Stress-Related Methylation of the Catechol-O-Methyltransferase Val158 Allele Predicts Human Prefrontal Cognition and Activity

The Journal of Neuroscience, May 4, 2011 • 31(18):6692– 6698

Gianluca Ursini,1,2 Valentina Bollati,3,4 Leonardo Fazio,1 Annamaria Porcelli,1 Luisa Iacovelli,5 Assia Catalani,Lorenzo Sinibaldi,2Barbara Gelao,1 Raffaella Romano,1 Antonio Rampino,1 Paolo Taurisano,1 Marina Mancini,Annabella Di Giorgio,1,6 Teresa Popolizio,6 Andrea Baccarelli,3,4,7 Antonio De Blasi,8 Giuseppe Blasi1 and Alessandro Bertolino1,6

1Psychiatric Neuroscience Group, Department of Neurological and Psychiatric Sciences, University “Aldo Moro”, 71024 Bari, Italy,

2Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy,
3Center for Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, University of Milan, Milan, Italy,
4Istituto Di Ricovero e Cura a Carattere Scientifico Maggiore Hospital, Mangiagalli and Regina Elena Foundation, 20122 Milan, Italy,
5Department of Physiology and Pharmacology “V. Erspamer”, University of Rome “Sapienza”, 00185 Rome, Italy,
6Department of Neuroradiology, IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy,
7Exposure, Epidemiology, and Risk Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115-
8Department of Molecular Medicine, University of Rome “Sapienza”, 00185 Rome, Italy


DNAmethylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol-O -methyltransferase (COMT) Val158 allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val158 allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val158 allele with stress, gene expression,WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.

Affective Response to a Loved One’s Pain: Insula Activity as a Function of Individual Differences

PLoS ONE 5(12): e15268. doi:10.1371/journal.pone.0015268

Viridiana Mazzola1*, Valeria Latorre1,2, Annamaria Petito3, Nicoletta Gentili1,4, Leonardo Fazio5, Teresa Popolizio6, Giuseppe Blasi5, Giampiero Arciero1, Guido Bondolfi7

1 Istituto di Psicologia Post-Razionalista IPRA Rome, Rome, Italy, 2 Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy, 3 Institute of Psychiatry and Clinical Psychology, Department of Medical Sciences, University of Foggia, Foggia, Italy, 4 National Child and Deaf Family Service, South West London and St George’s NHS Trust, London, United Kingdom, 5 Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy, 6 Department of Neuroradiology, IRCCSS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy, 7 Departement de Psychiatrie, Hopitaux Universitaires de Geneve, Geneve, Switzerland


Individual variability in emotion processing may be associated with genetic variation as well as with psychological predispositions such as dispositional affect styles. Our previous fMRI study demonstrated that amygdala reactivity was independently predicted by affective-cognitive styles (phobic prone or eating disorders prone) and genotype of the serotonin transporter in a discrimination task of fearful facial expressions. Since the insula is associated with the subjective evaluation of bodily states and is involved in human feelings, we explored whether its activity could also vary in function of individual differences. In the present fMRI study, the association between dispositional affects and insula reactivity has been examined in two groups of healthy participants categorized according to affective-cognitive styles (phobic prone or eating disorders prone). Images of the faces of partners and strangers, in both painful and neutral situations, were used as visual stimuli. Interaction analyses indicate significantly different activations in the two groups in reaction to a loved one’s pain: the phobic prone group exhibited greater activation in the left posterior insula. These results demonstrate that affective-cognitive style is associated with insula activity in pain empathy processing, suggesting a greater involvement of the insula in feelings for a certain cohort of people. In the mapping of individual differences, these results shed new light on variability in neural networks of emotion.

Citation: Mazzola V, Latorre V, Petito A, Gentili N, Fazio L, et al. (2010) Affective Response to a Loved One’s Pain: Insula Activity as a Function of Individual Differences. PLoS ONE 5(12): e15268. doi:10.1371/journal.pone.0015268

Editor: Ben J. Harrison, The University of Melbourne, Australia

Received: August 3, 2010; Accepted: November 3, 2010; Published: December 16, 2010

Copyright: © 2010 Mazzola et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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Activity in medial prefrontal cortex during cognitive evaluation of threatening stimuli as a function of personality style

Brain Research Bulletin 74 (2007) 250–257

Valeria Rubinoa, Giuseppe Blasia, Valeria Latorrea, Leonardo Fazioa, Immacolata d’Erricob, Viridiana Mazzolab, Grazia Caforioa, Marcello Nardinia, Teresa Popolizioc, Ahmad Haririd, Giampiero Arcierob, Alessandro Bertolinoa,c
aPsychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatric and Neurological Sciences, University of Bari, Bari, Italy
bIstituto di Psicoterapia Postrazionalista, Rome, Italy
cDepartment of Neuroradiology, IRCCSS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy
dDevelopmental Imaging Genomics Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA



Cognitive evaluation of emotional stimuli involves a network of brain regions including the medial prefrontal cortex (mPFC).However, threatening stimuli may be perceived with differential salience in different individuals. The goal of our study was to evaluate how different personality styles are associated with differential modulation of brain activity during explicit recognition of fearful and angry facial expressions. Twenty-eight healthy subjects underwent fMRI. Based on a cognitivist model, subjects were categorized according to how they attribute salience to emotional stimuli and how they regulate their emotional activation. We compared 14 phobic prone (PP) subjects, whose identity is more centered on the inner experience (“inward”) and around control of environmental threat, and 14 eating disorders prone (EDP) subjects, whose identity is more centered on external referential contexts (“outward”) and much less around control of threatening stimuli. During fMRI subjects either matched the identity of one of two angry and fearful faces to that of a simultaneously presented target face or identified the expression of a target face by choosing one of two simultaneously presented linguistic labels. The fMRI results indicated that PP subjects had greater mPFC activation when compared with EDP subjects during cognitive labeling of threatening stimuli. Activity in the mPFC also correlated with personality style scores.

These results demonstrate that PP subjects recruit greater neuronal resources in mPFC whose activity is associated with cognitive aspects that are closely intertwined with emotional processing. These findings are consistent with the contention that cognitive evaluation and salience of emotional stimuli are associated with different personality styles.
Keywords: Emotion recognition; Fear; Prefrontal cortex; fMRI; Personality

Available online 19 July 2007. Link

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