Publications by authors named "Diego A Pizzagalli"

233 Publications

Concurrent electrophysiological recording and cognitive testing in a rodent touchscreen environment.

Sci Rep 2021 Jun 3;11(1):11665. Epub 2021 Jun 3.

Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA, 02478, USA.

Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing conditions used in human participants. In addition, advances in electrophysiological techniques have identified neurophysiological signatures associated with characteristics of neuropsychiatric illness. The present studies integrated these methodologies by developing a rat flanker task with electrophysiological recordings based on reverse-translated protocols used in human electroencephalogram (EEG) studies of cognitive control. Various touchscreen-based stimuli were evaluated for their ability to efficiently gain stimulus control and advance to flanker test sessions. Optimized stimuli were then examined for their elicitation of prototypical visual evoked potentials (VEPs) across local field potential (LFP) wires and EEG skull screws. Of the stimuli evaluated, purple and green photographic stimuli were associated with efficient training and expected flanker interference effects. Orderly stimulus-locked outcomes were also observed in VEPs across LFP and EEG recordings. These studies along with others verify the feasibility of concurrent electrophysiological recordings and rodent touchscreen-based cognitive testing and encourage future use of this integrated approach in therapeutics development.
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http://dx.doi.org/10.1038/s41598-021-91091-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175731PMC
June 2021

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression.

Nat Commun 2021 05 26;12(1):3166. Epub 2021 May 26.

Department of Psychology, Emory University, Atlanta, GA, USA.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.
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http://dx.doi.org/10.1038/s41467-021-23284-9DOI Listing
May 2021

Reduced adaptation of glutamatergic stress response is associated with pessimistic expectations in depression.

Nat Commun 2021 05 26;12(1):3166. Epub 2021 May 26.

Department of Psychology, Emory University, Atlanta, GA, USA.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.
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http://dx.doi.org/10.1038/s41467-021-23284-9DOI Listing
May 2021

Increased attention allocation to socially threatening faces in social anxiety disorder: A replication study.

J Affect Disord 2021 May 1;290:169-177. Epub 2021 May 1.

New York State Psychiatric Institute and Department of Psychiatry, Columbia University Irving Medical Center, NY, USA.

Background: Threat-related attention bias has been implicated in the etiology and maintenance of social anxiety disorder (SAD), with attentional research increasingly using eye-tracking methodology to overcome the poor psychometric properties of response-time-based tasks and measures. Yet, extant eye-tracking research in social anxiety has mostly failed to report on psychometrics and attempts to replicate past results are rare. Therefore, we attempted to replicate a previously published eye-tracking study of gaze patterns in socially anxious and nonanxious participants as they viewed social threatening and neutral faces, while also exploring the psychometric properties of the attentional measures used.

Methods: Gaze was monitored as participants freely viewed 60 different matrices comprised of eight socially-threatening and eight neutral faces, presented for 6000 ms each. Gaze patterns directed at threat and neutral areas of interest (AOIs) were compared by group. Internal consistency and test-retest reliability were also evaluated.

Results: Relative to healthy controls, socially anxious patients dwelled significantly longer on threat faces, replicating prior findings with the same task. Internal consistency of total dwell time on threat and neutral AOIs was high, and two-week test-retest reliability was acceptable.

Limitations: Test-retest reliability was only examined for the control group, which had a small sample size.

Conclusion: Increased dwell time on socially threatening stimuli is a reliable, stable, and generalizable measure of attentional bias in adults with social anxiety.
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http://dx.doi.org/10.1016/j.jad.2021.04.063DOI Listing
May 2021

Computational phenotyping of brain-behavior dynamics underlying approach-avoidance conflict in major depressive disorder.

PLoS Comput Biol 2021 May 10;17(5):e1008955. Epub 2021 May 10.

Department of Cognitive, Linguistic & Psychological Sciences, Brown University, Providence, Rhode Island, United States of America.

Adaptive behavior requires balancing approach and avoidance based on the rewarding and aversive consequences of actions. Imbalances in this evaluation are thought to characterize mood disorders such as major depressive disorder (MDD). We present a novel application of the drift diffusion model (DDM) suited to quantify how offers of reward and aversiveness, and neural correlates thereof, are dynamically integrated to form decisions, and how such processes are altered in MDD. Hierarchical parameter estimation from the DDM demonstrated that the MDD group differed in three distinct reward-related parameters driving approach-based decision making. First, MDD was associated with reduced reward sensitivity, measured as the impact of offered reward on evidence accumulation. Notably, this effect was replicated in a follow-up study. Second, the MDD group showed lower starting point bias towards approaching offers. Third, this starting point was influenced in opposite directions by Pavlovian effects and by nucleus accumbens activity across the groups: greater accumbens activity was related to approach bias in controls but avoid bias in MDD. Cross-validation revealed that the combination of these computational biomarkers were diagnostic of patient status, with accumbens influences being particularly diagnostic. Finally, within the MDD group, reward sensitivity and nucleus accumbens parameters were differentially related to symptoms of perceived stress and depression. Collectively, these findings establish the promise of computational psychiatry approaches to dissecting approach-avoidance decision dynamics relevant for affective disorders.
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http://dx.doi.org/10.1371/journal.pcbi.1008955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136861PMC
May 2021

Reward-Related Neural Circuitry in Depressed and Anxious Adolescents: A Human Connectome Project.

J Am Acad Child Adolesc Psychiatry 2021 May 6. Epub 2021 May 6.

Objective: Although depression and anxiety often have distinct etiologies, they frequently co-occur in adolescence. Recent initiatives have underscored the importance of developing new ways of classifying mental illness based on underlying neural dimensions that cuts across traditional diagnostic boundaries. Accordingly, the aim of the study was to clarify reward-related neural circuitry that may characterize depressed-anxious youth.

Method: The Boston Adolescent Neuroimaging of Depression and Anxiety Human Connectome Project tested group differences regarding subcortical volume and nucleus accumbens activation during an incentive processing task among 14-17-year-old adolescents presenting with a primary depressive and/or anxiety disorder (n=129) or no lifetime history of mental disorders (n=64). Additionally, multimodal modeling examined predictors of depression and anxiety symptom change over a 6-month follow-up period.

Results: Our findings highlighted considerable convergence. Relative to healthy youth, depressed-anxious adolescents exhibited reduced nucleus accumbens volume and activation following reward receipt. These findings remained when removing all medicated participants (∼59% of depressed-anxious youth); subgroup analyses comparing anxious-only, depressed-anxious, and healthy youth also were largely consistent. Multimodal modeling showed that only structural alterations predicted depressive symptoms over time.

Conclusion: Multimodal findings highlight alterations within nucleus accumbens structure and function that characterize depressed-anxious adolescents. In the current hypothesis-driven analyses, only reduced nucleus accumbens volume, however, predicted depressive symptoms over time. An important next step will be to clarify why structural alterations impact reward-related processes and associated symptoms.
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http://dx.doi.org/10.1016/j.jaac.2021.04.014DOI Listing
May 2021

Perseverative Cognition in the Positive Valence Systems: An Experimental and Ecological Investigation.

Brain Sci 2021 Apr 30;11(5). Epub 2021 Apr 30.

Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy.

Perseverative cognition (PC) is a transdiagnostic risk factor that characterizes both hypo-motivational (e.g., depression) and hyper-motivational (e.g., addiction) disorders; however, it has been almost exclusively studied within the context of the negative valence systems. The present study aimed to fill this gap by combining laboratory-based, computational and ecological assessments. Healthy individuals performed the Probabilistic Reward Task (PRT) before and after the induction of PC or a waiting period. Computational modeling was applied to dissociate the effects of PC on reward sensitivity and learning rate. Afterwards, participants underwent a one-week ecological momentary assessment of daily PC occurrence, as well as anticipatory and consummatory reward-related behavior. Induction of PC led to increased response bias on the PRT compared to waiting, likely due to an increase in learning rate but not in reward sensitivity, as suggested by computational modeling. In daily-life, PC increased the discrepancy between expected and obtained rewards (i.e., prediction error). Current converging experimental and ecological evidence suggests that PC is associated with abnormalities in the functionality of positive valence systems. Given the role of PC in the prediction, maintenance, and recurrence of psychopathology, it would be clinically valuable to extend research on this topic beyond the negative valence systems.
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http://dx.doi.org/10.3390/brainsci11050585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147166PMC
April 2021

Genetic and depressive traits moderate the reward-enhancing effects of acute nicotine in young light smokers.

Nicotine Tob Res 2021 Apr 12. Epub 2021 Apr 12.

Department of Psychology, Southern Illinois University.

Rates of light smoking have increased in recent years and are associated with adverse health outcomes. Reducing light smoking is a challenge because it is unclear why some but not others, progress to heavier smoking. Nicotine has profound effects on brain reward systems and individual differences in nicotine's reward-enhancing effects may drive variability in smoking trajectories. Therefore, we examined whether a genetic risk factor and personality traits known to moderate reward processing, also moderate the reward-enhancing effects of nicotine. Light smokers (n=116) performed a Probabilistic Reward Task to assess reward responsiveness after receiving either nicotine or placebo (order counterbalanced). Individuals were classified as nicotine dependence 'risk' allele carriers (rs16969968 A-allele carriers) or non-carriers (non-A-allele carriers), and self-reported negative affective traits were also measured. Across the whole sample, reward responsiveness was greater following nicotine compared to placebo (p=0.045). For Caucasian A-allele carriers but not non-A-allele carriers, nicotine enhanced reward responsiveness compared to placebo for those who received the placebo first (p=0.010). Furthermore, for A-allele carriers but not non-A-allele carriers who received nicotine first, the enhanced reward responsiveness in the nicotine condition carried over to the placebo condition (p<0.001). Depressive traits also moderated the reward-enhancing effects of nicotine (p=0.010) and were associated with more blunted reward responsiveness following placebo but enhanced reward responsiveness following nicotine. These findings suggest that individual differences in a genetic risk factor and depressive traits alter nicotine's effect on reward responsiveness in light smokers and may be important factors underpinning variability in smoking trajectories in this growing population.
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http://dx.doi.org/10.1093/ntr/ntab072DOI Listing
April 2021

Concordant neurophysiological signatures of cognitive control in humans and rats.

Neuropsychopharmacology 2021 06 21;46(7):1252-1262. Epub 2021 Mar 21.

McLean Hospital & Harvard Medical School, Belmont, MA, USA.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.
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http://dx.doi.org/10.1038/s41386-021-00998-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134486PMC
June 2021

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

Am J Psychiatry 2021 May 3;178(5):437-446. Epub 2021 Mar 3.

Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Costi, Morris, Corniquel, Bevilacqua, Jha, Collins, Murrough); Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York (Kirkwood, Bagiella); Department of Psychology, University of California Los Angeles (Hoch); Mood and Anxiety Disorders Program, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Vo-Le, Iqbal, Ursu, Swann, Salas, Mathew); Michael E. Debakey VA Medical Center, Houston (Vo-Le, Iqbal, Ursu, Swann, Salas, Mathew); Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York (Chadha); Department of Psychiatry, Harvard Medical School, Boston, and McLean Hospital, Belmont, Mass. (Pizzagallli, Whitton); School of Medical Sciences, University of Sydney, Australia (Whitton); Montefiore Medical Center/Albert Einstein College of Medicine, New York (Parides); Department of Psychiatry, New York University School of Medicine, New York (Stern, Iosifescu); Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y. (Collins, Stern, Iosifescu); Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Han, Murrough); Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York (Han); Center for Affective Neuroscience, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York (Han).

Objective: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.

Methods: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.

Results: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.

Conclusions: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
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http://dx.doi.org/10.1176/appi.ajp.2020.20050653DOI Listing
May 2021

Associations between insomnia and reward learning in clinical depression.

Psychol Med 2021 Feb 26:1-10. Epub 2021 Feb 26.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Background: Depression and insomnia commonly co-occur. Yet, little is known about the mechanisms through which insomnia influences depression. Recent research and theory highlight reward system dysfunction as a potential mediator of the relationship between insomnia and depression. This study is the first to examine the impact of insomnia on reward learning, a key component of reward system functioning, in clinical depression.

Methods: The sample consisted of 72 veterans with unipolar depression who endorsed sleep disturbance symptoms. Participants completed the Structured Clinical Interview for DSM-IV, self-report measures of insomnia, depression, and reward processing, and a previously validated signal detection task (Pizzagalli et al., 2005, Biological Psychiatry, 57(4), 319-327). Trial-by-trial response bias (RB) estimates calculated for each of the 200 task trials were examined using linear mixed-model analyses to investigate change in reward learning.

Results: Findings demonstrated diminished rate and magnitude of reward learning in the Insomnia group relative to the Hypersomnia/Mixed Symptom group across the task. Within the Insomnia group, participants with more severe insomnia evidenced the lowest rates of reward learning, with increased RB across the task with decreasing insomnia severity.

Conclusions: Among individuals with depression, insomnia is associated with decreased ability to learn associations between neutral stimuli and rewarding outcomes and/or modify behavior in response to differential receipt of reward. This attenuated reward learning may contribute to clinically meaningful decreases in motivation and increased withdrawal in this comorbid group. Results extend existing theory by highlighting impairments in reward learning specifically as a potential mediator of the association between insomnia and depression.
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http://dx.doi.org/10.1017/S003329172100026XDOI Listing
February 2021

Reward Responsiveness in Patients with Opioid Use Disorder on Opioid Agonist Treatment: Role of Comorbid Chronic Pain.

Pain Med 2021 Feb 24. Epub 2021 Feb 24.

Intramural Research Program, National Institute on Drug Abuse.

Objective: Evidence suggests that blunted reward responsiveness may account for poor clinical outcomes in both opioid use disorder (OUD) and chronic pain. Understanding how individuals with OUD and comorbid chronic pain (OUD+CP) respond to rewards is, therefore, of clinical interest because it may reveal a potential point of behavioral intervention.

Methods: Patients with OUD (N = 28) and OUD+CP (N = 19) on opioid agonist treatment (OAT) were compared on: 1) the probabilistic reward task, an objective behavioral measure of reward response bias; and 2) ecological momentary assessment of affective responses to pleasurable events.

Results: Both the OUD and the OUD+CP groups evidenced an increase in reward response bias in the probabilistic reward task. The rate of change in response bias across blocks was statistically significant on in the OUD group (B = 0.06, SE = 0.02, t = 3.92, p<0.001, 95% CI: 0.03, 0.09), not in the OUD+CP (B = 0.03, SE = 0.02, t = 1.90, p = 0.07, 95% CI: -0.002, 0.07). However, groups did not significantly differ in the rate of change in response bias across blocks (B = 0.03, SE = 0.02, t = 1.21, p = 0.23, 95% CI: -0.02, 0.07). Groups did not significantly differ on state measures of reward responsiveness (p's ≥ 0.50).

Conclusions: Overall, findings across objective and subjective measures were mixed, necessitating follow up with a larger sample. The results suggest that although there is a reward response bias in patients with OUD+CP treated with OAT compared to OUD patients without CP, it is modest and does not appear to translate into patients' responses to rewarding events as they unfold in daily life.
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http://dx.doi.org/10.1093/pm/pnab031DOI Listing
February 2021

A New Chapter for Cognitive, Affective & Behavioral Neuroscience.

Cogn Affect Behav Neurosci 2021 Apr 16;21(2):267-268. Epub 2021 Feb 16.

McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA.

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http://dx.doi.org/10.3758/s13415-021-00867-zDOI Listing
April 2021

Mapping Disease Course Across the Mood Disorder Spectrum Through a Research Domain Criteria Framework.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 26. Epub 2021 Jan 26.

Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: The National Institute of Mental Health Research Domain Criteria (RDoC) initiative aims to establish a neurobiologically valid framework for classifying mental illness. Here, we examined whether the RDoC construct of reward learning and three aspects of its underlying neurocircuitry predicted symptom trajectories in individuals with mood pathology.

Methods: Aligning with the RDoC approach, we recruited individuals (n = 80 with mood disorders [58 unipolar and 22 bipolar] and n = 32 control subjects; 63.4% female) based on their performance on a laboratory-based reward learning task rather than clinical diagnosis. We then assessed 1) anterior cingulate cortex prediction errors using electroencephalography, 2) striatal reward prediction errors using functional magnetic resonance imaging, and 3) medial prefrontal cortex glutamatergic function (mPFC Gln/Glu) using H magnetic resonance spectroscopy. Severity of anhedonia, (hypo)mania, and impulsivity were measured at baseline, 3 months, and 6 months.

Results: Greater homogeneity in aspects of brain function (mPFC Gln/Glu) was observed when individuals were classified according to reward learning ability rather than diagnosis. Furthermore, mPFC Gln/Glu levels predicted more severe (hypo)manic symptoms cross-sectionally, predicted worsening (hypo)manic symptoms longitudinally, and explained greater variance in future (hypo)manic symptoms than diagnostic information. However, rather than being transdiagnostic, this effect was specific to individuals with bipolar disorder. Prediction error indices were unrelated to symptom severity.

Conclusions: Although findings are preliminary and require replication, they suggest that heightened mPFC Gln/Glu warrants further consideration as a predictor of future (hypo)mania. Importantly, this work highlights the value of an RDoC approach that works in tandem with, rather than independent of, traditional diagnostic frameworks.
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http://dx.doi.org/10.1016/j.bpsc.2021.01.004DOI Listing
January 2021

Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.

Neuropsychopharmacology 2021 06 21;46(7):1263-1271. Epub 2021 Jan 21.

Department of Emergency Medicine, Boston Medical Center, Boston, MA, USA.

Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.
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http://dx.doi.org/10.1038/s41386-020-00946-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134491PMC
June 2021

A simultaneous [C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism.

Transl Psychiatry 2021 01 11;11(1):33. Epub 2021 Jan 11.

Department of Psychiatry, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27514, USA.

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [C]raclopride, voxel-wise binding potential (BP) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BP differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.
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http://dx.doi.org/10.1038/s41398-020-01170-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801430PMC
January 2021

Bioenergetics and abnormal functional connectivity in psychotic disorders.

Mol Psychiatry 2021 Jan 4. Epub 2021 Jan 4.

Psychotic Disorders Division, McLean Hospital, Belmont, MA, 02478, USA.

Psychotic Disorders such as schizophrenia (SZ) and bipolar disorder (BD) are characterized by abnormal functional connectivity (FC) within neural networks such as the default mode network (DMN), as well as attenuated anticorrelation between DMN and task-positive networks (TPN). Bioenergetic processes are critical for synaptic connectivity and are also abnormal in psychotic disorders. We therefore examined the association between brain energy metabolism and FC in psychotic disorders. P magnetization transfer spectroscopy from medial prefrontal cortex (MPFC) and whole-brain fMRI data were collected from demographically matched groups of SZ, BD, and healthy control (HC) subjects. The creatine kinase (CK) reaction flux calculated from spectroscopy was used as an index of regional energy production rate. FC maps were generated with MPFC as the seed region. Compared to HC, SZ showed significantly lower CK flux, while both BD and SZ patients showed decreased anticorrelation between MPFC and TPN. CK flux was significantly correlated with FC between MPFC and other DMN nodes in HC. This positive correlation was reduced modestly in BD and strongly in SZ. CK flux was negatively correlated with the anticorrelation between MPFC and TPN in HC, but this relationship was not observed in BD or SZ. These results indicate that MPFC energy metabolism rates are associated with stronger FC within networks and stronger anticorrelation between networks in HC. However, this association is decreased in SZ and BD, where bioenergetic and FC abnormalities are evident. This pattern may suggest that impairment in energy production in psychotic disorders underlies the impaired neural connectivity.
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http://dx.doi.org/10.1038/s41380-020-00993-zDOI Listing
January 2021

Electrophysiological scarring in remitted depressed patients: Elevated EEG functional connectivity between the posterior cingulate cortex and the subgenual prefrontal cortex as a neural marker for rumination.

J Affect Disord 2021 02 24;281:493-501. Epub 2020 Dec 24.

Ghent University, Department of Psychiatry and Medical Psychology, Corneel Heymanslaan 10, 9000 Ghent Belgium.

Introduction: Prior resting state fMRI studies have revealed that elevated connectivity between the default mode network (DMN) and subgenual prefrontal cortex (sgPFC) connectivity may underly maladaptive rumination, which is a major risk factor for depression. To further evaluate such relationship, we investigated whether posterior regions of the DMN, showed elevated connectivity with the sgPFC in remitted depressed patients (rMDD) and whether this connectivity was related to maladaptive rumination.

Methods: We examined whether rMDD (N = 20) had elevated EEG posterior DMN - sgPFC functional connectivity when compared to age and sex matched healthy controls (N = 17), and whether this posterior DMN - sgPFC connectivity positively correlated with rumination. Using minimum norm as the source estimation method, we extracted current density maps from six regions of interest (ROIs) within the posterior DMN. EEG source-space functional connectivity was calculated using the Amplitude Envelope Correlation method.

Results: Relative to controls, rMDD showed increased posterior cingulate cortex (PCC) - sgPFC connectivity in the beta-3 (25-30 Hz) band. As hypothesized, PCC - sgPFC connectivity was positively associated with rumination for rMDD, even after controlling for depression and anxiety.

Limitations: The absence of an MDD patient group and the relatively small sample size can limit the generalizability of the results.

Conclusions: EEG resting state PCC - sgPFC functional connectivity is significantly elevated in rMDD and is associated with rumination, suggesting that EEG PCC - sgPFC connectivity may be useful as a neural marker to identify individuals at risk for depression.
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http://dx.doi.org/10.1016/j.jad.2020.12.081DOI Listing
February 2021

Does inflammation link stress to poor COVID-19 outcome?

Stress Health 2020 Dec 14. Epub 2020 Dec 14.

Department of Psychology, Queen's University, Kingston, Ontario, Canada.

Coronavirus disease 2019 (COVID-19) continues to ravage communities across the world. Despite its primary effect on the respiratory system, the virus does not solely impact those with underlying lung conditions as initially predicted. Indeed, prognosis is worsened (often fatal) in patients with pre-existing hyperinflammatory responses (e.g., hypertension, obesity and diabetes), yet the mechanisms by which this occurs are unknown. A number of psychological conditions are associated with inflammation, suggesting that these may also be significant risk factors for negative outcomes of COVID-19. In this review, we evaluate preclinical and clinical literature suggesting that chronic stress-induced hyperinflammation interacts synergistically with COVID-19-related inflammation, contributing to a potentially fatal cytokine storm syndrome. In particular, we hypothesize that both chronic stress and COVID-19-related hyperinflammation are a product of glucocorticoid insufficiency. We discuss the devastating effects of SARS-CoV-2 on structural and functional aspects of the biological stress response and how these induce exaggerated inflammatory responses, particularly interleukin (IL)-6 hypersecretion. We postulate that chronic stress should be considered a significant risk factor for adverse COVID-19-related health outcomes, given overlapping peripheral and central immune dysregulation in both conditions. We conclude by discussing how people with a history of chronic stress could mitigate their risk for COVID-19 complications, identifying specific strategies that can be implemented during self-isolation.
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http://dx.doi.org/10.1002/smi.3017DOI Listing
December 2020

Translational Assessments of Reward Responsiveness in the Marmoset.

Int J Neuropsychopharmacol 2021 May;24(5):409-418

McLean Hospital, Belmont, Massachusetts, USA.

Background: Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias.

Methods: The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0-10.0 mg/kg), a US Food and Drug Administration-approved rapid-acting antidepressant, and phencyclidine (0.01-0.1 mg/kg), a pharmacologically similar N-methyl-D-aspartate receptor antagonist with no known antidepressant efficacy, were evaluated.

Results: Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability.

Conclusions: Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.
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http://dx.doi.org/10.1093/ijnp/pyaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130205PMC
May 2021

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

Magn Reson Med 2021 05 20;85(5):2359-2369. Epub 2020 Nov 20.

Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, Massachusetts, USA.

Purpose: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes.

Methods: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water).

Results: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44).

Conclusion: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.
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http://dx.doi.org/10.1002/mrm.28587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902337PMC
May 2021

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

Psychol Med 2020 Nov 20:1-9. Epub 2020 Nov 20.

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.

Background: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner.

Methods: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16.

Results: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline.

Conclusion: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.
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http://dx.doi.org/10.1017/S0033291720004286DOI Listing
November 2020

Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders.

Cerebellum 2020 Nov 18. Epub 2020 Nov 18.

Department of Psychology, ISEC 672D, Northeastern University, Boston, MA, 02115, USA.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.
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http://dx.doi.org/10.1007/s12311-020-01213-8DOI Listing
November 2020

Disentangling vulnerability, state and trait features of neurocognitive impairments in depression.

Brain 2020 12;143(12):3865-3877

Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.

Depression is a debilitating disorder that often starts manifesting in early childhood and peaks in onset during adolescence. Neurocognitive impairments have emerged as clinically important characteristics of depression, but it remains controversial which domains specifically index pre-existing vulnerability, state-related or trait-related markers. Here, we disentangled these effects by analysing the Adolescent Brain Cognitive Development dataset (n = 4626). Using information of participants' current and past mental disorders, as well as family mental health history, we identified low-risk healthy (n = 2100), high-risk healthy (n = 2023), remitted depressed (n = 401) and currently depressed children (n = 102). Factor analysis of 11 cognitive variables was performed to elucidate latent structure and canonical correlation analyses conducted to probe regional brain volumes reliably associated with the cognitive factors. Bayesian model comparison of various a priori hypotheses differing in how low-risk healthy, high-risk healthy, remitted depressed and currently depressed children performed in various cognitive domains was performed. Factor analysis revealed three domains: language and reasoning, cognitive flexibility and memory recall. Deficits in language and reasoning ability, as well as in volumes of associated regions such as the middle temporal and superior frontal gyrus, represented state- and trait-related markers of depression but not pre-existing vulnerability. In contrast, there was no compelling evidence of impairments in other domains. These findings-although cross-sectional and specific to 9-10-year-old children-might have important clinical implications, suggesting that cognitive dysfunction may not be useful targets of preventive interventions. Depressed patients, even after remission, might also benefit from less commonly used treatments such as cognitive remediation therapy.
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http://dx.doi.org/10.1093/brain/awaa314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805803PMC
December 2020

Reward Functioning Abnormalities in Adolescents at High Familial Risk for Depressive Disorders.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 03 6;6(3):270-279. Epub 2020 Sep 6.

Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Background: A parental history of major depressive disorder (MDD) is an established risk factor for MDD in youth, and clarifying the mechanisms related to familial risk transmission is critical. Aberrant reward processing is a promising biomarker of MDD risk; accordingly, the aim of this study was to test behavioral measures of reward responsiveness and underlying frontostriatal resting activity in healthy adolescents both with (high-risk) and without (low-risk) a maternal history of MDD.

Methods: Low-risk and high-risk 12- to 14-year-old adolescents completed a probabilistic reward task (n = 74 low-risk, n = 27 high-risk) and a resting-state functional magnetic resonance imaging scan (n = 61 low-risk, n = 25 high-risk). Group differences in response bias toward reward and resting ventral striatal and medial prefrontal cortex (mPFC) fractional amplitude of low-frequency fluctuations (fALFFs) were examined. Computational modeling was applied to dissociate reward sensitivity from learning rate.

Results: High-risk adolescents showed a blunted response bias compared with low-risk adolescents. Computational modeling analyses revealed that relative to low-risk adolescents, high-risk adolescents exhibited reduced reward sensitivity but similar learning rate. Although there were no group differences in ventral striatal and mPFC fALFFs, groups differed in their relationships between mPFC fALFFs and response bias. Specifically, among high-risk adolescents, higher mPFC fALFFs correlated with a blunted response bias, whereas there was no fALFFs-response bias relationship among low-risk youths.

Conclusions: High-risk adolescents exhibit reward functioning impairments, which are associated with mPFC fALFFs. The blunted response bias-mPFC fALFFs association may reflect an excessive mPFC-mediated suppression of reward-driven behavior, which may potentiate MDD risk.
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http://dx.doi.org/10.1016/j.bpsc.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936004PMC
March 2021

Socio-demographic and trauma-related predictors of depression within eight weeks of motor vehicle collision in the AURORA study.

Psychol Med 2020 Oct 29:1-14. Epub 2020 Oct 29.

Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience.

Methods: We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression.

Results: Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma.

Conclusions: These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.
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http://dx.doi.org/10.1017/S0033291720003773DOI Listing
October 2020

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

Mol Psychiatry 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychological Sciences, University of Missouri - St. Louis, St. Louis, MO, USA.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.
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http://dx.doi.org/10.1038/s41380-020-00911-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053721PMC
October 2020

Neurophysiological responses to safety signals and the role of cardiac vagal control.

Behav Brain Res 2021 01 22;396:112914. Epub 2020 Sep 22.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA; McLean Hospital, Belmont, MA, USA.

Background: Deficits in safety signal learning are well-established in fear-related disorders (e.g., PTSD, phobias). The current study used a fear conditioning paradigm to test associations among eye blink startle and event-related brain potential (ERP) latency measures of safety signal learning, as well as the role of cardiac vagal control (a measure of top-down inhibition necessary for safety learning).

Methods: Participants were 49 trauma-exposed women ages 17 to 28 years. Eyeblink startle response and ERP amplitudes/latencies were derived for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus. ERPs included the P100 and late positive potential (LPP), which index early visual processing and sustained emotional encoding, respectively. Cardiac vagal control was assessed with resting heart rate variability (HRV).

Results: P100 and LPP latencies for the CS- (safety signal stimulus) were significantly negatively associated with startle to the CS-, but not the CS + . LPP CS- latencies were significantly negatively associated with PTSD Intrusion scores, and this relationship was moderated by vagal control, such that the effect was only present among those with low HRV.

Conclusions: ERP-based markers of safety signal learning were associated with startle response to the CS- (but not CS+) and PTSD symptoms, indicating that these markers may have relevance for fear-related disorders. Cardiac vagal control indexed by HRV is a moderating factor in these associations and may be relevant to safety signal learning.
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http://dx.doi.org/10.1016/j.bbr.2020.112914DOI Listing
January 2021

Prior sleep problems and adverse post-traumatic neuropsychiatric sequelae of motor vehicle collision in the AURORA study.

Sleep 2021 03;44(3)

Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI.

Study Objectives: Many patients in Emergency Departments (EDs) after motor vehicle collisions (MVCs) develop post-traumatic stress disorder (PTSD) or major depressive episode (MDE). This report from the AURORA study focuses on associations of pre-MVC sleep problems with these outcomes 8 weeks after MVC mediated through peritraumatic distress and dissociation and 2-week outcomes.

Methods: A total of 666 AURORA patients completed self-report assessments in the ED and at 2 and 8 weeks after MVC. Peritraumatic distress, peritraumatic dissociation, and pre-MVC sleep characteristics (insomnia, nightmares, daytime sleepiness, and sleep duration in the 30 days before the MVC, trait sleep stress reactivity) were assessed retrospectively in the ED. The survey assessed acute stress disorder (ASD) and MDE at 2 weeks and at 8 weeks assessed PTSD and MDE (past 30 days). Control variables included demographics, MVC characteristics, and retrospective reports about PTSD and MDE in the 30 days before the MVC.

Results: Prevalence estimates were 41.0% for 2-week ASD, 42.0% for 8-week PTSD, 30.5% for 2-week MDE, and 27.2% for 8-week MDE. Pre-MVC nightmares and sleep stress reactivity predicted 8-week PTSD (mediated through 2-week ASD) and MDE (mediated through the transition between 2-week and 8-week MDE). Pre-MVC insomnia predicted 8-week PTSD (mediated through 2-week ASD). Estimates of population attributable risk suggest that blocking effects of sleep disturbance might reduce prevalence of 8-week PTSD and MDE by as much as one-third.

Conclusions: Targeting disturbed sleep in the immediate aftermath of MVC might be one effective way of reducing MVC-related PTSD and MDE.
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http://dx.doi.org/10.1093/sleep/zsaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953217PMC
March 2021