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Understanding the neurobiology of fear and...
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Uncertain Threat L y = 22 Certain Threat L y = 24 Claire M. Kaplan 1 *, Megan Brinkman 1 , Luiz Pessoa 1 , Jason F. Smith 1 *, Alexander J. Shackman 1,2 1 Department of Psychology and Maryland Neuroimaging Center, 2 Department of Neuroscience and Cognitive Sciences, University of Maryland, College Park 20742 USA References Shackman, A. J. & Fox, A. S. (in press). Contributions of the central extended amygdala to fear and anxiety. Journal of Neuroscience. Somerville LH, Wagner DD, Wig GS, Moran JM, Whalen PJ, Kelley WM (2013) Interactions between transient and sustained neural signals support the generation and regulation of anxious emotion. Cereb Cortex 23:49-60. Understanding the neurobiology of fear and anxiety Method + Equal contributions Anxiety disorders are extremely common, debilitating, and challenging to treat, underscoring the importance of developing a deeper understanding of the neural systems underlying states of fear and anxiety. Threats differ along several major dimensions—probability, imminence, and duration—yet, we know remarkably little about how the brain represents and responds to them. Conceptual progress has been slowed by neuroimaging paradigms that confound these key dimensions (e.g., if vs. when threat will occur; brief cues vs. prolonged contexts) or other perceptual characteristics (e.g., emotional faces vs. threat-of-shock; Shackman & Fox 2016). Here, we present results from an ongoing study using a novel task and multiband fMRI to identify neural systems sensitive to temporally certain and uncertain threat in healthy young adults. Background and Significance A total of 42 healthy young adults (20 F, M=22.3 years, SD=2.4) provided usable datasets. All procedures were approved by the University of Maryland Institutional Review Board. Imaging data were collected on a 3T Siemens TIM Trio scanner equipped with a 32-channel head coil. A total of 578 oblique-axial EPI volumes were collected during each functional scan (multiband acceleration=6, TR=1 s, TE=39.4 ms, 60 2.2-mm slices, 2.18 x 2.18 mm in-plane resolution). Images were collected at an oblique angle (approximately -20°relative to the ACPC plane) to minimize susceptibility artifacts. Image preprocessing was done using an in-house mix of software packages including ANTS, AFNI, and FSL. See the Detailed fMRI Method section in the lower-right corner for details. Statistical analyses were conducted with SPM12 and results are reported at FDR q<0.05 whole-brain corrected for multiple comparisons. Predictions : 1a. The dorsal amygdala in the region of the Ce will show phasic responses during the final 4-s of Certain-Threat. 1b. The BST will show sustained responses across the 18-s of Uncertain-Threat. Competing Hypotheses 1. Functional Segregation: It is widely believed that phasic responses to certain-and-imminent threat (‘fear’) are organized by the central 2. nucleus of the amygdala (Ce), whereas sustained responses to 3. uncertain threat (‘anxiety’) are organized by the neighboring bed 4. nucleus of the stria terminalis (BST; e.g., Somerville et al., 2013). 2. Functional Integration: Recent work in humans, monkeys, and rodents suggests that these two regions represent a tightly interconnected neural system, one that assembles states of fear and anxiety in response to a broad spectrum of dangers, including both certain and uncertain threat (Shackman & Fox, 2016). Predictions : 2a. The Ce and BST will both show phasic responses during the final 4-s of Certain-Threat. 2b. The Ce and BST will both sustained responses across the 18-s of Uncertain-Threat. MultiThreat Countdown Task (2 x 2 Factorial Design) Results Threat increases subjective anxiety, indexed by on-line ratings • Threat was associated with significantly greater anxiety than Safe, p<0.001 • Consistent with prior work (Somerville et al., 2013), the Threat x Certainty interaction was significant, p=0.01 • Follow up analyses revealed that Uncertain-Threat was associated with greater anxiety than Certain-Threat, p=0.005 Threat increases objective arousal, indexed by EDA during the countdown • Threat was associated with significantly greater electrodermal activity (EDA) than Safe, p<0.001 • The Threat x Certainty interaction was significant, p<0.001 • Follow up analyses revealed that Uncertain-Threat was associated with greater anxiety than Certain-Threat, p=0.01 Discussion and Future Directions Contrary to the Functional Segregation hypothesis, both the amygdala and BST show phasic responses to clear-and-imminent threat. Contrary to the Functional Integration hypothesis, only the BST exhibited sustained activation during Uncertain-Threat. These results are broadly consistent with recent work in monkeys showing that although both regions play a role in orchestrating responses to acute threat, the BST plays a role in organizing persistent responses to more diffuse or uncertain dangers (Shackman et al., Molecular Psychiatry, in press). A key challenge for future research will be to formally assess the Region x Condition interaction. Our results also highlight a set of cortical regions—the MCC and AI—regions not typically considered in the rodent literature, that show both phasic and sustained responses to threat. Collectively, these results showcase the value of the MultiThreat Countdown Task and provide a novel framework for understanding the neurobiology of fear and anxiety. Detailed fMRI Method The first 3 volumes of each EPI scan were discarded. EPI data were despiked and slice-time corrected. The first volume of each EPI scan was co-registered to the corresponding T1-weighted anatomical image using Boundary-Based Registration technique with fieldmap correction. Motion correction, co-registration, and normalization to the 1-mm MNI152 template were applied in in a single step. Normalized EPI data were resliced to 2-mm isotropic voxels (fifth-order b-splines) and smoothed (6 mm FWHM). All datasets were visually inspected for quality assurance. First-level modeling was performed on high-pass (128-s) filtered data using SPM12 and in-house MATLAB code. Separate models were estimated for the complete 18-s countdown period and for the final 4-s. Nuisance variates included estimates of motion and WM/CSF signals. Using a duration-modulated boxcar function convolved with a canonical hemodynamic response, the countdown period was separately modeled for the Certain-Threat, Uncertain-Threat, and Uncertain-Safe conditions. Certain-Safe served as the implicit baseline. Aversive reinforcers, neutral reinforcers, and rating prompts were also modeled. Hypothesis testing focused on two theoretically important contrasts: Certain-Threat vs. Certain-Safe and Uncertain-Threat vs. Uncertain-Safe. The Amygdala and BST both show phasic responses during the final 4-s of Certain-Threat y = -1 L N = 42, FDR q<.05, whole-brain corrected BST mask (green) provided by Dr. Jennifer Blackford, Vanderbilt Mai Atlas (Plate 21) L y = 3 N = 42, FDR q<.05, whole-brain corrected BST mask (green) provided by Dr. Jennifer Blackford, Vanderbilt L y = 2 The mid-cingulate cortex (MCC) and anterior insula (AI) show phasic responses to Certain-Threat and sustained responses to Uncertain-Threat N = 42, FDR q<.05, whole-brain corrected cmkaplan@umd .edu | This work was supported by the University of Maryland, NSF, and NIH DA040717, MH107444). The BST shows sustained responses across the 18-s of Uncertain-Threat
Transcript of Understanding the neurobiology of fear and...
Uncertain Threat
L y = 22
Certain Threat
L y = 24
Claire M. Kaplan1*, Megan Brinkman1, Luiz Pessoa1, Jason F. Smith1*, Alexander J. Shackman1,2
1 Department of Psychology and Maryland Neuroimaging Center, 2 Department of Neuroscience and Cognitive Sciences,University of Maryland, College Park 20742 USA
ReferencesShackman, A. J. & Fox, A. S. (in press). Contributions of the central extended amygdala to fear and anxiety. Journal of Neuroscience.Somerville LH, Wagner DD, Wig GS, Moran JM, Whalen PJ, Kelley WM (2013) Interactions between transient and sustained neural signals support the generation and regulation of anxious emotion. Cereb Cortex 23:49-60.
Understanding the neurobiology of fear and anxiety
Method
+Equal contributions
Anxiety disorders are extremely common, debilitating, and challenging to treat, underscoring theimportance of developing a deeper understanding of the neural systems underlying states of fearand anxiety.
Threats differ along several major dimensions—probability, imminence, and duration—yet, weknow remarkably little about how the brain represents and responds to them. Conceptualprogress has been slowed by neuroimaging paradigms that confound these key dimensions (e.g.,if vs. when threat will occur; brief cues vs. prolonged contexts) or other perceptual characteristics(e.g., emotional faces vs. threat-of-shock; Shackman & Fox 2016).
Here, we present results from an ongoing study using a novel task and multiband fMRI to identifyneural systems sensitive to temporally certain and uncertain threat in healthy young adults.
Background and Significance
A total of 42 healthy young adults (20 F, M=22.3 years, SD=2.4) provided usable datasets. All procedureswere approved by the University of Maryland Institutional Review Board.
Imaging data were collected on a 3T Siemens TIM Trio scanner equipped with a 32-channel head coil. A totalof 578 oblique-axial EPI volumes were collected during each functional scan (multiband acceleration=6,TR=1 s, TE=39.4 ms, 60 2.2-mm slices, 2.18 x 2.18 mm in-plane resolution). Images were collected at anoblique angle (approximately -20°relative to the ACPC plane) to minimize susceptibility artifacts. Imagepreprocessing was done using an in-house mix of software packages including ANTS, AFNI, and FSL. See theDetailed fMRI Method section in the lower-right corner for details. Statistical analyses were conducted withSPM12 and results are reported at FDR q<0.05 whole-brain corrected for multiple comparisons.
Predictions:1a. The dorsal amygdala in the region of the Ce will show phasic
responses during the final 4-s of Certain-Threat.1b. The BST will show sustained responses across the 18-s of
Uncertain-Threat.
Competing Hypotheses1. Functional Segregation: It is widely believed that phasic responses to
certain-and-imminent threat (‘fear’) are organized by the central2. nucleus of the amygdala (Ce), whereas sustained responses to3. uncertain threat (‘anxiety’) are organized by the neighboring bed4. nucleus of the stria terminalis (BST; e.g., Somerville et al., 2013).
2. Functional Integration: Recent work in humans,monkeys, and rodents suggests that these two regionsrepresent a tightly interconnected neural system, one thatassembles states of fear and anxiety in response to a broadspectrum of dangers, including both certain and uncertainthreat (Shackman & Fox, 2016).
Predictions:2a. The Ce and BST will both show phasic responses during the final 4-s of Certain-Threat.2b. The Ce and BST will both sustained responses across the 18-s of Uncertain-Threat.
MultiThreat Countdown Task (2 x 2 Factorial Design)
ResultsThreat increases subjective anxiety, indexed by on-line ratings
• Threat was associated with significantly greater anxiety than Safe, p<0.001• Consistent with prior work (Somerville et al., 2013), the Threat x Certainty
interaction was significant, p=0.01• Follow up analyses revealed that Uncertain-Threat was associated with greater
anxiety than Certain-Threat, p=0.005
Threat increases objective arousal, indexed by EDA during the countdown
• Threat was associated with significantly greater electrodermal activity (EDA)than Safe, p<0.001
• The Threat x Certainty interaction was significant, p<0.001• Follow up analyses revealed that Uncertain-Threat was associated with greater
anxiety than Certain-Threat, p=0.01
Discussion and Future DirectionsContrary to the Functional Segregation hypothesis, both the amygdala and BST show phasicresponses to clear-and-imminent threat. Contrary to the Functional Integration hypothesis, onlythe BST exhibited sustained activation during Uncertain-Threat. These results are broadlyconsistent with recent work in monkeys showing that although both regions play a role inorchestrating responses to acute threat, the BST plays a role in organizing persistent responses tomore diffuse or uncertain dangers (Shackman et al., Molecular Psychiatry, in press). A keychallenge for future research will be to formally assess the Region x Condition interaction.
Our results also highlight a set of cortical regions—the MCC and AI—regions not typicallyconsidered in the rodent literature, that show both phasic and sustained responses to threat.
Collectively, these results showcase the value of the MultiThreat Countdown Task and provide anovel framework for understanding the neurobiology of fear and anxiety.
Detailed fMRI MethodThe first 3 volumes of each EPI scan were discarded. EPI data were despiked and slice-time corrected. The first volume of each EPI scan was co-registered to the correspondingT1-weighted anatomical image using Boundary-Based Registration technique with fieldmap correction. Motion correction, co-registration, and normalization to the 1-mmMNI152 template were applied in in a single step. Normalized EPI data were resliced to 2-mm isotropic voxels (fifth-order b-splines) and smoothed (6 mm FWHM). All datasetswere visually inspected for quality assurance. First-level modeling was performed on high-pass (128-s) filtered data using SPM12 and in-house MATLAB code. Separate modelswere estimated for the complete 18-s countdown period and for the final 4-s. Nuisance variates included estimates of motion and WM/CSF signals. Using a duration-modulatedboxcar function convolved with a canonical hemodynamic response, the countdown period was separately modeled for the Certain-Threat, Uncertain-Threat, and Uncertain-Safeconditions. Certain-Safe served as the implicit baseline. Aversive reinforcers, neutral reinforcers, and rating prompts were also modeled. Hypothesis testing focused on twotheoretically important contrasts: Certain-Threat vs. Certain-Safe and Uncertain-Threat vs. Uncertain-Safe.
The Amygdala and BST both show phasic responses during the final 4-s of Certain-Threat
y = -1L
N = 42, FDR q<.05, whole-brain corrected
BST mask (green) provided by Dr. Jennifer Blackford, Vanderbilt
Mai Atlas (Plate 21)L y = 3
N = 42, FDR q<.05, whole-brain corrected
BST mask (green) provided by Dr. Jennifer Blackford, Vanderbilt
L y = 2
The mid-cingulate cortex (MCC) and anterior insula (AI) show phasic responses to Certain-Threat and sustained responses to Uncertain-Threat
N = 42, FDR q<.05, whole-brain corrected
[email protected] | This work was supported by the University of Maryland, NSF, and NIH DA040717, MH107444).
The BST shows sustained responses across the 18-s of Uncertain-Threat
