, Yara A. Halasa, Robin Room, Ratilal Lalloo, Carolina Batis Ruvalcaba, Panniyammakal Jeemon, Elisabete Weiderpass, Jürgen Rehm, Ejaz Ahmad Khan, Alicia Aleman, Zacharie Tsala Dimbuene, Elena Alvarez, Rachelle Buchbinder, Randah R. Hamadeh, Bryan Hubbell, Sadaf G. Sepanlou, Farhad Islami, Costas A. Christophi, Heidi Stöckl, Ismael R. Campos-Nonato, Nigel Bruce, Edward J Mills, Samuel A L Perry, Taavi Lai, Baffour Awuah, Mete Saylan, Karen J. Courville, Arindam Basu, Vanessa De la Cruz-Góngora, Teresita González de Cosío, Naohiro Yonemoto, Frida Namnyak Ngalesoni, Muluken Azage Yenesew, Atte Meretoja, Michael Brauer, Cyrus Cooper, Giorgia Giussani, Valentina S. Arsic Arsenijevic, Vasiliy Victorovich Vlassov, André Karch, Leilei Duan, Matthew M Coates, Omid Ameli, Gelin Xu, Matthias Endres, Ganesan Karthikeyan, Ione Jayce Ceola Schneider, Mohamed Hsairi, Palwasha Anwari, Mazin J. Al Khabouri, Dariush Mozaffarian, Juan R. Sanabria, Pablo M. Lavados, Sumeet S. Chugh, Johan Ärnlöv, Ivo Rakovac, Maurice Giroud, Haidong Kan, Ibrahim Abdelmageem Mohamed Ginawi, José Luis Texcalac-Sangrador, Luigi Naldi, Erica Leigh Slepak, Deena Alasfoor, James E. Saunders, Richard Matzopoulos, Talal Bakfalouni, Stein Emil Vollset, Andrea Werdecker, Lennert J. Veerman, Lorenzo Monasta, Henrica A. F. M. Jansen, Reyna A Gutiérrez, Brittany Wurtz, Luz Maria Sanchez, Lijing L. Yan, M. Patrice Lindsay, Michele Meltzer, Sanjay Basu, Steven van de Vijver, Alaa Badawi, Thomas Claßen, Young-Ho Khang, Brett M. Kissela, Jun Zhu, In-Hwan Oh, Fiona J Charlson, Maria Cecilia Bahit, Dinorah González-Castell, Rosario Cárdenas, Dan Poenaru, Sayed Saidul Alam, Mitchell T. Wallin, Harish Chander Gugnani, James Leigh, Ferrán Catalá-López, Lidia Morawska, Jim van Os, Stephanie J. London, Kaire Innos, Isabelle Romieu, Fiorella Cavalleri, Adrian Davis, Hwee Pin Phua, Chakib Nejjari, Héctor Gómez Dantés, Boris I. Pavlin, Karen Sliwa, Lynne Gaffikin, Constance D. Pond, Michael F. MacIntyre, Blake Thomson, Norberto Perico, Ronny Westerman, Samantha M. Colquhoun, Michael H. Criqui, Ana Maria Nogales Vasconcelos, Wubegzier Mekonnen, Bulat Idrisov, Ana Basto-Abreu, Andrew G. M. Bulloch, Jasvinder A. Singh, Vinod K. Paul, Emin Murat Tuzcu, Svetlana Popova, Hmwe H Kyu, Richard L. Guerrant, Mohammed I. Albittar, Srikanth Mangalam, Steven E. Lipshultz, Lela Sturua, Semaw Ferede Abera, Eduardo Bernabé, George D. Thurston, Bruno F. Sunguya, Tiffany Ku, Alejandra G. Contreras, Abdullah Sulieman Terkawi, Charles Atkinson, Ashkan Afshin, Heidi J. Larson, Abdullatif Husseini, Jose C. Adsuar, Reza Assadi, Ademola Lukman Adelekan, Joshua A. Salomon, Yousef M. Elshrek, Gokalp Kadri Yentur, Devina Nand, Narayanaswamy Venketasubramanian, Graça Maria Ferreira De Lima, Maheswar Satpathy, Fotis Topouzis, Traolach S. Brugha, Hywel C Williams, Coen H. Van Gool, Andrew H. Kemp, Awoke Misganaw, Amado D Quezada, Norito Kawakami, Bert Brunekreef, Peter Burney, Tati S. Warouw, Jongmin Lee, Inga Dora Sigfusdottir, Marcel Tanner, Solveig A. Cunningham, Benjamin O. Anderson, Tariku Jibat Beyene, Lars Barregard, Xia Wan, Giuseppe Remuzzi, Bernadette Thomas, Lilia S Pedraza, Massimo Cirillo, Alina Rodriguez, Ricky Leung, Farshad Pourmalek, K. Srinath Reddy, Charles D.A. Wolfe, Ulrich O Mueller, Neeraj Bedi, Al Artaman, Lucia Hernandez, Itamar S. Santos, C. Arden Pope, Norlinah Mohamed Ibrahim, Carlo Irwin A. Panelo, Selen Begüm Uzun, Miltiadis K. Tsilimbaris, Anwar Rafay, Daniel Dicker, Melvin Barrientos Marzan, Sajjad Ur Rahman, Mohammed O. Basulaiman, Edgar P. Simard, Mohammad T Mashal, Maysaa El Sayed Zaki, Shiwei Liu, Don C. Des Jarlais, Bo Norrving, Salvador Villalpando, Miia Kivipelto, Yang Liu, Carolina Maria Teixeira, Catalina Medina, Sudha Jayaraman, Josep Maria Haro, Diego De Leo, Angel J Paternina Caicedo, Abigail C. McKay, Eric L. Ding, Mukesh Dherani, Ljiljana Pejin Stokic, Vinay Nangia, Sukanta Saha, Juan Liang, Elisabeth Cardis, Zourkaleini Younoussi, José R Nogueira, Braden Te Ao, Vasco Manuel Pedro Machado, Lionel Racapé, Ting Wu Chuang, Shahab Khatibzadeh, E Filipa de Castro, Barthelemy Kuate Defo, Ulises Trujillo, Alan D. Lopez, Soraya Seedat, Lope H Barrero, Linhong Wang, Daniel Pope, Alexandra Brazinova, Faris Lami, Valentina Colistro, G Anil Kumar, Derek F J Fay, Haidong Wang, Hwashin H. Shin, Raimundas Lunevicius, Suzanne Polinder, Dietrich Plass, David Rojas-Rueda, Stephen S Lim, Tania G Sánchez-Pimienta, K.M. Venkat Narayan, Yuantao Hao, Jung-Chen Chang, Corina Benjet, Seyed-Mohammad Fereshtehnejad, Luciano A. Sposato, Stan Biryukov, Kunihiro Matsushita, Beth E. Ebel, Cleusa P. Ferri, Soumya Swaminathan, K. Ryan Wessells, Gustavo Velasquez-Melendez, Leslie T. Cooper, David O. Carpenter, Nancy Lopez, Bryan L. Sykes, Sandra Nolte, Murray B. Stein, Paul N. Jensen, Fabiola Mejía-Rodríguez, Xiaonong Zou, Bradford D. Gessner, Dhruv S. Kazi, Dragos Virgil Davitoiu, Alejandra Jáuregui, Pouria Heydarpour, Megan Bohensky, Harvey Whiteford, Berrak Bora Basara, Zhengming Chen, Gregory R. Wagner, Paul I. Dargan, Hermann Brenner, Nima Hafezi-Nejad, John Nelson Opio, Scott Weichenthal, Deborah Salvo, Jun She, Tea Lallukka, Carolyn C. Gotay, Stephen G. Waller, Christian Kieling, Shivanthi Balalla, Valery L. Feigin, Qing Lan, Matias Trillini, Adam D M Briggs, Sungroul Kim, Niveen M E Abu-Rmeileh, Renata Micha, Sergey Petrovich Ermakov, Ole Frithjof Norheim, Zulfiqar A Bhutta, Paul S. F. Yip, Grant Nguyen, Ralph L. Sacco, Biju Abraham, Ken Takahashi, Jixiang Ma, Peter A. Meaney, Ayse Abbasoglu Ozgoren, Kimberly Cooperrider, M Rifat Kose, Shams Eldin Ali Hassan Khalifa, Rasmus Havmoeller, Alize J. Ferrari, Kebede Deribe, Nadim E. Karam, George A. Mensah, Bongani M. Mayosi, Konrad Pesudovs, Joanna Moschandreas, Ziad Nahas, James Damsere-Derry, Nsanzimana Sabin, Tonatiuh Barrientos-Gutiérrez, Ying Jiang, Andre Pascal Kengne, Peter Allebeck, Jonas Minet Kinge, Shankuan Zhu, Guy B. Marks, Daniel C Casey, Marco A Avila, Anna Roca, Lalit Dandona, Ami R. Moore, Adansi A. Amankwaa, David Gunnell, Andre Keren, Yohannes Adama Melaku, Nhung T Nguyen, Anthony D. Woolf, Mayuree Rao, Peter J. Allen, Christina Papachristou, Karzan Abdulmuhsin Mohammad, Ravi Kumar Balu, Marie Ng, Marcello Tonelli, Maziar Moradi-Lakeh, Maigeng Zhou, Emmanuela Gakidou, Mohammed K. Ali, Amanda W Pain, Dan J. Stein, Kawkab Shishani, Fortuné Gbètoho Gankpé, Howard J. Hoffman, James Scott, Nadine Steckling, Samia Alhabib, Deborah Jarvis, Kara Estep, Arsène Kouablan Adou, Ricardo Orozco, Holly Hagan, K. C. Astha, Reza Malekzadeh, Klara Dokova, Aliya Naheed, Ernst J. Kuipers, Valeria Caso, Derrick A Bennett, Andrea B. Feigl, Uche S. Uchendu, Holly E. Erskine, Shireen Sindi, Arjun Lakshmana Balaji, Francesco Saverio Violante, Monika Sawhney, Alejandra Cantoral, Ketevan Goginashvili, Raghib Ali, Fan Jiang, Robert G. Weintraub, Homie Razavi, Myriam Tobollik, Howard Hu, Emerito Jose A. Faraon, Irma Khonelidze, Patricia M. Riccio, Eun-Kee Park, Julio Cesar Campuzano, Ibrahim Abubakar, Jürgen C Schmidt, Konstantinos Stroumpoulis, Aref A. Bin Abdulhak, Graeme J. Hankey, Natan M. Bornstein, Mouhanad Hammami, Lee Richardson, Rintaro Mori, Alanur Çavlin, Ruth W Kimokoti, Samir Soneji, Mark J. Nieuwenhuijsen, John Q. Wong, Joseph Frostad, Tom Achoki, Rahman Shiri, Ashish Bhalla, Kurt Straif, Simon I. Hay, Scott B. Patten, Kalpana Balakrishnan, Awoke Misganaw Temesgen, Chandrashekhar T Sreeramareddy, Ryan M Barber, Rosana E. Norman, JianLi Wang, Siyi Shangguan, Luke Nyakarahuka, Kovin Naidoo, Charles D. H. Parry, Mercedes Colomar, H. Ross Anderson, Carlos Magis-Rodriguez, Joan M. Nolla, Muhammad Imran Nisar, Karen Devries, Andrew L. Thorne-Lyman, Denis Nash, Marape Marape, Rajiv Chowdhury, Dima M. Qato, Luca Ronfani, Nobhojit Roy, Daniel Kim, Yuichiro Yano, Luke D. Knibbs, Margaret Robinson, Hilda L Harb, Rogelio Pérez-Padilla, Janet L Leasher, Jonathan L. Wright, Peter Brooks, Cristiana Abbafati, Belinda K Lloyd, Victor Aboyans, Nikhil Tandon, Charles R. Newton, Simón Barquera, Ted R. Miller, Kinnari S. Murthy, Habib Benzian, Glen Mola, Paulo A. Lotufo, Burcu Kucuk Bicer, Peggy Pei-Chia Chiang, Alexander Kraemer, Solomon Meseret Woldeyohannes, Saman Fahimi, Lesley Rushton, Kim Moesgaard Iburg, Vafa Rahimi-Movaghar, Logan Sandar, Bruce Neal, Teresa Shamah Levy, Karen M. Tabb, Jeffrey A. Towbin, Christopher J L Murray, Ramesh Sahathevan, Aaron Cohen, Chanda Kulkarni, Van C. Lansingh, François Alla, Tasara T. Mazorodze, Murugesan Raju, Saeid Shahraz, Uchechukwu K.A. Sampson, Rajeev Gupta, Neil Pearce, Mustafa Z. Younis, Veena S. Kulkarni, Francisco A García-Guerra, Amanda G. Thrift, Stefan Ma, Samaya Ismayilova, Evariste Gasana, Amitava Banerjee, Aslam Pervaiz, Emilie Agardh, Abraham D. Flaxman, Farshad Farzadfar, Peter W. Gething, Ileana Heredia-Pi, Boris Bikbov, Wanqing Chen, Saad B. Omer, Ruben Castro, Neeraj Bhala, Sara Sheikhbahaei, Hilton Lam, Urbano Fra Paleo, Lidia Sanchez-Riera, Alicia Elena Beatriz Lawrynowicz, Kristen Delwiche, Richard G. Ellenbogen, Max Petzold, Yuri Y Varakin, Guilherme Borges, Guohong Jiang, Francis Guillemin, Kyle R. Heuton, Yohannes Kinfu, Victoria F Bachman, Joseph A Wagner, Carlos A Castañeda-Orjuela, Leonardo Trasande, Abbas Ali Mahdi, Josef Coresh, Chuanhua Yu, Kenji Shibuya, Berrin Serdar, Laetitia Huiart, Xiaofeng Liang, Jean de Dieu Ngirabega, Takayoshi Ohkubo, Natalie Stephens, Francis Apolinary Mhimbira, Jefferson Traebert, Amiran Gamkrelidze, Kjetil Søreide, Samath D Dharmaratne, Robert P. Dellavalle, George Mugambage Ruhago, Lakshmi Vijayakumar, Joannie Lortet-Tieulent, Dipan Bose, Tania C Aburto, Saleem M Rana, Miriam Levi, Mohammad Taghi Hedayati, Rodolfo S Pagcatipunan, Ron T. Gansevoort, H. D. Hosgood, Michael Burch, Mohsen Naghavi, Vegard Skirbekk, Ayfer Pekericli, Walter Mendoza, Pengpeng Ye, Gabrielle deVeber, Ali H. Mokdad, David M. Broday, Koranteng Adofo, Zewdie Aderaw Alemu, Shifalika Goenka, Carrie Beth Peterson, Nicolas J. C. Stapelberg, Edson Serván-Mori, Anil Kaul, Foad Abd-Allah, Marek Majdan, Rahul Gupta, Giancarlo Logroscino, Kardiyoloji, Peterson, Carrie B., Laboratoire de Physique des Solides (LPS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Wisconsin Division of Public Health, Laboratoire de psychologie sociale et de psychologie cognitive (LAPSCO), Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Erosion torrentielle neige et avalanches (UR ETGR (ETNA)), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), London South Bank University, Metropolitan Police Service, Hong Kong Baptist University (HKBU), Institut für Informatik [München/Munich] (LMU), Ludwig-Maximilians-Universität München (LMU), Neuroépidémiologie Tropicale (NET), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Chirurgie Thoracique et Vasculaire - Médecine vasculaire [CHU Limoges], CHU Limoges, Insight Centre for Data Analytics [Galway] (INSIGHT), National University of Ireland [Galway] (NUI Galway), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques Nancy, Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Institute, karolinska institute, Department of Molecular Biosciences, Department of Molecular Biosciences [Oslo], Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Centro de Estudios Avanzados en Zonas Aridas (CEAZA), Ecole Polytechnique Fédérale de Lausanne (EPFL), Regional Genetic Service, St Mary's Hospital, Manchester, Laboratoire d'Ingénierie des Matériaux (LIM), Centre National de la Recherche Scientifique (CNRS), Computer Science Department [Bristol], University of Bristol [Bristol], Universität Mannheim [Mannheim], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Samsung Research &Development Institute India - Bangalore (Groupe Samsung) (SRI-B), Computational Science and Engineering Department [Daresbury] (STFC), Science & Technologie Facilities Council, Multimedia Research Center (MRC), University of Alberta, Division of Biostatistics (Biostat - MINNEAPOLIS), University of Minnesota [Twin Cities], University of Minnesota System-University of Minnesota System, University of Southampton, Imperial College London, Neurology Department, Ichilov Medical Center, Interactions, transferts, ruptures artistiques et culturels - EA 6301 (InTRu), Université de Tours, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Risk Assessment Sciences Institute, Utrecht University [Utrecht], Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Respiratory Epidemiology and Public Health, Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute [UK], CIBER de Epidemiología y Salud Pública (CIBERESP), STAR laboratory, Stanford University [Stanford], Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Tennent Institute of Ophthalmology, National University of Singapore (NUS), Centre de Robotique (CAOR), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Multidisciplinary Nanotechnology Centre, Swansea University, Cyprus International Institute for the Environment and Public Health, Harvard School of Public Health, Genomics Research Center, Academia Sinica, Neuro Rehab Services LLP [New Delhi], Department of Signal Theory and Communications (TSC), Univ. Politec. de Catalunya, King‘s College London, Dept. Mat. Engn. De Ma, Sao Carlos, Fed. Univ. Sao Carlos UFSCar, RESPEC (RESPEC), RESPEC, Advanced Laboratories on Embedded Systems [Roma] (ALES), Department of Biology [Miami], University of Miami [Coral Gables], Health Care, Minister Of Labour-Ministry of Labor, Health and Social Affairs, Department of Nephrology, University Medical Center, University of Groningen, Division of Human Nutrition, Wageningen University and Research Centre [Wageningen] (WUR), Spatial Ecology and Epidemiology Group, University of Oxford [Oxford], College of Medicine, University of Hail, Saudi Arabia, Laboratory of Neurologic Diseases, Mario Negri Institute, Milan, Department of Civil Engineering [Hamirpur], National Institute of Technology [Hamirpur], GEMMA — Environmental Engineering and Microbiology Research Group, Department of Hydraulic, Maritime and Environmental Engineering, Universitat Politècnica de Catalunya [Barcelona] (UPC), Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Institut National de Recherche et d'Analyse Physico-Chimique (INRAP), Institut National de Recherche et d'Analyse Physico-chimique (Ariana, Tunisie) (INRAP), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Obesity Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University-Shahid Beheshti University, Center for Applied Medical Research (CIMA), University of Tehran, Secretariat of the Pacific Community, Public Health Division, Sociétés, Acteurs, Gouvernement en Europe (SAGE), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), College of Precision Instrument and Optoelectronics Engineering, Tianjin University, George Washington University (GW), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent [Ghent], Washington State University (WSU), Laboratoire de Physique de l'ENS Lyon (Phys-ENS), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, School of Computer Science - China University of Geosciences (China University of Geosciences (East Area)), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Fachbereich Physik [Berlin], Freie Universität Berlin, Div Cyclotron & Radiopharmaceut Sci (DRDO, INMAS), Univ New Delhi, School of Physics and Astronomy, University of St Andrews [Scotland], University of Cape Town, Department of Neuroscience, Department of Computer Science and Engineering [Daejeon] (Chungnam National University), Lawrence University, Gastroenterology & Hepatology, Tata Research Development and Design Center (TRDDC), TCS Innovation Labs, University of Helsinki, Google Inc [Mountain View], Research at Google, Swedish Defense Research Agency (FOI), Servicio de Neurologia (SANTIAGO - Neurologie), Universidad del Desarrollo, Novartis Pharmaceutical Corporation, Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble [1985-2015] (OSUG [1985-2015]), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Department of Mechanical and Automation Engineering (CAD Laboratory), The Chinese University of Hong Kong [Hong Kong], Università degli studi di Bari, Department of Health and Human Services, National Institutes of Health [Bethesda] (NIH), Centre d'études et de recherche en informatique et communications (CEDRIC), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Heuristique et Diagnostic des Systèmes Complexes [Compiègne] (Heudiasyc), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), College of Information and Electrical Engineering [Beijing] (CIEE), China Agricultural University (CAU), Thales Research and Technology [Palaiseau], THALES, Department of Rheumatology and Connective Tissue Diseases, Medical University of Lublin, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Centre d'économie de la Sorbonne (CES), Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Paris School of Economics (PSE), École supérieure du professorat et de l'éducation - Académie de Grenoble [2013-2019] (ESPE Grenoble [2013-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Mathematics, University of Iowa [Iowa City], College of Medicine, Alfaisal University, Saudi Ministry of Health, Institut national des recherches agricoles du Bénin, Centre de Recherches agricoles du Sud, Departments of Epidemiology and Nutrition, Unit of Human Nutrition, Agricultural University of Athens, Department of Animal Science, Pennsylvania State University (Penn State), Penn State System-Penn State System, University of Virginia, University of Virginia [Charlottesville], Epidemiology and Biostatistics Unit, Institute for Maternal and Child Health - IRCCS ‘‘Burlo Garofolo', Jet Propulsion Laboratory (JPL), NASA-California Institute of Technology (CALTECH), Division of Cardiovascular Medicine and Channing Division of Network Medicine, Brigham and Women's Hospital [Boston], American University of Beirut [Beyrouth] (AUB), Department of Chemistry, Scientific Computing Research Unit, Department of dermatology, Milano University-Azienda Ospedaleria Ospedali Riuniti di Bergamo, Mailman School of Public Health, Columbia University [New York], The Georges Institute for International Health, The University of Sydney, Department of epidemiology and Public Health, Faculty of Medicine, Département Optique (OPT), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Laboratoire des signaux et systèmes (L2S), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Universitat Pompeu Fabra [Barcelona], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona]-Catalunya ministerio de salud, Nutriments Lipidiques et Prévention des Maladies Métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université de la Méditerranée - Aix-Marseille 2, Department of Neurology Lunds University Hospital Lund, Unit of Functional Bionanomaterials, School of Biosciences, University of Birmingham [Birmingham], Electrical Engineering and Computer Science Department - Case Western Reserve University, Case Western Reserve University [Cleveland], World Health Organization, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Nordic School of Public Health, The James Hutton Institute, Horia Hulubei National Institute for Physics and Nuclear Engineering, Department of Pediatrics, University of Washington [Seattle], Institute of Public Health, Department of Physics, Clarendon Laboratory, Center for TeleInFrastruktur (CTIF), Aalborg University [Denmark] (AAU), Physikalisches Institut [Freiburg], Albert-Ludwigs-Universität Freiburg, Savoirs, Textes, Langage (STL) - UMR 8163 (STL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Dept.of Computer Science, Indian Institute of Technology Madras (IIT Madras), Istituto Mario Negri Bergamo, Centro Ricerche e Trapianti Villa Camozzi, Universidade Estadual Paulista Júlio de Mesquita Filho [São José do Rio Preto] (UNESP), Laboratoire de Génie Informatique et Ingénierie de Production (LGI2P), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut geològic de Catalunya (IGC), Institut Geològic de Catalunya-IGC, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physiologie et Génomique des Poissons (LPGP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Recherche Agronomique (INRA), Politecnico di Milano [Milan] (POLIMI), Symantec, University of Oviedo, European Microsoft Innovation Center (EMIC), Microsoft Corporation [Redmond, Wash.], Technion - Israel Institute of Technology [Haifa], Laboratoire de Mécanique, Physique et Géosciences (LMPG), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU), Department of Physics, Cavendish Laboratory, University of Cambridge [UK] (CAM), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Departments of Applied Physics [New Haven], Yale University [New Haven], Center for Mathematical Modeling (CMM), Department of Global Health and Development, London School of Hygiene and Tropical Medicine (LSHTM), University of Occupational and Environmental Health [Kitakyushu] (UEOH), Department of Computer Science and Engineering [New Delhi], Indian Institute of Technology Delhi (IIT Delhi), Institut de Recherche sur les Phénomènes Hors Equilibre (IRPHE), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), GlaxoSmithKline, Imperial College London-Clinical Imaging Center, Universidade Federal de Pernambuco [Recife] (UFPE), Maclean Building, Benson Lane, Crowmarsh Gifford, Centre for Ecology and Hydrology, Nanoscience Institute (NEST), Dipartimento di Fisica, Università di Pisa, Aristotle University of Thessaloniki, Laboratory Of Immune Cell Biology (LICB), JRC Institute for Environment and Sustainability (IES), European Commission - Joint Research Centre [Ispra] (JRC), Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] (LNCC / MCT), Occupational Health Unit, Bologna University Hospital-Sant'Orsola-Malpighi Polyclinic, Royal Institute of Technology [Stockholm] (KTH ), NICTA [Eveleigh], National ICT Australia [Sydney] (NICTA), Division of Solid Mechanics, Lund University [Lund], University of Calgary, BioWare Corp, Manchester Academic Health Sciences Centre, Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Ghent University [Belgium] (UGENT), Imaging Sciences and Biomedical Engineering Division [London], Guy's and St Thomas' Hospital [London]-King‘s College London, Children’s Hospital of Philadelphia (CHOP ), Perelman School of Medicine, University of Pennsylvania [Philadelphia], Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Génie Civil et Mécanique (GeM), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, Augusta University - Medical College of Georgia, University System of Georgia (USG)-University System of Georgia (USG), Neurorestoration Group, Wolfson Centre for Age-related Diseases-King‘s College London, Electronic Navigation Research Institute (ENRI), Ministry of Land, Infrastructure, Transport and Tourism, Department of Computer Science [KAIST] (CS), Korea Advanced Institute of Science and Technology (KAIST), Centre for Undergraduate Studies, University of the Punjab, Siemens Corporate Research, Siemens AG [Munich], University of Massachusetts [Boston] (UMass Boston), University of Massachusetts System (UMASS), Department of Materials Science, Sichuan University [Chengdu] (SCU), Natl Engn Res Ctr Vegetables, Key Lab Biol & Genet Improvement Hort Crops N Chi, Beijing Acad Agr & Forestry Sci, University Hospital Puerta de Hierro, Madrid, Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Shahid Beheshti University of Medical Sciences, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), MOLTECH-ANJOU (MOLTECH-ANJOU), Université d'Angers (UA)-Centre National de la Recherche Scientifique (CNRS), Universidad de Santiago de Chile [Santiago] (USACH)-Universidad del Desarrollo, Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), École supérieure du professorat et de l'éducation - Académie de Grenoble (ESPE Grenoble), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Grenoble Alpes (UGA), California Institute of Technology (CALTECH)-NASA, Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Sud - Paris 11 (UP11), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Santiago de Chile [Santiago] (USACH), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris), King‘s College London-Wolfson Centre for Age-related Diseases, Sichuan University, Universitat de Barcelona, Interne Geneeskunde, Medische Sociologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Psychiatrie & Neuropsychologie, CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology [2007-2019] (Grenoble INP [2007-2019])-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Mines-Télécom [Paris] (IMT)-Télécom Bretagne-Université européenne de Bretagne - European University of Brittany (UEB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), RS: MHeNs - R2 - Mental Health, Laboratoire de Physique des Solides ( LPS ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de psychologie sociale et de psychologie cognitive ( LAPSCO ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ), Erosion torrentielle neige et avalanches ( UR ETGR ), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ), Hong Kong Baptist University ( HKBU ), Institut für Informatik [München/Munich] ( LMU ), Ludwig-Maximilians-Universität München, Neuroépidémiologie Tropicale ( NET ), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST ), Université de Limoges ( UNILIM ) -Université de Limoges ( UNILIM ), Insight Centre for Data Analytics (National University of Ireland Galway (NUIG)) ( INSIGHT ), Maladies chroniques, santé perçue, et processus d'adaptation ( APEMAC ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Cancéropôle du Grand Est-Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Oslo ( UiO ) -University of Oslo ( UiO ), Centro de Estudios Avanzados en Zonas Aridas ( CEAZA ), Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Laboratoire d'Ingénierie des Matériaux ( LIM ), Centre National de la Recherche Scientifique ( CNRS ), Lawrence Berkeley National Laboratory [Berkeley] ( LBNL ), Samsung Research &Development Institute India - Bangalore (Groupe Samsung) ( SRI-B ), Computational Science and Engineering Department [Daresbury] ( STFC ), Multimedia Research Center ( MRC ), University of Alberta [Edmonton], Division of Biostatistics ( Biostat - MINNEAPOLIS ), University of Minnesota [Minneapolis], University of Southampton [Southampton], Interactions, transferts, ruptures artistiques et culturels - EA 6301 ( InTRu ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), University Medical Center Utrecht, Biologie Fonctionnelle et Adaptative ( BFA ), Imperial College London-Royal Brompton Hospital-National Heart and Lung Institute, Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), National University of Singapore ( NUS ), Centre de Robotique ( CAOR ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Department of Signal Theory and Communications ( TSC ), RESPEC ( RESPEC ), Advanced Laboratories on Embedded Systems [Roma] ( ALES ), Wageningen University and Research Centre [Wageningen] ( WUR ), Universitat Politècnica de Catalunya [Barcelona] ( UPC ), Institut National de Recherche et d'Analyse Physico-Chimique ( INRAP ), Institut National de Recherche et d'Analyse Physico-chimique (INRAP-Tunisie), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) ( FEMTO-ST ), Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure de Mécanique et des Microtechniques ( ENSMM ) -Université de Technologie de Belfort-Montbeliard ( UTBM ), Tehran University, Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM - U912 INSERM - AMU - IRD ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Washington State University ( WSU ), Laboratoire de Physique de l'ENS Lyon ( Phys-ENS ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche en informatique de Toulouse ( IRIT ), Institut National Polytechnique [Toulouse] ( INP ) -Université Toulouse 1 Capitole ( UT1 ) -Université Toulouse - Jean Jaurès ( UT2J ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Automatique de Nancy ( CRAN ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Université Catholique de Louvain ( UCL ), Freie Universität Berlin [Berlin], Div Cyclotron & Radiopharmaceut Sci ( DRDO, INMAS ), Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Tata Research Development and Design Center ( TRDDC ), Laboratoire MOLTECH-Anjou [Angers] ( MOLTECH ANJOU ), Université d'Angers ( UA ) -Centre National de la Recherche Scientifique ( CNRS ), University of Helsinki [Helsinki], Swedish Defense Research Agency ( FOI ), Servicio de Neurologia ( SANTIAGO - Neurologie ), Universidad de Santiago de Chile [Santiago] ( USACH ) -Universidad del Desarrollo, Novartis Pharmaceutical Corp., East Hanover NJ 07936, USA, Laboratoire de glaciologie et géophysique de l'environnement ( LGGE ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Mechanical and Automation Engineering ( CAD Laboratory ), National Institutes of Health ( NIH ), Centre d'étude et de recherche en informatique et communications ( CEDRIC ), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise ( ENSIIE ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Heuristique et Diagnostic des Systèmes Complexes [Compiègne] ( Heudiasyc ), Université de Technologie de Compiègne ( UTC ) -Centre National de la Recherche Scientifique ( CNRS ), College of Information and Electrical Engineering [Beijing] ( CIEE ), China Agricultural University ( CAU ), Queen Mary University of London ( QMUL ), Centre d'économie de la Sorbonne ( CES ), Université Panthéon-Sorbonne ( UP1 ) -Centre National de la Recherche Scientifique ( CNRS ), Paris School of Economics ( PSE ), École supérieure du professorat et de l'éducation - Académie de Grenoble ( ESPE Grenoble ), Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Université Grenoble Alpes ( UGA ), PennState University [Pennsylvania] ( PSU ), Jet Propulsion Laboratory ( JPL ), NASA-California Institute of Technology ( CALTECH ), American University of Beirut [Beyrouth], The University of Sydney [Sydney], Département Optique ( OPT ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Laboratoire des signaux et systèmes ( L2S ), Université Paris-Sud - Paris 11 ( UP11 ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Center for Research in Environmental Epidemiology ( CREAL ), Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique ( INRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Center for TeleInFrastruktur ( CTIF ), Aalborg University [Denmark] ( AAU ), Savoirs, Textes, Langage (STL) - UMR 8163 ( STL ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Indian Institute of Technology Madras ( IIT Madras ), Universidade Estadual Paulista Júlio de Mesquita ( UNESP ), Laboratoire de Génie Informatique et Ingénierie de Production ( LGI2P ), IMT - Mines Alès Ecole Mines - Télécom ( IMT - MINES ALES ), Institut geològic de Catalunya ( IGC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Physiologie et Génomique des Poissons ( LPGP ), Institut National de la Recherche Agronomique ( INRA ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Politecnico di Milano [Milan], European Microsoft Innovation Center ( EMIC ), Laboratoire de Mécanique, Physique et Géosciences ( LMPG ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ), University of Cambridge [UK] ( CAM ), Laboratoire de Probabilités et Modèles Aléatoires ( LPMA ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Center for Mathematical Modeling ( CMM ), Universidad de Santiago de Chile [Santiago] ( USACH ), London School of Hygiene and Tropical Medicine ( LSHTM ), University of Occupational and Environmental Health [Kitakyushu] ( UEOH ), Indian Institute of Technology Delhi ( IIT Delhi ), Institut de Recherche sur les Phénomènes Hors Equilibre ( IRPHE ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Universidade Federal de Pernambuco [Recife] ( UFPE ), Nanoscience Institute ( NEST ), Laboratory Of Immune Cell Biology ( LICB ), JRC Institute for Environment and Sustainability ( IES ), European Commission - Joint Research Centre [Ispra] ( JRC ), Bonn Universität [Bonn], Laboratorio Nacional de Computação Cientifica [Rio de Janeiro] ( LNCC / MCT ), Royal Institute of Technology [Stockholm] ( KTH ), National ICT Australia [Sydney] ( NICTA ), Institut d'Histoire et de Philosophie des Sciences et des Techniques ( IHPST ), Université Panthéon-Sorbonne ( UP1 ) -Département d'Etudes Cognitives - ENS Paris ( DEC ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Ghent University [Belgium] ( UGENT ), Children’s Hospital of Philadelphia ( CHOP ), Univeristy of Pennsylvania Medical School, Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique ( LHEEA ), École Centrale de Nantes ( ECN ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche en Génie Civil et Mécanique ( GeM ), Université de Nantes ( UN ) -École Centrale de Nantes ( ECN ) -Centre National de la Recherche Scientifique ( CNRS ), Medical College of Georgia, Electronic Navigation Research Institute ( ENRI ), Department of Computer Science [KAIST] ( CS ), Korea Advanced Institute of Science and Technology ( KAIST ), Laboratoire de l'Accélérateur Linéaire ( LAL ), University of Massachusetts [Boston] ( UMass Boston ), Forouzanfar, Mohammad H, Alexander, Lily, Anderson, H. Ro, Bachman, Victoria F, Biryukov, Stan, Brauer, Michael, Burnett, Richard, Casey, Daniel, Coates, Matthew M, Cohen, Aaron, Delwiche, Kristen, Estep, Kara, Frostad, Joseph J, Kc, Astha, Kyu, Hmwe H, Moradi Lakeh, Maziar, Ng, Marie, Slepak, Erica Leigh, Thomas, Bernadette A, Wagner, Joseph, Aasvang, Gunn Marit, Abbafati, Cristiana, Ozgoren, Ayse Abbasoglu, Abd Allah, Foad, Abera, Semaw F, Aboyans, Victor, Abraham, Biju, Abraham, Jerry Puthenpurakal, Abubakar, Ibrahim, Abu Rmeileh, Niveen M. E, Aburto, Tania C, Achoki, Tom, Adelekan, Ademola, Adofo, Koranteng, Adou, Arsène K, Adsuar, José C, Afshin, Ashkan, Agardh, Emilie E, Al Khabouri, Mazin J, Al Lami, Faris H, Alam, Sayed Saidul, Alasfoor, Deena, Albittar, Mohammed I, Alegretti, Miguel A, Aleman, Alicia V, Alemu, Zewdie A, Alfonso Cristancho, Rafael, Alhabib, Samia, Ali, Raghib, Ali, Mohammed K, Alla, Françoi, Allebeck, Peter, Allen, Peter J, Alsharif, Ubai, Alvarez, Elena, Alvis Guzman, Nelson, Amankwaa, Adansi A, Amare, Azmeraw T, Ameh, Emmanuel A, Ameli, Omid, Amini, Heresh, Ammar, Walid, Anderson, Benjamin O, Antonio, Carl Abelardo T, Anwari, Palwasha, Cunningham, Solveig Argeseanu, Arnlöv, Johan, Arsenijevic, Valentina S. Arsic, Artaman, Al, Asghar, Rana J, Assadi, Reza, Atkins, Lydia S, Atkinson, Charle, Avila, Marco A, Awuah, Baffour, Badawi, Alaa, Bahit, Maria C, Bakfalouni, Talal, Balakrishnan, Kalpana, Balalla, Shivanthi, Balu, Ravi Kumar, Banerjee, Amitava, Barber, Ryan M, Barker Collo, Suzanne L, Barquera, Simon, Barregard, Lar, Barrero, Lope H, Barrientos Gutierrez, Tonatiuh, Basto Abreu, Ana C, Basu, Arindam, Basu, Sanjay, Basulaiman, Mohammed O, Ruvalcaba, Carolina Bati, Beardsley, Justin, Bedi, Neeraj, Bekele, Tolesa, Bell, Michelle L, Benjet, Corina, Bennett, Derrick A, Benzian, Habib, Bernabé, Eduardo, Beyene, Tariku J, Bhala, Neeraj, Bhalla, Ashish, Bhutta, Zulfiqar A, Bikbov, Bori, Abdulhak, Aref A. Bin, Blore, Jed D, Blyth, Fiona M, Bohensky, Megan A, Başara, Berrak Bora, Borges, Guilherme, Bornstein, Natan M, Bose, Dipan, Boufous, Soufiane, Bourne, Rupert R, Brainin, Michael, Brazinova, Alexandra, Breitborde, Nicholas J, Brenner, Hermann, Briggs, Adam D. M, Broday, David M, Brooks, Peter M, Bruce, Nigel G, Brugha, Traolach S, Brunekreef, Bert, Buchbinder, Rachelle, Bui, Linh N, Bukhman, Gene, Bulloch, Andrew G, Burch, Michael, Burney, Peter G. J, Campos Nonato, Ismael R, Campuzano, Julio C, Cantoral, Alejandra J, Caravanos, Jack, Cárdenas, Rosario, Cardis, Elisabeth, Carpenter, David O, Caso, Valeria, Castañeda Orjuela, Carlos A, Castro, Ruben E, Catalá López, Ferrán, Cavalleri, Fiorella, Çavlin, Alanur, Chadha, Vineet K, Chang, Jung Chen, Charlson, Fiona J, Chen, Honglei, Chen, Wanqing, Chen, Zhengming, Chiang, Peggy P, Chimed Ochir, Odgerel, Chowdhury, Rajiv, Christophi, Costas A, Chuang, Ting Wu, Chugh, Sumeet S, Cirillo, Massimo, Claßen, Thomas Kd, Colistro, Valentina, Colomar, Mercede, Colquhoun, Samantha M, Contreras, Alejandra G, Cooper, Cyru, Cooperrider, Kimberly, Cooper, Leslie T, Coresh, Josef, Courville, Karen J, Criqui, Michael H, Cuevas Nasu, Lucia, Damsere Derry, Jame, Danawi, Hadi, Dandona, Lalit, Dandona, Rakhi, Dargan, Paul I, Davis, Adrian, Davitoiu, Dragos V, Dayama, Anand, de Castro, E. Filipa, De la Cruz Góngora, Vanessa, De Leo, Diego, de Lima, Graça, Degenhardt, Louisa, Del Pozo Cruz, Borja, Dellavalle, Robert P, Deribe, Kebede, Derrett, Sarah, Jarlais, Don C. De, Dessalegn, Muluken, Deveber, Gabrielle A, Devries, Karen M, Dharmaratne, Samath D, Dherani, Mukesh K, Dicker, Daniel, Ding, Eric L, Dokova, Klara, Dorsey, E. Ray, Driscoll, Tim R, Duan, Leilei, Durrani, Adnan M, Ebel, Beth E, Ellenbogen, Richard G, Elshrek, Yousef M, Endres, Matthia, Ermakov, Sergey P, Erskine, Holly E, Eshrati, Babak, Esteghamati, Alireza, Fahimi, Saman, Faraon, Emerito Jose A, Farzadfar, Farshad, Fay, Derek F. J, Feigin, Valery L, Feigl, Andrea B, Fereshtehnejad, Seyed Mohammad, Ferrari, Alize J, Ferri, Cleusa P, Flaxman, Abraham D, Fleming, Thomas D, Foigt, Nataliya, Foreman, Kyle J, Paleo, Urbano Fra, Franklin, Richard C, Gabbe, Belinda, Gaffikin, Lynne, Gakidou, Emmanuela, Gamkrelidze, Amiran, Gankpé, Fortuné G, Gansevoort, Ron T, García Guerra, Francisco A, Gasana, Evariste, Geleijnse, Johanna M, Gessner, Bradford D, Gething, Pete, Gibney, Katherine B, Gillum, Richard F, Ginawi, Ibrahim A. M, Giroud, Maurice, Giussani, Giorgia, Goenka, Shifalika, Goginashvili, Ketevan, Dantes, Hector Gomez, Gona, Philimon, de Cosio, Teresita Gonzalez, González Castell, Dinorah, Gotay, Carolyn C, Goto, Atsushi, Gouda, Hebe N, Guerrant, Richard L, Gugnani, Harish C, Guillemin, Franci, Gunnell, David, Gupta, Rahul, Gupta, Rajeev, Gutiérrez, Reyna A, Hafezi Nejad, Nima, Hagan, Holly, Hagstromer, Maria, Halasa, Yara A, Hamadeh, Randah R, Hammami, Mouhanad, Hankey, Graeme J, Hao, Yuantao, Harb, Hilda L, Haregu, Tilahun Nigatu, Haro, Josep Maria, Havmoeller, Rasmu, Hay, Simon I, Hedayati, Mohammad T, Heredia Pi, Ileana B, Hernandez, Lucia, Heuton, Kyle R, Heydarpour, Pouria, Hijar, Martha, Hoek, Hans W, Hoffman, Howard J, Hornberger, John C, Hosgood, H. Dean, Hoy, Damian G, Hsairi, Mohamed, Hu, Guoqing, Hu, Howard, Huang, Cheng, Huang, John J, Hubbell, Bryan J, Huiart, Laetitia, Husseini, Abdullatif, Iannarone, Marissa L, Iburg, Kim M, Idrisov, Bulat T, Ikeda, Nayu, Innos, Kaire, Inoue, Manami, Islami, Farhad, Ismayilova, Samaya, Jacobsen, Kathryn H, Jansen, Henrica A, Jarvis, Deborah L, Jassal, Simerjot K, Jauregui, Alejandra, Jayaraman, Sudha, Jeemon, Panniyammakal, Jensen, Paul N, Jha, Vivekanand, Jiang, Fan, Jiang, Guohong, Jiang, Ying, Jonas, Jost B, Juel, Knud, Kan, Haidong, Roseline, Sidibe S. Kany, Karam, Nadim E, Karch, André, Karema, Corine K, Karthikeyan, Ganesan, Kaul, Anil, Kawakami, Norito, Kazi, Dhruv S, Kemp, Andrew H, Kengne, Andre P, Keren, Andre, Khader, Yousef S, Khalifa, Shams Eldin Ali Hassan, Khan, Ejaz A, Khang, Young Ho, Khatibzadeh, Shahab, Khonelidze, Irma, Kieling, Christian, Kim, Daniel, Kim, Sungroul, Kim, Yunjin, Kimokoti, Ruth W, Kinfu, Yohanne, Kinge, Jonas M, Kissela, Brett M, Kivipelto, Miia, Knibbs, Luke D, Knudsen, Ann Kristin, Kokubo, Yoshihiro, Kose, M. Rifat, Kosen, Soewarta, Kraemer, Alexander, Kravchenko, Michael, Krishnaswami, Sanjay, Kromhout, Han, Ku, Tiffany, Defo, Barthelemy Kuate, Bicer, Burcu Kucuk, Kuipers, Ernst J, Kulkarni, Chanda, Kulkarni, Veena S, Kumar, G. Anil, Kwan, Gene F, Lai, Taavi, Balaji, Arjun Lakshmana, Lalloo, Ratilal, Lallukka, Tea, Lam, Hilton, Lan, Qing, Lansingh, Van C, Larson, Heidi J, Larsson, Ander, Laryea, Dennis O, Lavados, Pablo M, Lawrynowicz, Alicia E, Leasher, Janet L, Lee, Jong Tae, Leigh, Jame, Leung, Ricky, Levi, Miriam, Li, Yichong, Li, Yongmei, Liang, Juan, Liang, Xiaofeng, Lim, Stephen S, Lindsay, M. Patrice, Lipshultz, Steven E, Liu, Shiwei, Liu, Yang, Lloyd, Belinda K, Logroscino, Giancarlo, London, Stephanie J, Lopez, Nancy, Lortet Tieulent, Joannie, Lotufo, Paulo A, Lozano, Rafael, Lunevicius, Raimunda, Ma, Jixiang, Ma, Stefan, Machado, Vasco M. P, Macintyre, Michael F, Magis Rodriguez, Carlo, Mahdi, Abbas A, Majdan, Marek, Malekzadeh, Reza, Mangalam, Srikanth, Mapoma, Christopher C, Marape, Marape, Marcenes, Wagner, Margolis, David J, Margono, Christopher, Marks, Guy B, Martin, Randall V, Marzan, Melvin B, Mashal, Mohammad T, Masiye, Felix, Mason Jones, Amanda J, Matsushita, Kunihiro, Matzopoulos, Richard, Mayosi, Bongani M, Mazorodze, Tasara T, Mckay, Abigail C, Mckee, Martin, Mclain, Abigail, Meaney, Peter A, Medina, Catalina, Mehndiratta, Man Mohan, Mejia Rodriguez, Fabiola, Mekonnen, Wubegzier, Melaku, Yohannes A, Meltzer, Michele, Memish, Ziad A, Mendoza, Walter, Mensah, George A, Meretoja, Atte, Mhimbira, Francis Apolinary, Micha, Renata, Miller, Ted R, Mills, Edward J, Misganaw, Awoke, Mishra, Santosh, Ibrahim, Norlinah Mohamed, Mohammad, Karzan A, Mokdad, Ali H, Mola, Glen L, Monasta, Lorenzo, Hernandez, Julio C. 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Srinath, Refaat, Amany H, Rehm, Jürgen, Remuzzi, Giuseppe, Ribeiro, Antonio L, Riccio, Patricia M, Richardson, Lee, Riederer, Anne, Robinson, Margaret, Roca, Anna, Rodriguez, Alina, Rojas Rueda, David, Romieu, Isabelle, Ronfani, Luca, Room, Robin, Roy, Nobhojit, Ruhago, George M, Rushton, Lesley, Sabin, Nsanzimana, Sacco, Ralph L, Saha, Sukanta, Sahathevan, Ramesh, Sahraian, Mohammad Ali, Salomon, Joshua A, Salvo, Deborah, Sampson, Uchechukwu K, Sanabria, Juan R, Sanchez, Luz Maria, Sánchez Pimienta, Tania G, Sanchez Riera, Lidia, Sandar, Logan, Santos, Itamar S, Sapkota, Amir, Satpathy, Maheswar, Saunders, James E, Sawhney, Monika, Saylan, Mete I, Scarborough, Peter, Schmidt, Jürgen C, Schneider, Ione J. C, Schöttker, Ben, Schwebel, David C, Scott, James G, Seedat, Soraya, Sepanlou, Sadaf G, Serdar, Berrin, Servan Mori, Edson E, Shaddick, Gavin, Shahraz, Saeid, Levy, Teresa Shamah, Shangguan, Siyi, She, Jun, Sheikhbahaei, Sara, Shibuya, Kenji, Shin, Hwashin H, Shinohara, Yukito, Shiri, Rahman, Shishani, Kawkab, Shiue, Ivy, Sigfusdottir, Inga D, Silberberg, Donald H, Simard, Edgar P, Sindi, Shireen, Singh, Abhishek, Singh, Gitanjali M, Singh, Jasvinder A, Skirbekk, Vegard, Sliwa, Karen, Soljak, Michael, Soneji, Samir, Søreide, Kjetil, Soshnikov, Sergey, Sposato, Luciano A, Sreeramareddy, Chandrashekhar T, Stapelberg, Nicolas J. C, Stathopoulou, Vasiliki, Steckling, Nadine, Stein, Dan J, Stein, Murray B, Stephens, Natalie, Stöckl, Heidi, Straif, Kurt, Stroumpoulis, Konstantino, Sturua, Lela, Sunguya, Bruno F, Swaminathan, Soumya, Swaroop, Mamta, Sykes, Bryan L, Tabb, Karen M, Takahashi, Ken, Talongwa, Roberto T, Tandon, Nikhil, Tanne, David, Tanner, Marcel, Tavakkoli, Mohammad, Te Ao, Braden J, Teixeira, Carolina M, Téllez Rojo, Martha M, Terkawi, Abdullah S, Texcalac Sangrador, José Lui, Thackway, Sarah V, Thomson, Blake, Thorne Lyman, Andrew L, Thrift, Amanda G, Thurston, George D, Tillmann, Taavi, Tobollik, Myriam, Tonelli, Marcello, Topouzis, Foti, Towbin, Jeffrey A, Toyoshima, Hideaki, Traebert, Jefferson, Tran, Bach X, Trasande, Leonardo, Trillini, Matia, Trujillo, Ulise, Dimbuene, Zacharie Tsala, Tsilimbaris, Miltiadi, Tuzcu, Emin Murat, Uchendu, Uche S, Ukwaja, Kingsley N, Uzun, Selen B, van de Vijver, Steven, Van Dingenen, Rita, van Gool, Coen H, van Os, Jim, Varakin, Yuri Y, Vasankari, Tommi J, Vasconcelos, Ana Maria N, Vavilala, Monica S, Veerman, Lennert J, Velasquez Melendez, Gustavo, Venketasubramanian, N, Vijayakumar, Lakshmi, Villalpando, Salvador, Violante, Francesco S, Vlassov, Vasiliy Victorovich, Vollset, Stein Emil, Wagner, Gregory R, Waller, Stephen G, Wallin, Mitchell T, Wan, Xia, Wang, Haidong, Wang, Jianli, Wang, Linhong, Wang, Wenzhi, Wang, Yanping, Warouw, Tati S, Watts, Charlotte H, Weichenthal, Scott, Weiderpass, Elisabete, Weintraub, Robert G, Werdecker, Andrea, Wessells, K. Ryan, Westerman, Ronny, Whiteford, Harvey A, Wilkinson, James D, Williams, Hywel C, Williams, Thomas N, Woldeyohannes, Solomon M, Wolfe, Charles D. A, Wong, John Q, Woolf, Anthony D, Wright, Jonathan L, Wurtz, Brittany, Xu, Gelin, Yan, Lijing L, Yang, Gonghuan, Yano, Yuichiro, Ye, Pengpeng, Yenesew, Muluken, Yentür, Gökalp K, Yip, Paul, Yonemoto, Naohiro, Yoon, Seok Jun, Younis, Mustafa Z, Younoussi, Zourkaleini, Yu, Chuanhua, Zaki, Maysaa E, Zhao, Yong, Zheng, Yingfeng, Zhou, Maigeng, Zhu, Jun, Zhu, Shankuan, Zou, Xiaonong, Zunt, Joseph R, Lopez, Alan D, Vos, Theo, Murray, Christopher J., Cell biology, Epidemiology, Neurosciences, Health Technology Assessment (HTA), Public Health, General practice, Bachman, Victoria F., Coates, Matthew M., Frostad, Joseph J., Astha, K.C., Kyu, Hmwe H., Moradi-Lakeh, Maziar, Thomas, Bernadette A., Abbasoglu Ozgoren, Ayse, Abd-Allah, Foad, Abera, Semaw F., Puthenpurakal Abraham, Jerry, Abu-Rmeileh, Niveen M.E., Aburto, Tania C., Adou, Arsène K., Adsuar, José C., Agardh, Emilie E., Al Khabouri, Mazin J., Al Lami, Faris H., Albittar, Mohammed I., Alegretti, Miguel A., Aleman, Alicia V., Alemu, Zewdie A., Alfonso-Cristancho, Rafael, Ali, Mohammed K., Allen, Peter J., Alvis-Guzman, Nelson, Amankwaa, Adansi A., Amare, Azmeraw T., Ameh, Emmanuel A., Anderson, Benjamin O., Antonio, Carl Abelardo T., Argeseanu Cunningham, Solveig, Arsic Arsenijevic, Valentina S., Asghar, Rana J., Atkins, Lydia S., Avila, Marco A., Bahit, Maria C., Barber, Ryan M., Barker-Collo, Suzanne L., Barrero, Lope H., Barrientos-Gutierrez, Tonatiuh, Basto-Abreu, Ana C., Basulaiman, Mohammed O., Batis Ruvalcaba, Carolina, Bell, Michelle L., Bennett, Derrick A., Beyene, Tariku J., Bhutta, Zulfiqar A., Bin Abdulhak, Aref A., Blore, Jed D., Blyth, Fiona M., Bohensky, Megan A., Bora Başara, Berrak, Bornstein, Natan M., Bourne, Rupert R., Breitborde, Nicholas J., Briggs, Adam D.M., Broday, David M., Brooks, Peter M., Bruce, Nigel G., Brugha, Traolach S., Bui, Linh N., Bulloch, Andrew G., Burney, Peter G.J., Campos-Nonato, Ismael R., Campuzano, Julio C., Cantoral, Alejandra J., Carpenter, David O., Castañeda-Orjuela, Carlos A., Castro, Ruben E., Catalá-López, Ferrán, Chadha, Vineet K., Chang, Jung-Chen, Charlson, Fiona J., Chiang, Peggy P., Chimed-Ochir, Odgerel, Christophi, Costas A., Chuang, Ting-Wu, Chugh, Sumeet S., Claßen, Thomas K.D., Colquhoun, Samantha M., Contreras, Alejandra G., Cooper, Leslie T., Courville, Karen J., Criqui, Michael H., Cuevas-Nasu, Lucia, Damsere-Derry, Jame, Dargan, Paul I., Davitoiu, Dragos V., De Castro, E. Filipa, De La Cruz-Góngora, Vanessa, De Lima, Graça, Del Pozo-Cruz, Borja, Dellavalle, Robert P., Des Jarlais, Don C., Deveber, Gabrielle A., Devries, Karen M., Dharmaratne, Samath D., Dherani, Mukesh K., Ding, Eric L., Driscoll, Tim R., Durrani, Adnan M., Ebel, Beth E., Ellenbogen, Richard G., Elshrek, Yousef M., Ermakov, Sergey P., Erskine, Holly E., Faraon, Emerito Jose A., Fay, Derek F.J., Feigin, Valery L., Feigl, Andrea B., Fereshtehnejad, Seyed-Mohammad, Ferrari, Alize J., Ferri, Cleusa P., Flaxman, Abraham D., Fleming, Thomas D., Foreman, Kyle J., Fra Paleo, Urbano, Franklin, Richard C., Gankpé, Fortuné G., Gansevoort, Ron T., García-Guerra, Francisco A., Geleijnse, Johanna M., Gessner, Bradford D., Gibney, Katherine B., Gillum, Richard F., Ginawi, Ibrahim A.M., Gomez Dantes, Hector, Gonzalez De Cosio, Teresita, González-Castell, Dinorah, Gotay, Carolyn C., Gouda, Hebe N., Guerrant, Richard L., Gugnani, Harish C., Gutiérrez, Reyna A., Hafezi-Nejad, Nima, Halasa, Yara A., Hamadeh, Randah R., Hankey, Graeme J., Harb, Hilda L., Hay, Simon I., Hedayati, Mohammad T., Heredia-Pi, Ileana B., Heuton, Kyle R., Hoek, Hans W., Hoffman, Howard J., Hornberger, John C., Hosgood, H., Hoy, Damian G., Huang, John J., Hubbell, Bryan J., Iannarone, Marissa L., Iburg, Kim M., Idrisov, Bulat T., Jacobsen, Kathryn H., Jansen, Henrica A., Jarvis, Deborah L., Jassal, Simerjot K., Jensen, Paul N., Jonas, Jost B., Kany Roseline, Sidibe S., Karam, Nadim E., Karema, Corine K., Kazi, Dhruv S., Kemp, Andrew H., Kengne, Andre P., Khader, Yousef S., Ali Hassan Khalifa, Shams Eldin, Khan, Ejaz A., Khang, Young-Ho, Kimokoti, Ruth W., Kinge, Jonas M., Kissela, Brett M., Knibbs, Luke D., Kuate Defo, Barthelemy, Kucuk Bicer, Burcu, Kuipers, Ernst J., Kulkarni, Veena S., Kwan, Gene F., Lakshmana Balaji, Arjun, Lansingh, Van C., Larson, Heidi J., Laryea, Dennis O., Lavados, Pablo M., Lawrynowicz, Alicia E., Leasher, Janet L., Lee, Jong-Tae, Lim, Stephen S., Lipshultz, Steven E., Lloyd, Belinda K., London, Stephanie J., Lortet-Tieulent, Joannie, Lotufo, Paulo A., Machado, Vasco M.P., Macintyre, Michael F., Magis-Rodriguez, Carlo, Mahdi, Abbas A., Mapoma, Christopher C., Margolis, David J., Marks, Guy B., Martin, Randall V., Marzan, Melvin B., Mashal, Mohammad T., Mason-Jones, Amanda J., Mayosi, Bongani M., Mazorodze, Tasara T., Mckay, Abigail C., Meaney, Peter A., Mejia-Rodriguez, Fabiola, Melaku, Yohannes A., Memish, Ziad A., Mensah, George A., Apolinary Mhimbira, Franci, Miller, Ted R., Mills, Edward J., Mohamed Ibrahim, Norlinah, Mohammad, Karzan A., Mokdad, Ali H., Mola, Glen L., Montañez Hernandez, Julio C., Moore, Ami R., Moturi, Wilkister N., Mueller, Ulrich O., Mullany, Erin C., Murthy, Kinnari S., Naidoo, Kovin S., Narayan, K.M. Venkat, Neupane, Sudan P., Newton, Charles R., Ngalesoni, Frida N., Ngirabega, Jean De Dieu, Nguyen, Nhung T., Nieuwenhuijsen, Mark J., Nisar, Muhammad I., Nogueira, José R., Nolla, Joan M., Norheim, Ole F., Norman, Rosana E., Oh, In-Hwan, Olusanya, Bolajoko O., Omer, Saad B., Pagcatipunan, Rodolfo S., Pain, Amanda W., Pandian, Jeyaraj D., Panelo, Carlo Irwin A., Park, Eun-Kee, Parry, Charles D., Paternina Caicedo, Angel J., Patten, Scott B., Paul, Vinod K., Pavlin, Boris I., Pedraza, Lilia S., Pejin Stokic, Ljiljana, Pereira, David M., Perez-Padilla, Rogelio, Perez-Ruiz, Fernando, Perry, Samuel A.L., Phillips, Michael R., Polanczyk, Guilherme V., Pond, Constance D., Prasad, Noela M., Qato, Dima M., Quezada, Amado D., Quistberg, D. Alex A., Rahimi-Movaghar, Vafa, Ur Rahman, Sajjad, Rana, Saleem M., Refaat, Amany H., Ribeiro, Antonio L., Riccio, Patricia M., Rojas-Rueda, David, Ruhago, George M., Sacco, Ralph L., Salomon, Joshua A., Sampson, Uchechukwu K., Sanabria, Juan R., Sánchez-Pimienta, Tania G., Sanchez-Riera, Lidia, Santos, Itamar S., Saunders, James E., Saylan, Mete I., Schmidt, Jürgen C., Schneider, Ione J.C., Schwebel, David C., Scott, James G., Sepanlou, Sadaf G., Servan-Mori, Edson E., Shamah Levy, Teresa, Shin, Hwashin H., Sigfusdottir, Inga D., Silberberg, Donald H., Simard, Edgar P., Singh, Gitanjali M., Singh, Jasvinder A., Sposato, Luciano A., Sreeramareddy, Chandrashekhar T., Stapelberg, Nicolas J.C., Stein, Dan J., Stein, Murray B., Sunguya, Bruno F., Sykes, Bryan L., Tabb, Karen M., Talongwa, Roberto T., Te Ao, Braden J., Teixeira, Carolina M., Téllez Rojo, Martha M., Terkawi, Abdullah S., Texcalac-Sangrador, José Lui, Thackway, Sarah V., Thorne-Lyman, Andrew L., Thrift, Amanda G., Thurston, George D., Towbin, Jeffrey A., Tran, Bach X., Tsala Dimbuene, Zacharie, Uchendu, Uche S., Ukwaja, Kingsley N., Uzun, Selen B., Van De Vijver, Steven, Van Gool, Coen H., Van Os, Jim, Varakin, Yuri Y., Vasankari, Tommi J., Vasconcelos, Ana Maria N., Vavilala, Monica S., Veerman, Lennert J., Velasquez-Melendez, Gustavo, Venketasubramanian, N., Violante, Francesco S., Victorovich Vlassov, Vasiliy, Wagner, Gregory R., Waller, Stephen G., Wallin, Mitchell T., Warouw, Tati S., Watts, Charlotte H., Weintraub, Robert G., Whiteford, Harvey A., Wilkinson, James D., Williams, Hywel C., Williams, Thomas N., Woldeyohannes, Solomon M., Wolfe, Charles D.A., Wong, John Q., Woolf, Anthony D., Wright, Jonathan L., Yan, Lijing L., Yentür, Gökalp K., Yoon, Seok-Jun, Younis, Mustafa Z., Zaki, Maysaa E., Zunt, Joseph R., Lopez, Alan D., and Temesgen, A.M.

Subjects
Male, Fine particulate matter, Nutrition and Disease, MESH : Sanitation, Health Behavior, Diseases, MESH: Metabolic Diseases, MESH: Global Health, 030204 cardiovascular system & hematology, MESH: Risk Assessment, Global Health, MESH : Nutritional Status, MESH: Occupational Exposure, 0302 clinical medicine, Unsafe Sex, MESH: Risk Factors, Risk Factors, Voeding en Ziekte, Medicine, Air-pollution, MESH : Female, 030212 general & internal medicine, MESH : Risk Assessment, Sanitation, Wasting, 2. Zero hunger, Factors de risc en les malalties, Medicine (all), [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, MESH : Occupational Diseases, MESH: Nutritional Status, All-cause mortality, MESH : Risk Factors, humanities, Environmental Exposure, Female, Humans, Metabolic Diseases, Nutritional Status, Occupational Diseases, Occupational Exposure, Risk Assessment, Tobacco smoking, 3. Good health, Nutritional Statu, MESH : Occupational Exposure, MESH : Metabolic Diseases, Cohort, medicine.symptom, Risk assessment, Blood-pressure, Human, MESH: Occupational Diseases, Risk factors in diseases, Coronary-heart-disease, MESH : Male, MESH: Health Behavior, MESH: Environmental Exposure, Population health, Body-mass index, 03 medical and health sciences, Household cooking, Cardiovascular-disease, Environmental health, General & Internal Medicine, parasitic diseases, Life Science, MESH: Sanitation, Risk factor, MESH : Health Behavior, VLAG, GBD2013, MESH: Humans, business.industry, Risk Factor, Global Burden of Disease Study, 79 behavioural, environmental and occupational, and metabolic risks, Long-term exposure, MESH : Humans, CAUSE-SPECIFIC MORTALITY, MESH: Male, Metabolic Disease, Occupational Disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, MALE BRITISH DOCTORS, Years of potential life lost, Relative risk, Malalties, MESH : Global Health, OUTDOOR AIR-POLLUTION, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH : Environmental Exposure, MESH: Female
Abstract

Summary Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian metaregression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5−89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. Funding Bill & Melinda Gates Foundation. Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the fi rst of a series of annual updates of the GBD. Risk factor quantifi cation, particularly of modifi able risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the fi rst level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular fi ltration rate. For most risks, data for exposure were synthesised with a Bayesian metaregression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5−89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. Funding Bill & Melinda Gates Foundation.

Published
2015

41. EP 31. Deep brain stimulation-induced neurogenesis is gender-independent

Author

Ziad Nahas, Wassim Abou-Kheir, Farah Chamaa, W. Sweidan, and Nayef E. Saadé

Subjects
medicine.medical_specialty, Deep brain stimulation, Movement disorders, medicine.medical_treatment, Dentate gyrus, Neurogenesis, Stimulation, Hippocampal formation, medicine.disease, Sensory Systems, Basal (phylogenetics), Endocrinology, Neurology, Mood disorders, Physiology (medical), Internal medicine, medicine, Neurology (clinical), medicine.symptom, Psychology, Neuroscience
Abstract

Background Deep brain stimulation (DBS) provides substantial clinical benefits for a variety of movement disorders and lately emerged as a potential treatment for cognitive and mood disorders. Regulation of adult hippocampal neurogenesis may play a chief role in mediating DBS effects. Nevertheless, there exist significant sex differences in the regulation of neurogenesis influenced mainly by gonadal hormone exposure. Objective To investigate the hippocampal neurogenic differences between male and female awake and unrestrained rats in response to unilateral anteromedial thalamic nucleus (AMN) stimulation. Methods Four groups of adult Sprague-Dawley male and female rats received unilateral stimulation ( n = 6 each) or sham surgery of electrode implantation with no current delivery ( n = 4 each) in the right AMN; A naive group of males and females ( n = 4 each) was also included. Rats received 4 injections (50 mg/Kg/injection) of 5′-bromo-2′-deoxyuridine (BrdU) 3 days post-surgery and were euthanized 24h later. The fractionator method was used together with confocal immunofluorescent analysis to probe for BrdU-, GFAP- and NeuN-positive cells in the dentate gyrus (DG). Results Focal neurogenesis was induced in the ipsilateral DG after AMN stimulation. Stimulation-induced effects were gender-independent and translated into a 76% increase in proliferation of neural stem/progenitor cells. Conclusions Despite the difference in basal neurogenic level between male and female rats, the current study demonstrates that DBS elicits gender-independent neurogenic effects that might have implications in the treatment of cognitive and behavioral disorders irrespective of sex of patients.

Published
2016

42. Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus

Author

Farah Chamaa, Hisham F. Bahmad, Ahmad-Kareem Makkawi, Reda M. Chalhoub, Elie D. Al-Chaer, George B. Bikhazi, Ziad Nahas, and Wassim Abou-Kheir

Subjects
0301 basic medicine, medicine.medical_specialty, hippocampus, Hippocampus, Hippocampal formation, lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, anesthetics, medicine, dentate gyrus, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, nitrous oxide, Cell growth, Dentate gyrus, Neurogenesis, Antagonist, equipment and supplies, neurogenesis, 030104 developmental biology, Endocrinology, chemistry, depression, NMDA receptor, 030217 neurology & neurosurgery, Bromodeoxyuridine, Neuroscience
Abstract

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2). Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.

Published
2017

43. Optimization of epidural cortical stimulation for treatment-resistant depression

Author

Thomas Hopkins, Brandon S. Bentzley, Ziad Nahas, Nolan R. Williams, Mark S. George, Jaspreet Pannu, Gregory L. Sahlem, Istvan Takacs, and Edward Baron Short

Subjects
business.industry, General Neuroscience, Biophysics, Stimulation, medicine.disease, lcsh:RC321-571, 030227 psychiatry, 03 medical and health sciences, 0302 clinical medicine, Anesthesia, medicine, Neurology (clinical), business, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Treatment-resistant depression, 030217 neurology & neurosurgery
Published
2018

44. Neutral face distractors differentiate performance between depressed and healthy adolescents during an emotional working memory task

Author

Lucy Tavitian, David A. Brent, Beatrice Khater, Ziad Nahas, Cecile D. Ladouceur, and Fadi T. Maalouf

Subjects
Male, medicine.medical_specialty, Adolescent, Emotions, Significant group, Population, Audiology, Memory load, behavioral disciplines and activities, Developmental psychology, Task (project management), Reaction Time, Developmental and Educational Psychology, medicine, Humans, Attention, Child, education, Depressive Disorder, Major, Facial expression, education.field_of_study, Working memory, Attentional control, General Medicine, medicine.disease, Facial Expression, Psychiatry and Mental health, Memory, Short-Term, Case-Control Studies, Pediatrics, Perinatology and Child Health, Major depressive disorder, Female, Psychology
Abstract

The aim of the present study is to examine the effect of neutral and emotional facial expressions on voluntary attentional control using a working memory (WM) task in adolescents with major depressive disorder (MDD). We administered the Emotional Face n-back (EFNBACK) task, a visual WM task with neutral, happy and angry faces as distractors to 22 adolescents with MDD (mean age 15.7 years) and 21 healthy controls (HC) (mean age 14.7 years). There was a significant group by distractor type interaction (p = 0.045) for mean percent accuracy rates. Group comparisons showed that MDD youth were less accurate on neutral trials than HC (p = 0.027). The two groups did not differ on angry, happy and blank trials (p > 0.05). Reaction time did not differ across groups. In addition, when comparing the differences between accuracies on neutral trials and each of the happy and angry trials, respectively [(HAP-NEUT) and (ANG-NEUT)], there was a group effect on (HAP-NEUT) where the difference was larger in MDD than HC (p = 0.009) but not on ANG-NEUT (p > 0.05). Findings were independent of memory load. Findings indicate that attentional control to neutral faces is impaired and negatively affected performance on a WM task in adolescents with MDD. Such an impact of neutral faces on attentional control in MDD may be at the core of the social-cognitive impairment observed in this population.

Published
2013

45. The Painfulness of Active, but not Sham, Transcranial Magnetic Stimulation Decreases Rapidly Over Time: Results From the Double-Blind Phase of the OPT-TMS Trial

Author

Valerie Durkalski, Harold A. Sackeim, John Teal, William M. McDonald, James Long, Jeffrey J. Borckardt, Martina Pavlicova, Mark S. George, David H. Avery, Sarah H. Lisanby, and Ziad Nahas

Subjects
OPT-TMS, medicine.medical_specialty, Visual analogue scale, medicine.medical_treatment, Biophysics, Prefrontal Cortex, Pain, Stimulation, behavioral disciplines and activities, Article, law.invention, lcsh:RC321-571, Physical medicine and rehabilitation, Randomized controlled trial, Double-Blind Method, law, medicine, Humans, Session (computer science), Prefrontal cortex, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Pain Measurement, Depressive Disorder, Major, Depression, General Neuroscience, musculoskeletal, neural, and ocular physiology, Transcranial magnetic stimulation, Clinical trial, nervous system, TMS, Physical therapy, Antidepressant, Neurology (clinical), Psychology
Abstract

Background Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) over several weeks is an FDA approved treatment for major depression. Although rTMS is generally safe when administered using the FDA guidelines, there are a number of side effects that can make it difficult for patients to complete a course of rTMS. Many patients report that rTMS is painful, although patients appear to accommodate to the initial painfulness. The reduction in pain is hypothesized to be due to prefrontal stimulation and is not solely explained by accommodation to the stimulation. Methods In a recent 4 site randomized controlled trial (using an active electrical sham stimulation system) investigating the antidepressant effects of daily left dorsolateral prefrontal rTMS (Optimization of TMS, or OPT-TMS), the procedural painfulness of TMS was assessed before and after each treatment session. Computerized visual analog scale ratings were gathered before and after each TMS session in the OPT-TMS trial. Stimulation was delivered with an iron core figure-8 coil (Neuronetics) with the following parameters: 10 Hz, 120% MT (EMG-defined), 4 s pulse train, 26 s inter-train interval, 3000 pulses per session, one 37.5 min session per day. After each session, procedural pain (pain at the beginning of the TMS session, pain toward the middle, and pain toward then end of the session) ratings were collected at all 4 sites. From the 199 patients randomized, we had usable data from 142 subjects for the initial 15 TMS sessions (double-blind phase) delivered over 3 weeks (142 × 2 × 15 = 4260 rating sessions). Results The painfulness of real TMS was initially higher than that of the active sham condition. Over the 15 treatment sessions, subjective reports of the painfulness of rTMS (during the beginning, middle and end of the session) decreased significantly 37% from baseline in those receiving active TMS, with no change in painfulness in those receiving sham. This reduction, although greatest in the first few days, continued steadily over the 3 weeks. Overall, there was a decay rate of 1.56 VAS points per session in subjective painfulness of the procedure in those receiving active TMS. Discussion The procedural pain of left, prefrontal rTMS decreases over time, independently of other emotional changes, and only in those receiving active TMS. These data suggest that actual TMS stimulation of prefrontal cortex maybe related to the reduction in pain, and that it is not a non-specific accommodation to pain. This painfulness reduction softly corresponds with later clinical outcome. Further work is needed to better understand this phenomenon and whether acute within-session or over time painfulness changes might be used as short-term biomarkers of antidepressant response.

Published
2013

46. Validation of an Arabic multi-informant psychiatric diagnostic interview for children and adolescents: Development and Well Being Assessment-Arabic (DAWBA-Arabic)

Author

S. Bawab, Ziad Nahas, Fadi T. Maalouf, Nayla Hariz, Mounir Khani, Mia Atwi, Lucy Tavitian, and Pia Zeinoun

Subjects
Male, medicine.medical_specialty, Adolescent, Psychometrics, lcsh:RC435-571, Arabic, MEDLINE, Personal Satisfaction, Surveys and Questionnaires, lcsh:Psychiatry, Interview, Psychological, Humans, Medicine, Translations, Medical diagnosis, Child, Psychiatry, Psychiatric Status Rating Scales, business.industry, Mental Disorders, Reproducibility of Results, medicine.disease, language.human_language, Arabs, Psychiatry and Mental health, Clinical Psychology, Mood disorders, Child, Preschool, Structured interview, Well-being, Quality of Life, language, Anxiety, Female, medicine.symptom, business, Clinical psychology
Abstract

Background Countries in the Arab region lack a valid Arabic psychiatric diagnostic interview for children and adolescents. We set out to establish the diagnostic validity of the Arabic version of the Development and Well Being Assessment (DAWBA-Arabic), a multi-informant structured interview for predicting DSM-IV-TR diagnoses. Methods The DAWBA was translated, updated, and administered to 45 participants (child and adolescent psychiatric outpatients and their parents) as part of a clinic registry. Two clinicians, blinded to their respective diagnoses, formulated the DAWBA diagnoses. Participants also underwent a clinical evaluation by a child and adolescent psychiatrist who generated clinical diagnoses according to the DSM-IV-TR. Results Inter-rater reliabilities were .93, .82, and .72 for disruptive disorders, mood disorders and anxiety disorders respectively. Agreement between DAWBA and clinical diagnoses was substantial for disruptive disorders (κ = .0.82) and mood disorders (κ = 0.74), and moderate for anxiety disorders (κ = 0.46). Conclusion The DAWBA-Arabic could serve as a valid and reliable clinical tool for assessing psychiatric disorders among children and adolescents in the Arab region.

Published
2013

47. A Feasibility Study of a New Method for Electrically Producing Seizures in Man: Focal Electrically Administered Seizure Therapy [FEAST]

Author

Mark S. George, Nancy A. Payne, Devangere P. Devanand, Carol Burns, Linda Fitzsimons, Harold A. Sackeim, Baron Short, Joan Prudic, Tarique D. Perera, Melanie Archer, Mitchell S. Nobler, Matthew Schmidt, Sarah H. Lisanby, and Ziad Nahas

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Biophysics, Neuropsychological Tests, lcsh:RC321-571, Electroconvulsive therapy, Seizures, Orientation, medicine, Humans, Bipolar disorder, Electroconvulsive Therapy, Prefrontal cortex, Psychiatry, Electrodes, Electrode placement, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Depression (differential diagnoses), Aged, Depression, General Neuroscience, Hamilton Rating Scale for Depression, Cognition, ECT, Middle Aged, medicine.disease, Seizure, Treatment Outcome, FEAST, Anesthesia, Feasibility Studies, Antidepressant, Female, Neurology (clinical), Psychology
Abstract

Background: Electroconvulsive therapy (ECT) remains the most effective acute treatment for severe major depression, but with significant risk of adverse cognitive effects. Unidirectional electrical stimulation with a novel electrode placement and geometry (Focal Electrically Administered Seizure Therapy (FEAST)) has been proposed as a means to initiate seizures in prefrontal cortex prior to secondary generalization. As such, it may have fewer cognitive side effects than traditional ECT. We report on its first human clinical application. Method: Seventeen unmedicated depressed adults (5 men; 3 bipolar disorder; age 53 ± 16 years) were recruited after being referred for ECT. Open-label FEAST was administered with a modified spECTrum 5000Q device and a traditional ECT dosing regimen until patients clinically responded. Clinical and cognitive assessments were obtained at baseline, and end of course. Time to orientation recovery, a predictor of long-term amnestic effects, was assessed at each treatment. Nonresponders to FEAST were transitioned to conventional ECT. Results: One patient withdrew from the study after a single titration session. After the course of FEAST (median 10 sessions), there was a 46.1 ± 35.5% improvement in Hamilton Rating Scale for Depression (HRSD24) scores compared to baseline (33.1 ± 6.8, 16.8 ± 10.9; P

Published
2013

48. Prefrontal rTMS for treating depression: Location and intensity results from the OPT-TMS multi-site clinical trial

Author

Harold A. Sackeim, David H. Avery, Xingbao Li, Mark S. George, Mirza Baig, Ziad Nahas, Sarah H. Lisanby, Paul E. Holtzheimer, Dave Ramsey, Kevin A. Johnson, Elisabeth Bernhardt, David R. Haynor, and William M. McDonald

Subjects
Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Biophysics, Prefrontal Cortex, Article, lcsh:RC321-571, law.invention, Physical medicine and rehabilitation, Randomized controlled trial, law, medicine, Humans, Prefrontal cortex, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, Psychiatry, Depressive Disorder, medicine.diagnostic_test, Depression, General Neuroscience, Motor Cortex, Magnetic resonance imaging, Middle Aged, Evoked Potentials, Motor, Magnetic Resonance Imaging, Transcranial Magnetic Stimulation, Intensity (physics), Transcranial magnetic stimulation, Clinical trial, Treatment Outcome, medicine.anatomical_structure, Brain stimulation, Female, Transcranial Magnetic Stimulation (TMS), Neurology (clinical), Psychology, Neuroscience, Motor cortex
Abstract

Background: Motor cortex localization and motor threshold determination often guide Transcranial Magnetic Stimulation (TMS) placement and intensity settings for non-motor brain stimulation. However, anatomic variability results in variability of placement and effective intensity. Objective: Post-study analysis of the OPT-TMS Study reviewed both the final positioning and the effective intensity of stimulation (accounting for relative prefrontal scalp-cortex distances). Methods: We acquired MRI scans of 185 patients in a multi-site trial of left prefrontal TMS for depression. Scans had marked motor sites (localized with TMS) and marked prefrontal sites (5 cm anterior of motor cortex by the “5 cm rule”). Based on a visual determination made before the first treatment, TMS therapy occurred either at the 5 cm location or was adjusted 1 cm forward. Stimulation intensity was 120% of resting motor threshold. Results: The “5 cm rule” would have placed stimulation in premotor cortex for 9% of patients, which was reduced to 4% with adjustments. We did not find a statistically significant effect of positioning on remission, but no patients with premotor stimulation achieved remission (0/7). Effective stimulation ranged from 93 to 156% of motor threshold, and no seizures were induced across this range. Patients experienced remission with effective stimulation intensity ranging from 93 to 146% of motor threshold, and we did not find a significant effect of effective intensity on remission. Conclusions: Our data indicates that individualized positioning methods are useful to reduce variability in placement. Stimulation at 120% of motor threshold, unadjusted for scalp-cortex distances, appears safe for a broad range of patients.

Published
2013

49. Health in times of uncertainty in the eastern Mediterranean region, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Author

Karen Sliwa, Christopher J L Murray, Mohammad Sadegh Hassanvand, Mustafa Z. Younis, Yousef Khader, Mohammad Yahya Saeedi, Ibrahim A Khalil, Amit R. Bhakta, Muhammad Imran Nisar, Carla Makhlouf Obermeyer, Irina Filip, Mahboubeh Parsaeian, Hayet Hamdouni, Abdullatif Husseini, Yousef M. Elshrek, Gulfaraz Khan, Theo Vos, Aref A. Bin Abdulhak, Caitlyn Steiner, Lidia Sanchez-Riera, Soufiane Boufous, Gholamreza Roshandel, Mohammad H. Forouzanfar, Haseeb Nawaz, Babak Eshrati, Abdulwahab A. Al-Nehmi, Margaret Robinson, Neeraj Bedi, Shahrzad Bazargan-Hejazi, Mostafa Qorbani, Matthew M Coates, Hilda L Harb, Andrea B. Feigl, Adnan M. Durrani, Mahmoud A. Alomari, Kelly Cercy, Faiez Zannad, Raghid Charara, Morteza Mansourian, Rami M. Habash, Hanan Al Ahmadi, Ali A. Mokdad, Charbel El Bcheraoui, Nawal Al-Hamad, Rana Jawad Asghar, Alaa Badawi, Raghib Ali, Palwasha Anwari, Mohammad Tavakkoli, Chakib Nejjari, Khalid A Altirkawi, Dima M. Qato, Mohammad Ab Alkhateeb, Jerry Puthenpurakal Abraham, Ziad A. Memish, Seyed-Mohammad Fereshtehnejad, Amany H Refaat, Serge Resnikoff, Fadia AlBuhairan, Rupert R A Bourne, Faris Lami, Samer Hamidi, Jamal Nasher, Sara Sheikhbahaei, Maziar Moradi-Lakeh, Walid Ammar, Gregory A. Roth, Hamid Asayesh, Zulfa A. Al Rayess, George A. Mensah, Nega Assefa Kassa, Sara Jaber, Samia Alhabib, Florian Fischer, Kazem Rahimi, Yohannes Kinfu, Amir Kasaeian, Vivekanand Jha, Kara Estep, Maheswar Satpathy, Fortuné Gbètoho Gankpé, Alem Mehari, Rajesh Kumar Rai, Wagner Marcenes, Ashkan Afshin, Pauline Kim, Mohamed Magdy Abd El Razek, Ubai Alsharif, Amir Radfar, Jost B. Jonas, Imad A.D. Faghmous, Farah Daoud, Mohammad Ali Sahraian, Farshad Pourmalek, Ryan M Barber, Sowmya R. Rao, Pouria Heydarpour, Tawfik Ahmed Muthafer Khoja, Emmanuel Peprah, Habibolah Masoudi Farid, Rajaa Al-Raddadi, Mohammad A. AlMazroa, Arjun Lakshmana Balaji, Mohamed E. Ibrahim, Heresh Amini, Karzan Abdulmuhsin Mohammad, Mohammed Basulaiman, Sajjad Ur Rahman, Mohamed H. Al-Thani, Jai K Das, Amare Deribew, Saeid Shahraz, Syed Danish Ali, Farshad Farzadfar, Saleh F. Aldhahri, Barthelemy Kuate Defo, Alan D. Lopez, Haidong Wang, Georges Saade, Reza Malekzadeh, Mazin J. Al Khabouri, Ali S. Akanda, Reza Assadi, Zulfiqar A Bhutta, Raimundas Lunevicius, Ali Assabri, Shadi Saleh, Randah R. Hamadeh, Azmeraw T. Amare, Sadaf G. Sepanlou, Kevin F. O'Rourke, Deena Alasfoor, Adrienne Chew, Ronny Westerman, Abdullah Sulieman Terkawi, Mohsen Naghavi, Eric L. Ding, Ali H. Mokdad, Abla Mehio-Sibai, Ejaz Ahmad Khan, Nihaya A. Al-sheyab, Saleem M Rana, Mohammad Taghi Hedayati, Umar Bacha, Joseph Wagner, Kawkab Shishani, Laith J. Abu-Raddad, Olalekan A. Uthman, Mohamed Hsairi, Ibrahim Abdelmageem Mohamed Ginawi, Anil Kaul, Foad Abd-Allah, Rahul Gupta, Nader Jahanmehr, Marwa Tuffaha, Nima Hafezi-Nejad, Aslam Pervaiz, Hannah Kravitz, Vafa Rahimi-Movaghar, Saad B. Omer, Anwar Rafay, Ardeshir Khosravi, Hadi Danawi, Suliman Alghnam, Alireza Esteghamati, Melkamu Dedefo Gishu, Abdullah A. Al Rabeeah, Tesfaye Setegn, Ziad Nahas, Shirina Alsowaidi, Safa Abdalla, Niveen M E Abu-Rmeileh, Shams Eldin Ali Hassan Khalifa, Nadim E. Karam, Amira Shaheen, Talal Bakfalouni, and Maysaa El Sayed Zaki

Subjects
Aging, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit, Global Burden of Disease, 0302 clinical medicine, Risk Factors, Medicine, Salut, 030212 general & internal medicine, Mediterranean region, Child, Wasting, DS, Cause of death, Aged, 80 and over, 2. Zero hunger, Middle East, lcsh:Public aspects of medicine, 1. No poverty, Health conditions, General Medicine, Middle Aged, 3. Good health, Cardiovascular Diseases, Health, Child, Preschool, 030220 oncology & carcinogenesis, Mediterrània oriental, Quality-Adjusted Life Years, medicine.symptom, Adult, Diarrhea, Social Problems, Eastern Mediterranean, Infections, 03 medical and health sciences, Life Expectancy, Humans, Population growth, Obesity, Risk factor, Noncommunicable Diseases, Aged, business.industry, Infant, Newborn, Infant, lcsh:RA1-1270, Health indicator, Quality-adjusted life year, Africa, Life expectancy, life expectancy, Wounds and Injuries, business, RA, Demography
Abstract

Background: The eastern Mediterranean region is comprised of 22 countries: Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, the United Arab Emirates, and Yemen. Since our Global Burden of Disease Study 2010 (GBD 2010), the region has faced unrest as a result of revolutions, wars, and the so-called Arab uprisings. The objective of this study was to present the burden of diseases, injuries, and risk factors in the eastern Mediterranean region as of 2013. Methods: GBD 2013 includes an annual assessment covering 188 countries from 1990 to 2013. The study covers 306 diseases and injuries, 1233 sequelae, and 79 risk factors. Our GBD 2013 analyses included the addition of new data through updated systematic reviews and through the contribution of unpublished data sources from collaborators, an updated version of modelling software, and several improvements in our methods. In this systematic analysis, we use data from GBD 2013 to analyse the burden of disease and injuries in the eastern Mediterranean region specifically. Findings: The leading cause of death in the region in 2013 was ischaemic heart disease (90·3 deaths per 100 000 people), which increased by 17·2% since 1990. However, diarrhoeal diseases were the leading cause of death in Somalia (186·7 deaths per 100 000 people) in 2013, which decreased by 26·9% since 1990. The leading cause of disability-adjusted life-years (DALYs) was ischaemic heart disease for males and lower respiratory infection for females. High blood pressure was the leading risk factor for DALYs in 2013, with an increase of 83·3% since 1990. Risk factors for DALYs varied by country. In low-income countries, childhood wasting was the leading cause of DALYs in Afghanistan, Somalia, and Yemen, whereas unsafe sex was the leading cause in Djibouti. Non-communicable risk factors were the leading cause of DALYs in high-income and middle-income countries in the region. DALY risk factors varied by age, with child and maternal malnutrition affecting the younger age groups (aged 28 days to 4 years), whereas high bodyweight and systolic blood pressure affected older people (aged 60–80 years). The proportion of DALYs attributed to high body-mass index increased from 3·7% to 7·5% between 1990 and 2013. Burden of mental health problems and drug use increased. Most increases in DALYs, especially from non-communicable diseases, were due to population growth. The crises in Egypt, Yemen, Libya, and Syria have resulted in a reduction in life expectancy; life expectancy in Syria would have been 5 years higher than that recorded for females and 6 years higher for males had the crisis not occurred. Interpretation: Our study shows that the eastern Mediterranean region is going through a crucial health phase. The Arab uprisings and the wars that followed, coupled with ageing and population growth, will have a major impact on the region's health and resources. The region has historically seen improvements in life expectancy and other health indicators, even under stress. However, the current situation will cause deteriorating health conditions for many countries and for many years and will have an impact on the region and the rest of the world. Based on our findings, we call for increased investment in health in the region in addition to reducing the conflicts. Funding: Bill & Melinda Gates Foundation. Bill & Melinda Gates Foundation. Qatar National Research Fund (NPRP 9-040-3-008). The Brien Holden Vision Institute. Oklahoma Council for Advancement of Science & Technology. UK National Institute for Health Research Oxford Biomedical Research Centre, National Institute for Health Research Career Development Fellowship, and Oxford Martin School.

Published
2016

50. Five-Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression

Author

Thomas Hopkins, Mark S. George, G. Sahlem, Jaspreet Pannu, Matt Schmidt, Jeffrey J. Borckardt, Jeffrey E. Korte, Ziad Nahas, E. Baron Short, Brandon S. Bentzley, Istvan Takacs, and Nolan R. Williams

Subjects
0301 basic medicine, Adult, Epidural Space, Male, medicine.medical_specialty, Deep brain stimulation, medicine.medical_treatment, Biophysics, Epidural cortical stimulation, Prefrontal Cortex, Electric Stimulation Therapy, lcsh:RC321-571, 03 medical and health sciences, Depressive Disorder, Treatment-Resistant, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Young adult, Prefrontal cortex, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Depression (differential diagnoses), Aged, Aged, 80 and over, General Neuroscience, Interventional psychiatry, Hamilton Rating Scale for Depression, Middle Aged, medicine.disease, Surgery, Dorsolateral prefrontal cortex, 030104 developmental biology, medicine.anatomical_structure, Treatment Outcome, Brain stimulation, Female, Neurology (clinical), Dura Mater, Treatment-resistant depression, Psychology, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD). Objective To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD. Methods Adults ( N = 5) who were 21–80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008–10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years. Results All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode ‘paddle’ infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization. Conclusion These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

Published
2016

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