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  1. Article ; Online: A neural oscillatory signature of sustained anxiety.

    Roxburgh, Ariel D / White, David J / Grillon, Christian / Cornwell, Brian R

    Cognitive, affective & behavioral neuroscience

    2023  Volume 23, Issue 6, Page(s) 1534–1544

    Abstract: Background: Anxiety is a sustained response to uncertain threats; yet few studies have explored sustained neurobiological activities underlying anxious states, particularly spontaneous neural oscillations. To address this gap, we reanalysed ... ...

    Abstract Background: Anxiety is a sustained response to uncertain threats; yet few studies have explored sustained neurobiological activities underlying anxious states, particularly spontaneous neural oscillations. To address this gap, we reanalysed magnetoencephalographic (MEG) data recorded during induced anxiety to identify differences in sustained oscillatory activity between high- and low-anxiety states.
    Methods: We combined data from three previous MEG studies in which healthy adults (total N = 51) were exposed to alternating periods of threat of unpredictable shock and safety while performing a range of cognitive tasks (passive oddball, mixed-saccade or stop-signal tasks). Spontaneous, band-limited, oscillatory activity was extracted from middle and late intervals of the threat and safe periods, and regional power distributions were reconstructed with adaptive beamforming. Conjunction analyses were used to identify regions showing overlapping spectral power differences between threat and safe periods across the three task paradigms.
    Results: MEG source analyses revealed a robust and widespread reduction in beta (14-30 Hz) power during threat periods in bilateral sensorimotor cortices extending into right prefrontal regions. Alpha (8-13 Hz) power reductions during threat were more circumscribed, with notable peaks in left intraparietal sulcus and thalamus.
    Conclusions: Threat-induced anxiety is underpinned by a sustained reduction in spontaneous beta- and alpha-band activity in sensorimotor and parietal cortical regions. This general oscillatory pattern likely reflects a state of heightened action readiness and vigilance to cope with uncertain threats. Our findings provide a critical reference for which to identify abnormalities in cortical oscillatory activities in clinically anxious patients as well as evaluating the efficacy of anxiolytic treatments.
    MeSH term(s) Adult ; Humans ; Anxiety ; Magnetoencephalography ; Prefrontal Cortex ; Anxiety Disorders ; Parietal Lobe
    Language English
    Publishing date 2023-10-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2029088-3
    ISSN 1531-135X ; 1530-7026
    ISSN (online) 1531-135X
    ISSN 1530-7026
    DOI 10.3758/s13415-023-01132-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A way forward for anxiolytic drug development: Testing candidate anxiolytics with anxiety-potentiated startle in healthy humans.

    Grillon, Christian / Ernst, Monique

    Neuroscience and biobehavioral reviews

    2020  Volume 119, Page(s) 348–354

    Abstract: This review introduces a research strategy that may radically transform the pursuit of new anxiolytics, via the use of human models of anxiety in healthy individuals. Despite enormous investments in developing novel pharmacological treatments for anxiety ...

    Abstract This review introduces a research strategy that may radically transform the pursuit of new anxiolytics, via the use of human models of anxiety in healthy individuals. Despite enormous investments in developing novel pharmacological treatments for anxiety disorders, pharmacotherapy for these conditions remains suboptimal. Most candidate anxiolytics from animal studies fail in clinical trials. We propose an additional screening step to help select candidate anxiolytics before launching clinical trials. This intermediate step moves the evidence for the potential anxiolytic property of candidate drugs from animals to humans, using experimental models of anxiety in healthy individuals. Anxiety-potentiated startle is a robust translational model of anxiety. The review of its face, construct, and predictive validity as well as its psychometric properties in humans establishes it as a promising tool for anxiolytic drug development. In conclusion, human models of anxiety may stir a faster, more efficient path for the development of clinically effective anxiolytics.
    MeSH term(s) Animals ; Anti-Anxiety Agents/pharmacology ; Anxiety/drug therapy ; Anxiety Disorders/drug therapy ; Humans ; Pharmaceutical Preparations ; Reflex, Startle
    Chemical Substances Anti-Anxiety Agents ; Pharmaceutical Preparations
    Language English
    Publishing date 2020-10-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 282464-4
    ISSN 1873-7528 ; 0149-7634
    ISSN (online) 1873-7528
    ISSN 0149-7634
    DOI 10.1016/j.neubiorev.2020.09.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Periaqueductal gray matter and medial prefrontal cortex reflect negative prediction errors during differential conditioning.

    Gorka, Adam X / Philips, Ryan T / Torrisi, Salvatore / Manbeck, Adrienne / Goodwin, Madeline / Ernst, Monique / Grillon, Christian

    Social cognitive and affective neuroscience

    2023  Volume 18, Issue 1

    Abstract: Computational models of associative learning posit that negative prediction errors (PEs) arising from the omission of aversive outcomes weaken aversive Pavlovian associations during differential conditioning and extinction. It is possible that negative ... ...

    Abstract Computational models of associative learning posit that negative prediction errors (PEs) arising from the omission of aversive outcomes weaken aversive Pavlovian associations during differential conditioning and extinction. It is possible that negative PEs may underlie exaggerated conditioned responses to the conditioned stimulus not paired with an aversitve outcome (CS-) during differential conditioning and to the conditioned stimulus originally paired with a aversive outcome (CS+) during extinction in patients with clinical anxiety disorders. Although previous research has demonstrated that manipulations of the periaqueductal gray matter (PAG) interfere with extinction learning in animals, the role of the PAG in processing negative PEs within the human brain is presently unclear. We set out to investigate how PAG responses and connectivity are impacted by negative PEs using ultra-high-field (7 T) functional magnetic resonance imaging and hierarchical Bayesian analysis. During differential conditioning, negative PEs were associated with larger responses within the lateral and dorsolateral PAG and increased connectivity between the dorsolateral PAG and medial areas of Brodmann area 9. Collectively, these results shed light on the association between activity within the PAG and medial prefrontal cortex and the omission of aversive outcomes during Pavlovian learning.
    MeSH term(s) Animals ; Humans ; Periaqueductal Gray/physiology ; Bayes Theorem ; Conditioning, Classical/physiology ; Brain ; Prefrontal Cortex/diagnostic imaging ; Magnetic Resonance Imaging
    Language English
    Publishing date 2023-05-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2236933-8
    ISSN 1749-5024 ; 1749-5016
    ISSN (online) 1749-5024
    ISSN 1749-5016
    DOI 10.1093/scan/nsad025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

    Casalvera, Abigail / Goodwin, Madeline / Lynch, Kevin / Teferi, Marta / Patel, Milan / Grillon, Christian / Ernst, Monique / Balderston, Nicholas L

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Background: Work on anxiety related attention control deficits suggests that elevated arousal impacts the ability to filter out distractors. To test this, we designed a task to look at distractor suppression during periods of threat. We administered ... ...

    Abstract Background: Work on anxiety related attention control deficits suggests that elevated arousal impacts the ability to filter out distractors. To test this, we designed a task to look at distractor suppression during periods of threat. We administered trials of a visual short-term memory (VSTM) task, during periods of unpredictable threat, and hypothesized that threat would impair performance during trials where subjects were required to filter out large numbers of distractors.
    Method: Experiment 1 involved fifteen healthy participants who completed one study visit. They performed four runs of a VSTM task comprising 32 trials each. Participants were presented with an arrow indicating left or right, followed by an array of squares. They were instructed to remember the target side and disregard the distractors on the off-target side. A subsequent target square was shown, and participants indicated whether it matched one of the previously presented target squares. The trial conditions included 50% matches and 50% mismatches, with an equal distribution of left and right targets. The number of target and distractor squares varied systematically, with high (4 squares) and low (2 squares) target and distractor conditions. Trials alternated between periods of safety and threat, with startle responses recorded using electromyography (EMG) following white noise presentations. Experiment 2 involved twenty-seven healthy participants who completed the same VSTM task inside an MRI scanner during a single study visit. The procedure mirrored that of Experiment 1, except for the absence of white noise presentations.
    Results: For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. However, results suggested that the white noise probes interfered with performance. For Experiment 2, we found that both accuracy was affected by threat, such that distractor load negatively impacted accuracy only in the threat condition.
    Conclusion: Overall, these findings suggest that threat affects distractor susceptibility during the short-term maintenance of visual information. The presence of threat makes it more difficult to filter out distracting information. We believe that this is related to hyperarousal of parietal cortex, which has been observed during unpredictable threat.
    Language English
    Publishing date 2023-11-23
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.22.23298914
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Attenuation of Anxiety-Potentiated Startle After Treatment With Escitalopram or Mindfulness Meditation in Anxiety Disorders.

    Hoge, Elizabeth A / Armstrong, Caroline H / Mete, Mihriye / Oliva, Isabelle / Lazar, Sara W / Lago, Tiffany R / Grillon, Christian

    Biological psychiatry

    2023  Volume 95, Issue 1, Page(s) 85–92

    Abstract: Background: Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated ...

    Abstract Background: Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders compared with nonanxious control individuals, and in pharmacological challenge studies in healthy adults. However, little is known about how startle may change with treatment for anxiety disorders, and no data are available regarding alterations due to mindfulness meditation training.
    Methods: Ninety-three individuals with anxiety disorders and 66 healthy individuals completed 2 sessions of the neutral, predictable, and unpredictable threat task, which employs a startle probe and the threat of shock to assess moment-by-moment fear and anxiety. Between the two testing sessions, patients received randomized 8-week treatment with either escitalopram or mindfulness-based stress reduction.
    Results: APS, but not FPS, was higher in participants with anxiety disorders compared with healthy control individuals at baseline. Further, there was a significantly greater decrease in APS for both treatment groups compared with the control group, with the patient groups showing reductions bringing them into the range of control individuals at the end of the treatment.
    Conclusions: Both anxiety treatments (escitalopram and mindfulness-based stress reduction) reduced startle potentiation during unpredictable (APS) but not predictable (FPS) threat. These findings further validate APS as a biological correlate of pathological anxiety and provide physiological evidence for the impact of mindfulness-based stress reduction on anxiety disorders, suggesting that there may be comparable effects of the two treatments on anxiety neurocircuitry.
    MeSH term(s) Adult ; Humans ; Anxiety ; Anxiety Disorders/therapy ; Escitalopram ; Meditation ; Mindfulness ; Reflex, Startle/physiology ; Case-Control Studies
    Chemical Substances Escitalopram (4O4S742ANY)
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2023.06.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: D-cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms.

    Grillon, Christian

    Biological psychiatry

    2009  Volume 66, Issue 7, Page(s) 636–641

    Abstract: Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this ... ...

    Abstract Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes.
    MeSH term(s) Animals ; Antimetabolites/pharmacology ; Antimetabolites/therapeutic use ; Anxiety/drug therapy ; Anxiety/physiopathology ; Anxiety/therapy ; Association Learning/drug effects ; Behavior Therapy/methods ; Conditioning, Classical/drug effects ; Cycloserine/pharmacology ; Cycloserine/therapeutic use ; Extinction, Psychological/drug effects ; Fear ; Humans ; Models, Psychological
    Chemical Substances Antimetabolites ; Cycloserine (95IK5KI84Z)
    Language English
    Publishing date 2009-06-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Review
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2009.04.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Gain in Translation: Is It Time for Thigmotaxis Studies in Humans?

    Grillon, Christian / Ernst, Monique

    Biological psychiatry

    2016  Volume 80, Issue 5, Page(s) 343–344

    MeSH term(s) Exploratory Behavior ; Humans
    Language English
    Publishing date 2016-08-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Comment
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2016.07.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Greater sustained anxiety but not phasic fear in women compared to men.

    Grillon, Christian

    Emotion (Washington, D.C.)

    2008  Volume 8, Issue 3, Page(s) 410–413

    Abstract: Startle reflex studies in rodents indicate that female are more reactive than rats in experimental models of sustained anxiety but not in models of phasic fear (Toufexis, 2007). This study examined evidence for a similar effect in humans. Participants ... ...

    Abstract Startle reflex studies in rodents indicate that female are more reactive than rats in experimental models of sustained anxiety but not in models of phasic fear (Toufexis, 2007). This study examined evidence for a similar effect in humans. Participants were exposed to three conditions, (1) predictable aversive shocks signaled by a cue, (2) unpredictable shocks, and (3) no shocks. Acoustic startle stimuli were delivered regularly across conditions. Phasic startle potential to the threat cue in the predictable condition was not affected by sex. In contrast, and consistent with basic research, the sustained increase in startle in the predictable and unpredictable conditions was greater in women compared to men. Animal studies suggest that such an effect may be mediated by the effects of sexual dimorphism in limbic structures, including the bed nucleus of the stria terminalis. However, psychosocial factors may also contribute to this effect.
    MeSH term(s) Adult ; Anxiety/diagnosis ; Anxiety/psychology ; Diagnostic and Statistical Manual of Mental Disorders ; Fear ; Female ; Humans ; Male ; Sex Factors
    Language English
    Publishing date 2008-06-10
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2102391-8
    ISSN 1931-1516 ; 1528-3542
    ISSN (online) 1931-1516
    ISSN 1528-3542
    DOI 10.1037/1528-3542.8.3.410
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Dynamic Time Warping Identifies Functionally Distinct fMRI Resting State Cortical Networks Specific to VTA and SNc: A Proof of Concept.

    Philips, Ryan T / Torrisi, Salvatore J / Gorka, Adam X / Grillon, Christian / Ernst, Monique

    Cerebral cortex (New York, N.Y. : 1991)

    2021  Volume 32, Issue 6, Page(s) 1142–1151

    Abstract: Functional connectivity (FC) is determined by similarity between functional magnetic resonance imaging (fMRI) signals from distinct brain regions. However, traditional FC analyses ignore temporal phase differences. Here, we addressed this limitation, ... ...

    Abstract Functional connectivity (FC) is determined by similarity between functional magnetic resonance imaging (fMRI) signals from distinct brain regions. However, traditional FC analyses ignore temporal phase differences. Here, we addressed this limitation, using dynamic time warping (DTW) within a machine-learning framework, to study cortical FC patterns of 2 spatially adjacent but functionally distinct subcortical regions, namely Substantia Nigra Pars Compacta (SNc) and ventral tegmental area (VTA). We evaluate: 1) the influence of pair of brain regions considered, 2) the influence of warping window sizes, 3) the classification efficacy of DTW, and 4) the uniqueness of features identified. Whole brain 7 Tesla resting state fMRI scans from 81 healthy participants were used. FC between 2 subcortical regions of interests (ROIs) and 360 cortical parcels were computed using: 1) Pearson correlations (PCs), 2) dynamic time-warped PCs (DTW-PC). The separability of SNc-cortical and VTA-cortical network was validated on 40 participants and tested on the remaining 41, using a support vector machine (SVM). The SVM separated the SNc-cortical versus VTA-cortical network with 74.39 and 97.56% test accuracy using PC and DTW-PC, respectively. SVM-recursive feature elimination yielded 20 DTW-PC features that most strongly contributed to the separation of the networks and revealed novel VTA versus SNc preferential connections (P < 0.05, Bonferroni-Holm corrected).
    MeSH term(s) Brain ; Humans ; Magnetic Resonance Imaging/methods ; Pars Compacta ; Ventral Tegmental Area/diagnostic imaging
    Language English
    Publishing date 2021-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 1077450-6
    ISSN 1460-2199 ; 1047-3211
    ISSN (online) 1460-2199
    ISSN 1047-3211
    DOI 10.1093/cercor/bhab273
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  10. Article ; Online: Response to sertraline is associated with reduction in anxiety-potentiated startle in premenstrual dysphoric disorder.

    Hantsoo, Liisa / Grillon, Christian / Sammel, Mary / Johnson, Rachel / Marks, Joanna / Epperson, C Neill

    Psychopharmacology

    2021  Volume 238, Issue 10, Page(s) 2985–2997

    Abstract: Rationale: Women with premenstrual dysphoric disorder (PMDD) appear to have altered central nervous system sensitivity to neuroactive steroid hormones, manifesting as affective symptoms and heightened arousal in the luteal phase of the menstrual cycle. ... ...

    Abstract Rationale: Women with premenstrual dysphoric disorder (PMDD) appear to have altered central nervous system sensitivity to neuroactive steroid hormones, manifesting as affective symptoms and heightened arousal in the luteal phase of the menstrual cycle. In particular, women with PMDD appear less sensitive to allopregnanolone, a positive allosteric GABA-A receptor (GABA-A-R) modulator.
    Objectives: This study evaluated psychophysiologic reactivity in women with PMDD in the follicular and luteal phases of the menstrual cycle, utilizing anxiety-potentiated startle (APS), a potential translational marker of GABA-A-R sensitivity. The study also assessed APS response to low-dose sertraline treatment in women with PMDD.
    Methods: Participants' APS and fear-potentiated startle (FPS) were assessed in the follicular and luteal phases. Women with PMDD received 50 mg sertraline in the following luteal phase to examine impact on APS and FPS.
    Results: There were no significant differences between controls (n = 41) and PMDD participants (n = 36) in change from follicular to luteal phases in baseline startle, APS nor FPS. However, among participants who responded to sertraline, APS was higher in the untreated luteal phase than the follicular phase, but lower in the treated luteal phase than the follicular phase.
    Conclusion: These data demonstrate elevated psychophysiologic arousal in the luteal phase among some women with PMDD, suggesting impaired ability to modulate arousal reactivity. Specifically, alterations in APS suggest potential GABA-A-R changes across the menstrual cycle and in response to sertraline among treatment responders.
    MeSH term(s) Anxiety/drug therapy ; Anxiety Disorders ; Female ; Humans ; Menstrual Cycle ; Premenstrual Dysphoric Disorder/drug therapy ; Premenstrual Syndrome/drug therapy ; Sertraline/therapeutic use
    Chemical Substances Sertraline (QUC7NX6WMB)
    Language English
    Publishing date 2021-07-22
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 130601-7
    ISSN 1432-2072 ; 0033-3158
    ISSN (online) 1432-2072
    ISSN 0033-3158
    DOI 10.1007/s00213-021-05916-6
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