Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder

In the paper

“The mean age of the participants was 27.3 (SD 4.5) years in the PTSD group and 26.6 (SD 3.3) years in the control group (t26 = 0.477, p = 0.64).”

In the paper

“Seven patients in the PTSD group met diagnostic criteria for depression and 1 had comorbid panic disorder, assessed by the MINI.46”

What the sources say

• Not checked yetcites [46] Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. quiz 4–57. [PubMed] [Google Scholar]

In the paper

“We scanned 30 veterans from OEF and OIF with (n = 15) or without (n = 15) a current PTSD diagnosis.”

In the paper

“All CAPS scores in the PTSD group were greater than or equal to 50 (mean 75.9, SD 17.2), and CAPS scores in the control group (mean 10.9, SD 7.7) were significantly lower than in the PTSD group (t26 = 12.9, p < 0.001).”

In the paper

“All participants were right-handed men between 21 and 37 years old.”

In the paper

“The left amygdala seed showed positive connectivity with the right amygdala, periamygdala, bilateral hippocampus and middle temporal gyrus, and anticorrelation with the dorsal ACC, rostral ACC, lateral PFC, inferior parietal cortex and precuneus (Table 1 and Fig. 1).”

In the paper

“The right amygdala seed showed positive connectivity with a number of regions, including the left amygdala, periamygdala, bilateral hippocampus and bilateral insula, and anticorrelation with the dorsal mPFC, rostral ACC and inferior parietal cortex (Table 1 and Fig. 1).”

In the paper

“The left amygdala seed showed positive connectivity with the right amygdala, periamygdala, bilateral hippocampus and bilateral insula, and anticorrelation with the dorsal ACC, lateral PFC, inferior parietal cortex and precuneus (Table 1 and Fig. 1).”

In the paper

“Using the thresholds and cluster sizes defined above, the corrected voxel-wise probabilities are as follows: hippocampus, p < 0.00097; ACC, p < 0.0003; and insular cortex, p < 0.00045.”

In the paper

“The right amygdala seed showed positive connectivity with a number of regions, including the left amygdala, bilateral periamygdala and bilateral hippocampus, and anticorrelation with the dorsal mPFC, dorsal ACC, precuneus, lateral PFC and inferior parietal cortex (Table 1 and Fig. 1).”

In the paper

“In our study, the amygdala was less anti-correlated with the PCC/precuneus in patients with PTSD than controls, though the extent of this activation was small (less than 10 voxels).”

In the paper

“relatively few have examined patterns of connectivity in the brains of patients with PTSD at rest”

What the sources say

• Not checked yetcites [2] Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35:169–91. doi: 10.1038/npp.2009.83. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“As amygdala hyperactivity tends to coincide with mPFC hypoactivity in healthy individuals,9,14”

What the sources say

• Not checked yetcites [9] Phan KL, Wager T, Taylor SF, et al. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002;16:331–48. doi: 10.1006/nimg.2002.1087. [DOI] [PubMed] [Google Scholar] source
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In the paper

“The amygdala has tight structural connections and reciprocal feedback loops with the mPFC and orbitofrontal cortex11 as well as with the dorsolateral PFC12 and ACC.13”

What the sources say

• Not checked yetcites [11] Ghashghaei HT, Hilgetag CC, Barbas H. Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage. 2007;34:905–23. doi: 10.1016/j.neuroimage.2006.09.046. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“of the mPFC as a modulatory region interconnected with limbic structures8 and involved in emotion regulation.9”

What the sources say

• Not checked yetcites [8] Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192–216. doi: 10.1038/npp.2009.104. [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [9] Phan KL, Wager T, Taylor SF, et al. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage. 2002;16:331–48. doi: 10.1006/nimg.2002.1087. [DOI] [PubMed] [Google Scholar] source

In the paper

“and is generally understood to reflect a lack of regulatory control over emotion in individuals with PTSD.”

In the paper

“Most PTSD neuroimaging studies to date have described abnormalities in emotion-generation regions, such as the amygdala or insula, and emotion-regulation regions, including the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC).”

What the sources say

• Not checked yetcites [2] Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35:169–91. doi: 10.1038/npp.2009.83. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“a [15O]-H2O positron emission tomography (PET) study of recently traumatized individuals found positive functional connectivity between the amygdala and ACC in response to trauma scripts.16”

What the sources say

• Not checked yetcites [16] Osuch EA, Willis MW, Bluhm R, et al. Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [15O]-H2O positron emission tomography. Biol Psychiatry. 2008;64:327–35. doi: 10.1016/j.biopsych.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“Roy and colleagues15 reported functional connectivity of the amygdala with ventral medial prefrontal regions (including the medial frontal gyrus and rostral ACC), insula, thalamus and striatum at rest and anticorrelations with the dorsal ACC, superior frontal gyrus, bilateral middle frontal gyrus and posterior cingulate cortex (PCC)”

What the sources say

• Not checked yetcites [15] Roy AK, Shehzad Z, Margulies DS, et al. Functional connectivity of the human amygdala using resting state fMRI. Neuroimage. 2009;45:614–26. doi: 10.1016/j.neuroimage.2008.11.030. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“In individuals with PTSD, amygdala connectivity during task-based studies has yielded inconsistent findings.”

What the sources say

• Not checked yetcites [16] Osuch EA, Willis MW, Bluhm R, et al. Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [15O]-H2O positron emission tomography. Biol Psychiatry. 2008;64:327–35. doi: 10.1016/j.biopsych.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar] source
• Not checked yetcites [17] Gilboa A, Shalev AY, Laor L, et al. Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatry. 2004;55:263–72. doi: 10.1016/j.biopsych.2003.08.004. [DOI] [PubMed] [Google Scholar] source

In the paper

“the known role of the amygdala as a key region in threat detection,5 fear conditioning6 and emotional salience,7”

What the sources say

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In the paper

“These relationships might potentially be better assessed, however, through connectivity analyses at rest, without the confounds of tasks that may be biased to elicit amygdala activity or provoke PTSD symptoms.”

In the paper

“Etkin and Wager’s meta-analysis10 also suggests coactivation of the right amygdala and insula across studies”

What the sources say

• Not checked yetcites [10] Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88. doi: 10.1176/appi.ajp.2007.07030504. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“the hippocampus, a medial temporal lobe region adjacent to the amygdala that is implicated in declarative memory,27 contextual memory28 and fear conditioning,29”

What the sources say

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In the paper

“The amygdala and insula are structurally interconnected,23”

What the sources say

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In the paper

“early PET studies reported increased insula activity in response to trauma script–driven imagery in individuals with PTSD,24 though in some studies no more than in combat-exposed controls.25”

What the sources say

• Not checked yetcites [24] Rauch SL, van der Kolk BA, Fisler RE, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry. 1996;53:380–7. doi: 10.1001/archpsyc.1996.01830050014003. [DOI] [PubMed] [Google Scholar] source
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In the paper

“an area responsible for interoception,20 disgust,21 emotion processing,22 emotion recall9 and anticipation of aversive stimuli.19”

What the sources say

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In the paper

“Recent fMRI studies have reported greater insula activation in anticipation of negative images19 and negative emotional faces18 in individuals with PTSD as well as enhanced coupling between the insula and amygdala during negative emotion induction in healthy volunteers26 and during symptom provocation in recently traumatized individuals.16”

What the sources say

• Not checked yetcites [19] Simmons AN, Paulus MP, Thorp SR, et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry. 2008;64:681–90. doi: 10.1016/j.biopsych.2008.05.027. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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• Not checked yetcites [16] Osuch EA, Willis MW, Bluhm R, et al. Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [15O]-H2O positron emission tomography. Biol Psychiatry. 2008;64:327–35. doi: 10.1016/j.biopsych.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“Functional MRI studies of individuals with PTSD have also demonstrated aberrant activity in the insula”

What the sources say

• Not checked yetcites [19] Simmons AN, Paulus MP, Thorp SR, et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry. 2008;64:681–90. doi: 10.1016/j.biopsych.2008.05.027. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“A quantitative meta-analysis, however, suggested overall reduced hippocampal activity in individuals with PTSD.10”

What the sources say

• Not checked yetcites [10] Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88. doi: 10.1176/appi.ajp.2007.07030504. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“which in turn have been linked to important functions such as processing speed37 and cognitive flexibility38 in health and in disease.”

What the sources say

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In the paper

“Recent studies have begun to investigate resting-state connectivity in individuals with PTSD and have reported alterations in subcortical31 and default network connectivity.32–35”

What the sources say

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In the paper

“it has been hypothesized that the hippocampus integrates context into emotional memories and modulates amygdala activity according to context,30”

What the sources say

• Not checked yetcites [30] Liberzon I, Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain Res. 2008;167:151–69. doi: 10.1016/S0079-6123(07)67011-3. [DOI] [PubMed] [Google Scholar] source

In the paper

“it has been reported to be altered in individuals with generalized anxiety disorder (GAD),39 social phobia,40 major depressive disorder (MDD)41,42 and bipolar disorder;43”

What the sources say

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In the paper

“Resting-state connectivity offers a powerful way to assess intrinsic connections between brain networks,3,4,36”

What the sources say

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In the paper

“Functional neuroimaging studies of the hippocampus in individuals with PTSD have yielded conflicting findings, with some showing hyperactivity and some showing hypoactivity.2”

What the sources say

• Not checked yetcites [2] Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35:169–91. doi: 10.1038/npp.2009.83. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“a function that might be disrupted in individuals with PTSD.”

In the paper

“Groups did not differ by race (n = 28, χ25 = 4.18, p = 0.52), marital status (n = 28, χ23 = 6.27, p = 0.099) or level of education (n = 26, χ23 = 5.39, p = 0.15).”

In the paper

“These combinations of activation threshold and cluster size were determined using AlphaSim52 to correspond to a false-positive rate of p < 0.05, corrected for multiple comparisons within ROIs.”

What the sources say

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In the paper

“Participants were screened for comorbid disorders using the Mini-International Neuropsychiatric Interview (MINI).46”

What the sources say

• Not checked yetcites [46] Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(Suppl 20):22–33. quiz 4–57. [PubMed] [Google Scholar]

In the paper

“The variance owing to physiologic responses (i.e., cardiac and respiratory sources) was removed using regression.47”

What the sources say

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In the paper

“Two patients with PTSD were using trazodone as a sleep aid; no other psychiatric medications were permitted.”

In the paper

“Imaging data from 1 control participant was lost owing to scanner malfunction, leaving a final sample of 15 patients with PTSD and 14 combat controls.”

In the paper

“Moreover, training patients with PTSD in emotion-regulation strategies has been shown to reduce negative emotional responses and normalize PFC responses to aversive stimuli.58”

What the sources say

• Not checked yetcites [58] New AS, Fan J, Murrough JW, et al. A functional magnetic resonance imaging study of deliberate emotion regulation in resilience and posttraumatic stress disorder. Biol Psychiatry. 2009;66:656–64. doi: 10.1016/j.biopsych.2009.05.020. [DOI] [PubMed] [Google Scholar]

In the paper

“If the ACC and mPFC play an important inhibitory role in modulating amygdala signal, our findings of a weaker anti-correlation between the amygdala and ACC might reflect diminished capacity of the medial prefrontal regions in individuals with PTSD to suppress amygdala activity.”

In the paper

“Gilboa and colleagues17 reported that during neutral emotion conditions, the ACC exerts an inhibitory influence on the amygdala, and this relation is diminished in individuals with PTSD.”

What the sources say

• Not checked yetcites [17] Gilboa A, Shalev AY, Laor L, et al. Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatry. 2004;55:263–72. doi: 10.1016/j.biopsych.2003.08.004. [DOI] [PubMed] [Google Scholar] source

In the paper

“Such a lack of inhibition from dorsal medial regions to the amygdala can be interpreted as a deficit in automatic emotion regulation10 or a lack of cognitive control over emotion.54”

What the sources say

• Not checked yetcites [10] Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry. 2007;164:1476–88. doi: 10.1176/appi.ajp.2007.07030504. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non–combat related PTSD.”

In the paper

“It is noteworthy that individuals with PTSD demonstrate both of these deficits in clinical settings.57”

What the sources say

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In the paper

“Animal studies of fear conditioning establish mPFC involvement in the extinction of conditioned fear,55”

What the sources say

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In the paper

“Resting-state amygdala connectivity studies also reveal anticorrelations between the dorsal mPFC and amygdala in low-anxious individuals and, interestingly, a lack of coupling in high-anxious individuals.14”

What the sources say

• Not checked yetcites [14] Kim MJ, Gee DG, Loucks RA, et al. Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest. Cereb Cortex. 2011;21:1667–73. doi: 10.1093/cercor/bhq237. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“The amygdala and insula have strong structural connections61 and exhibit high functional connectivity at rest.62”

What the sources say

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In the paper

“In individuals with PTSD, insula activation has been associated with trauma recall21 and viewing fearful faces,18”

What the sources say

• Not checked yetcites [21] Britton JC, Phan KL, Taylor SF, et al. Neural correlates of social and nonsocial emotions: an fMRI study. Neuroimage. 2006;31:397–409. doi: 10.1016/j.neuroimage.2005.11.027. [DOI] [PubMed] [Google Scholar] source
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In the paper

“however, in a more recent study with acutely traumatized individuals, they found PCC/precuneus-to-amygdala connectivity to be positively correlated with PTSD symptoms.33”

What the sources say

• Not checked yetcites [33] Lanius RA, Bluhm RL, Coupland NJ, et al. Default mode network connectivity as a predictor of post-traumatic stress disorder symptom severity in acutely traumatized subjects. Acta Psychiatr Scand. 2010;121:33–40. doi: 10.1111/j.1600-0447.2009.01391.x. [DOI] [PubMed] [Google Scholar] source

In the paper

“Indeed, insula responsivity to negative images in individuals with PTSD has previously been shown to be positively correlated with hyperarousal symptoms,19 re-experiencing symptoms63 and flashback intensity.64”

What the sources say

• Not checked yetcites [19] Simmons AN, Paulus MP, Thorp SR, et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry. 2008;64:681–90. doi: 10.1016/j.biopsych.2008.05.027. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“For example, patients with PTSD show exaggerated activity in both the amygdala and hippocampus while recollecting negative autobiographical memories65 and while viewing negative pictures,66 and the degree of this hyperactivity correlated with symptom severity.66”

What the sources say

• Not checked yetcites [65] St Jacques PL, Botzung A, Miles A, et al. Functional neuroimaging of emotionally intense autobiographical memories in post-traumatic stress disorder. J Psychiatr Res. 2011;45:630–7. doi: 10.1016/j.jpsychires.2010.10.011. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“Similar findings of enhanced connectivity between the insula and amygdala were previously reported in studies of recently traumatized individuals during symptom provocation.16”

What the sources say

• Not checked yetcites [16] Osuch EA, Willis MW, Bluhm R, et al. Neurophysiological responses to traumatic reminders in the acute aftermath of serious motor vehicle collisions using [15O]-H2O positron emission tomography. Biol Psychiatry. 2008;64:327–35. doi: 10.1016/j.biopsych.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“To our knowledge, there have been 4 previous studies of resting-state connectivity in individuals with PTSD, all using a thalamus or PCC/precuneus seed for connectivity analysis.”

In the paper

“co-occurring increases in insula and amygdala activity were found to be greater in individuals with PTSD than combat-exposed or non–combat exposed controls during trauma reminders59 and fear acquisition.60”

What the sources say

• Not checked yetcites [59] Vermetten E, Schmahl C, Southwick SM, et al. Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress disorder. Psychopharmacol Bull. 2007;40:8–30. [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“Bluhm and colleagues32 reported reduced functional connectivity between the PCC/precuneus and amygdala in individuals with PTSD;”

What the sources say

• Not checked yetcites [32] Bluhm RL, Williamson PC, Osuch EA, et al. Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma. J Psychiatry Neurosci. 2009;34:187–94. [PMC free article] [PubMed] [Google Scholar]

In the paper

“One study found that amygdala hyperactivity during fear extinction and hippocampal hypoactivity during extinction recall was associated with a behavioural deficit in extinction recall in individuals with PTSD.68”

What the sources say

• Not checked yetcites [68] Milad MR, Pitman RK, Ellis CB, et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009;66:1075–82. doi: 10.1016/j.biopsych.2009.06.026. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“A failure to properly contextualize threat and safety signals, or integrate corrective information into fear schemas, may be relevant to the development of PTSD symptomatology.”

In the paper

“our inclusion of depressed participants may render some of our effects attributable to the presence of depression independently or in interaction with PTSD.”

In the paper

“Recently, however, it had been convincingly argued that global regression does not introduce large-scale artifacts, and globally regressed connectivity maps more accurately depict the known anticorrelations between functional networks in the brain.72,73”

What the sources say

• Not checked yetcites [72] Fox MD, Zhang D, Snyder AZ, et al. The global signal and observed anticorrelated resting state brain networks. J Neurophysiol. 2009;101:3270–83. doi: 10.1152/jn.90777.2008. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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In the paper

“In sum, recent resting-state functional connectivity studies of the amygdala have used global regression and identified networks proposed to be anticorrelated with the amygdala (for example, see Roy and colleagues15)”

What the sources say

• Not checked yetcites [15] Roy AK, Shehzad Z, Margulies DS, et al. Functional connectivity of the human amygdala using resting state fMRI. Neuroimage. 2009;45:614–26. doi: 10.1016/j.neuroimage.2008.11.030. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“Fourth, our methods are essentially correlational and thus do not allow for inferences about causal relationships.”

In the paper

“Though depression commonly co-occurs with PTSD in veteran populations (up to 80% by some estimations70)”

What the sources say

• Not checked yetcites [70] Hankin CS, Spiro A, III, Miller DR, et al. Mental disorders and mental health treatment among U.S. Department of Veterans Affairs outpatients: the Veterans Health Study. Am J Psychiatry. 1999;156:1924–30. doi: 10.1176/ajp.156.12.1924. [DOI] [PubMed] [Google Scholar] source

In the paper

“A recent connectivity modelling analysis found a strong functional link between the PCC and the amygdala in healthy individuals.15”

What the sources say

• Not checked yetcites [15] Roy AK, Shehzad Z, Margulies DS, et al. Functional connectivity of the human amygdala using resting state fMRI. Neuroimage. 2009;45:614–26. doi: 10.1016/j.neuroimage.2008.11.030. [DOI] [PMC free article] [PubMed] [Google Scholar] source

In the paper

“Disruptions in this connection may point to default network disturbances in individuals with PTSD, a hypothesis that merits further research.”

In the paper

“Our findings of enhanced connectivity in emotion-experience regions (amygdala and insula) and reduced connectivity between these regions and emotion-regulation regions suggest plausible mechanisms involved in exaggerated emotional responses and apparent regulation dysfunction seen in patients with PTSD.”

In the paper

“However, our use of global regression is a limitation in that there is continued controversy about whether global regression introduces artifactual anticorrelation.71”

What the sources say

• Not checked yetcites [71] Murphy K, Birn RM, Handwerker DA, et al. The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? Neuroimage. 2009;44:893–905. doi: 10.1016/j.neuroimage.2008.09.036. [DOI] [PMC free article] [PubMed] [Google Scholar] source