Peripheral and prefrontal stress system markers and risk of relapse in alcoholism

Sara K Blaine, Dongju Seo, Rajita Sinha, Sara K Blaine, Dongju Seo, Rajita Sinha

Abstract

Previous research has shown that hyperactivation in ventral medial prefrontal cortex (VmPFC) and rostral anterior cingulate cortex (rACC) and high cortisol to corticotrophin ratio (cort:ACTH ratio) during neutral-relaxed states predict relapse in alcohol-dependent (AD) patients. Other studies have shown that VmPFC/rACC deactivation and blunted cortisol release to stress and alcohol cues are predictive of time to relapse and relapse severity. However, no previous study has assessed the relationship between these markers of central and peripheral nervous system dysfunction in AD participants and their potential joint effects on relapse risk. Forty early abstinent, treatment engaged AD patients underwent a laboratory experiment with exposure to neutral, alcohol and stress cues and a separate functional magnetic resonance imaging scan with similar cue exposure. Neutral-relaxed state cort:ACTH ratio was significantly associated with VmPFC hyperreactivity to neutral-relaxing cues, and also with hypoactivation in response to alcohol and stress cues in AD patients. Basal heart rate, neutral cort:ACTH ratio and neutral VmPFC hyperreactivty were each associated with risk of relapse. However, abnormal VmPFC activation and elevated cort:ACTH ratio overlap in predicting risk for relapse, and dysfunctional VmPFC response was the sole significant predictor of odds of relapse in a joint model of relapse risk. These findings suggest that the cort:ACTH ratio may serve as a peripheral marker of VmPFC brain dysfunction, while aberrant VmPFC responses need further evaluation as a potential biomarker of alcohol relapse risk in clinical outcome studies.

Keywords: ANS; HPA; alcohol dependence; fMRI; relapse; stress.

© 2015 Society for the Study of Addiction.

Figures

Figure 1
Figure 1
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and neutral state VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to neutral-relaxing cues during a separate fMRI session, r (39) = 0.58, p

Figure 2

Results of whole brain voxel…

Figure 2

Results of whole brain voxel correlation analysis showing relationship between neutral state cort:…

Figure 2
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and stress state VmPFC activation The cortisol to adrenocorticotropic hormone (cort: ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyopactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.33, p

Figure 3

Results of whole brain voxel…

Figure 3

Results of whole brain voxel correlation analysis showing relationship between neutral state cort:…

Figure 3
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and alcohol cue induced VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to alcohol cues during a separate fMRI session, r (39) = −0.45, p

Figure 4

Results of whole brain voxel…

Figure 4

Results of whole brain voxel correlation analysis showing relationship between stress state cort:…

Figure 4
Results of whole brain voxel correlation analysis showing relationship between stress state cort: ACTH ratio and stress state VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to stress cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.32, p

Figure 5

Results of whole brain voxel…

Figure 5

Results of whole brain voxel correlation analysis showing relationship between basal heart rate…

Figure 5
Results of whole brain voxel correlation analysis showing relationship between basal heart rate and stress state VmPFC activation. The Basal heart rate prior to fMRI stress imagery was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during the fMRI session, r (39) = −0.36, p
Similar articles
Cited by
References
    1. Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcoholism: Clinical and Experimental Research. 2003;27:1420–1427. - PubMed
    1. Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R. Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. Biological psychiatry. 2012;72(1):57–64. - PMC - PubMed
    1. Blaine SK, Ansell EB, Sinha R. Cumulative Adversity, Brain Structure, and Risk of Psychiatric Illness. Neuroscience & Biobehavioral Reviews under review.
    1. Blaine SK, Milivojevic V, Fox HC, Sinha R. Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk. Canadian Journal of Psychiatry in press. - PMC - PubMed
    1. Breese GR, Sinha R, Heilig M. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacology & therapeutics. 2011;129(2):149–171. - PMC - PubMed
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Figure 2
Figure 2
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and stress state VmPFC activation The cortisol to adrenocorticotropic hormone (cort: ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyopactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.33, p

Figure 3

Results of whole brain voxel…

Figure 3

Results of whole brain voxel correlation analysis showing relationship between neutral state cort:…

Figure 3
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and alcohol cue induced VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to alcohol cues during a separate fMRI session, r (39) = −0.45, p

Figure 4

Results of whole brain voxel…

Figure 4

Results of whole brain voxel correlation analysis showing relationship between stress state cort:…

Figure 4
Results of whole brain voxel correlation analysis showing relationship between stress state cort: ACTH ratio and stress state VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to stress cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.32, p

Figure 5

Results of whole brain voxel…

Figure 5

Results of whole brain voxel correlation analysis showing relationship between basal heart rate…

Figure 5
Results of whole brain voxel correlation analysis showing relationship between basal heart rate and stress state VmPFC activation. The Basal heart rate prior to fMRI stress imagery was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during the fMRI session, r (39) = −0.36, p
Similar articles
Cited by
References
    1. Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcoholism: Clinical and Experimental Research. 2003;27:1420–1427. - PubMed
    1. Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R. Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. Biological psychiatry. 2012;72(1):57–64. - PMC - PubMed
    1. Blaine SK, Ansell EB, Sinha R. Cumulative Adversity, Brain Structure, and Risk of Psychiatric Illness. Neuroscience & Biobehavioral Reviews under review.
    1. Blaine SK, Milivojevic V, Fox HC, Sinha R. Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk. Canadian Journal of Psychiatry in press. - PMC - PubMed
    1. Breese GR, Sinha R, Heilig M. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacology & therapeutics. 2011;129(2):149–171. - PMC - PubMed
Show all 39 references
MeSH terms
Full text links [x]
[x]
Cite
Copy Download .nbib .nbib
Format: AMA APA MLA NLM

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MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

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Figure 3
Figure 3
Results of whole brain voxel correlation analysis showing relationship between neutral state cort: ACTH ratio and alcohol cue induced VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to neutral-relaxing cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to alcohol cues during a separate fMRI session, r (39) = −0.45, p

Figure 4

Results of whole brain voxel…

Figure 4

Results of whole brain voxel correlation analysis showing relationship between stress state cort:…

Figure 4
Results of whole brain voxel correlation analysis showing relationship between stress state cort: ACTH ratio and stress state VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to stress cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.32, p

Figure 5

Results of whole brain voxel…

Figure 5

Results of whole brain voxel correlation analysis showing relationship between basal heart rate…

Figure 5
Results of whole brain voxel correlation analysis showing relationship between basal heart rate and stress state VmPFC activation. The Basal heart rate prior to fMRI stress imagery was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during the fMRI session, r (39) = −0.36, p
Similar articles
Cited by
References
    1. Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcoholism: Clinical and Experimental Research. 2003;27:1420–1427. - PubMed
    1. Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R. Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. Biological psychiatry. 2012;72(1):57–64. - PMC - PubMed
    1. Blaine SK, Ansell EB, Sinha R. Cumulative Adversity, Brain Structure, and Risk of Psychiatric Illness. Neuroscience & Biobehavioral Reviews under review.
    1. Blaine SK, Milivojevic V, Fox HC, Sinha R. Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk. Canadian Journal of Psychiatry in press. - PMC - PubMed
    1. Breese GR, Sinha R, Heilig M. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacology & therapeutics. 2011;129(2):149–171. - PMC - PubMed
Show all 39 references
MeSH terms
Full text links [x]
[x]
Cite
Copy Download .nbib .nbib
Format: AMA APA MLA NLM

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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

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Figure 4
Figure 4
Results of whole brain voxel correlation analysis showing relationship between stress state cort: ACTH ratio and stress state VmPFC activation. The cortisol to adrenocorticotropic hormone (cort:ACTH) ratio in response to stress cues during a laboratory session was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during a separate fMRI session, r (39) = −0.32, p

Figure 5

Results of whole brain voxel…

Figure 5

Results of whole brain voxel correlation analysis showing relationship between basal heart rate…

Figure 5
Results of whole brain voxel correlation analysis showing relationship between basal heart rate and stress state VmPFC activation. The Basal heart rate prior to fMRI stress imagery was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during the fMRI session, r (39) = −0.36, p
Similar articles
Cited by
References
    1. Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ. Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcoholism: Clinical and Experimental Research. 2003;27:1420–1427. - PubMed
    1. Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R. Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. Biological psychiatry. 2012;72(1):57–64. - PMC - PubMed
    1. Blaine SK, Ansell EB, Sinha R. Cumulative Adversity, Brain Structure, and Risk of Psychiatric Illness. Neuroscience & Biobehavioral Reviews under review.
    1. Blaine SK, Milivojevic V, Fox HC, Sinha R. Alcohol Effects on Stress Pathways: Impact on Craving and Relapse Risk. Canadian Journal of Psychiatry in press. - PMC - PubMed
    1. Breese GR, Sinha R, Heilig M. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacology & therapeutics. 2011;129(2):149–171. - PMC - PubMed
Show all 39 references
MeSH terms
Full text links [x]
[x]
Cite
Copy Download .nbib .nbib
Format: AMA APA MLA NLM
Figure 5
Figure 5
Results of whole brain voxel correlation analysis showing relationship between basal heart rate and stress state VmPFC activation. The Basal heart rate prior to fMRI stress imagery was significantly associated with neural hyperactivation in the Ventromedial Prefrontal Cortex (VmPFC) in response to stress cues during the fMRI session, r (39) = −0.36, p

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