Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 27
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Collazzoni, Alberto Stratta, Paolo Tosone, Adele Rossetti, Maria Cristina D'Onofrio, Simona and Rossi, Alessandro 2016. Different roles of resilience in a non clinical sample evaluated for family stress and psychiatric symptoms. Personality and Individual Differences, Vol. 100, p. 12.

    Grellmann, Claudia Neumann, Jane Bitzer, Sebastian Kovacs, Peter Tönjes, Anke Westlye, Lars T. Andreassen, Ole A. Stumvoll, Michael Villringer, Arno and Horstmann, Annette 2016. Random Projection for Fast and Efficient Multivariate Correlation Analysis of High-Dimensional Data: A New Approach. Frontiers in Genetics, Vol. 7,

    Lavoie, Marc E. Champagne, Julie Glaser, Emma and Mendrek, Adrianna 2016. Mémoire émotionnelle et activités électrocorticales en schizophrénie. Santé mentale au Québec, Vol. 41, Issue. 1, p. 85.

    Poletti, Sara Vai, Benedetta Smeraldi, Enrico Cavallaro, Roberto Colombo, Cristina and Benedetti, Francesco 2016. Adverse childhood experiences influence the detrimental effect of bipolar disorder and schizophrenia on cortico-limbic grey matter volumes. Journal of Affective Disorders, Vol. 189, p. 290.

    Bosia, Marta Pigoni, Alessandro and Cavallaro, Roberto 2015. Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back. Expert Opinion on Drug Discovery, Vol. 10, Issue. 2, p. 125.

    Collazzoni, A. Capanna, C. Bustini, M. Marucci, C. Prescenzo, S. Ragusa, M. Tosone, A. Di Ubaldo, V. Stratta, P. and Rossi, A. 2015. A Comparison of Humiliation Measurement in a Depressive Versus Non-clinical Sample: A Possible Clinical Utility. Journal of Clinical Psychology, Vol. 71, Issue. 12, p. 1218.

    Cui, Long-Biao Liu, Jian Wang, Liu-Xian Li, Chen Xi, Yi-Bin Guo, Fan Wang, Hua-Ning Zhang, Lin-Chuan Liu, Wen-Ming He, Hong Tian, Ping Yin, Hong and Lu, Hongbing 2015. Anterior cingulate cortex-related connectivity in first-episode schizophrenia: a spectral dynamic causal modeling study with functional magnetic resonance imaging. Frontiers in Human Neuroscience, Vol. 9,

    Grellmann, Claudia Bitzer, Sebastian Neumann, Jane Westlye, Lars T. Andreassen, Ole A. Villringer, Arno and Horstmann, Annette 2015. Comparison of variants of canonical correlation analysis and partial least squares for combined analysis of MRI and genetic data. NeuroImage, Vol. 107, p. 289.

    Kalmakis, Karen A. and Chandler, Genevieve E. 2015. Health consequences of adverse childhood experiences: A systematic review. Journal of the American Association of Nurse Practitioners, Vol. 27, Issue. 8, p. 457.

    Poletti, Sara Mazza, Elena Bollettini, Irene Locatelli, Clara Cavallaro, Roberto Smeraldi, Enrico and Benedetti, Francesco 2015. Adverse childhood experiences influence white matter microstructure in patients with schizophrenia. Psychiatry Research: Neuroimaging, Vol. 234, Issue. 1, p. 35.

    Vai, B. Sferrazza Papa, G. Poletti, S. Radaelli, D. Donnici, E. Bollettini, I. Falini, A. Cavallaro, R. Smeraldi, E. and Benedetti, F. 2015. Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia. European Psychiatry, Vol. 30, Issue. 5, p. 590.

    Benedetti, F. Bollettini, I. Radaelli, D. Poletti, S. Locatelli, C. Falini, A. Smeraldi, E. and Colombo, C. 2014. Adverse childhood experiences influence white matter microstructure in patients with bipolar disorder. Psychological Medicine, Vol. 44, Issue. 14, p. 3069.

    Benedetti, Francesco Riccaboni, Roberta Poletti, Sara Radaelli, Daniele Locatelli, Clara Lorenzi, Cristina Pirovano, Adele Smeraldi, Enrico and Colombo, Cristina 2014. The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder. Bipolar Disorders, Vol. 16, Issue. 8, p. 857.

    Benedetti, Francesco Poletti, Sara Radaelli, Daniele Pozzi, Elena Giacosa, Chiara and Smeraldi, Enrico 2014. Adverse childhood experiences and gender influence treatment seeking behaviors in obsessive–compulsive disorder. Comprehensive Psychiatry, Vol. 55, Issue. 2, p. 298.

    Collazzoni, Alberto Capanna, Cristina Bustini, Massimiliano Stratta, Paolo Ragusa, Marzia Marino, Antonio and Rossi, Alessandro 2014. Humiliation and interpersonal sensitivity in depression. Journal of Affective Disorders, Vol. 167, p. 224.

    Kalmakis, Karen A. and Chandler, Genevieve E. 2014. Adverse childhood experiences: towards a clear conceptual meaning. Journal of Advanced Nursing, Vol. 70, Issue. 7, p. 1489.

    Mishra, Arabinda Rogers, Baxter P. Chen, Li Min and Gore, John C. 2014. Functional connectivity-based parcellation of amygdala using self-organized mapping: A data driven approach. Human Brain Mapping, Vol. 35, Issue. 4, p. 1247.

    Poletti, Sara Colombo, Cristina and Benedetti, Francesco 2014. Adverse childhood experiences worsen cognitive distortion during adult bipolar depression. Comprehensive Psychiatry, Vol. 55, Issue. 8, p. 1803.

    Poletti, Sara Locatelli, Clara Radaelli, Daniele Lorenzi, Cristina Smeraldi, Enrico Colombo, Cristina and Benedetti, Francesco 2014. Effect of early stress on hippocampal gray matter is influenced by a functional polymorphism in EAAT2 in bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 51, p. 146.

    Walsh, Nicholas D. Dalgleish, Tim Lombardo, Michael V. Dunn, Valerie J. Van Harmelen, Anne-Laura Ban, Maria and Goodyer, Ian M. 2014. General and specific effects of early-life psychosocial adversities on adolescent grey matter volume. NeuroImage: Clinical, Vol. 4, p. 308.


Emotional reactivity in chronic schizophrenia: structural and functional brain correlates and the influence of adverse childhood experiences

  • F. Benedetti (a1) (a2), D. Radaelli (a1) (a2), S. Poletti (a1) (a2) (a3), A. Falini (a2) (a4), R. Cavallaro (a1), S. Dallaspezia (a1) (a2), R. Riccaboni (a1) (a2), G. Scotti (a2) (a4) and E. Smeraldi (a1) (a2)
  • DOI:
  • Published online: 09 June 2010

Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression).


Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population.


Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions.


Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs.

Corresponding author
*Address for correspondence: F. Benedetti, M.D., Istituto Scientifico Ospedale San Raffaele, Department of Clinical Neurosciences, San Raffaele Turro, Via Stamira d'Ancona 20, Milan, Italy. (Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

NC Andreasen , M Pressler , P Nopoulos , D Miller , BC Ho (2010). Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry 67, 255262.

J Ashburner , KJ Friston (2005). Unified segmentation. Neuroimage 26, 839851.

L Barrelet , F Ferrero , L Szigethy , C Giddey , G Pellizzer (1990). Expressed emotion and first-admission schizophrenia. Nine-month follow-up in a French cultural environment. British Journal of Psychiatry 156, 357362.

FM Benes (2010). Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology 35, 239257.

G Blasi , T Popolizio , P Taurisano , G Caforio , R Romano , A Di Giorgio , F Sambataro , V Rubino , V Latorre , L Lo Bianco , L Fazio , M Nardini , DR Weinberger , A Bertolino (2009). Changes in prefrontal and amygdala activity during olanzapine treatment in schizophrenia. Psychiatry Research 173, 3138.

JH Callicott , A Bertolino , VS Mattay , FJ Langheim , J Duyn , R Coppola , TE Goldberg , DR Weinberger (2000). Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cerebral Cortex 10, 10781092.

A Ceccarelli , MA Rocca , E Pagani , A Falini , G Comi , M Filippi (2009). Cognitive learning is associated with gray matter changes in healthy human individuals: a tensor-based morphometry study. Neuroimage 48, 585589.

D Collip , I Myin-Germeys , J Van Os (2008). Does the concept of ‘sensitization’ provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophrenia Bulletin 34, 220225.

LP Cutting , JM Aakre , NM Docherty (2006). Schizophrenic patients' perceptions of stress, expressed emotion, and sensitivity to criticism. Schizophrenia Bulletin 32, 743750.

P Das , AH Kemp , G Flynn , AW Harris , BJ Liddell , TJ Whitford , A Peduto , E Gordon , LM Williams (2007). Functional disconnections in the direct and indirect amygdala pathways for fear processing in schizophrenia. Schizophrenia Research 90, 284294.

E Fakra , P Salgado-Pineda , P Delaveau , AR Hariri , O Blin (2008). Neural bases of different cognitive strategies for facial affect processing in schizophrenia. Schizophrenia Research 100, 191205.

VM Goghari , SR Sponheim , AW Macdonald 3rd (2010). The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. Neuroscience and Biobehavioral Reviews 34, 468486.

CD Good , IS Johnsrude , J Ashburner , RN Henson , KJ Friston , RS Frackowiak (2001). A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14, 2136.

RC Gur , L Schroeder , T Turner , C McGrath , RM Chan , BI Turetsky , D Alsop , J Maldjian , RE Gur (2002). Brain activation during facial emotion processing. Neuroimage 16, 651662.

RE Gur , J Loughead , CG Kohler , MA Elliott , K Lesko , K Ruparel , DH Wolf , WB Bilker , RC Gur (2007). Limbic activation associated with misidentification of fearful faces and flat affect in schizophrenia. Archives of General Psychiatry 64, 13561366.

AR Hariri , VS Mattay , A Tessitore , B Kolachana , F Fera , D Goldman , MF Egan , DR Weinberger (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400403.

JD Henry , MJ Green , A de Lucia , C Restuccia , S McDonald , M O'Donnell (2007). Emotion dysregulation in schizophrenia: reduced amplification of emotional expression is associated with emotional blunting. Schizophrenia Research 95, 197204.

DJ Holt , L Kunkel , AP Weiss , DC Goff , CI Wright , LM Shin , SL Rauch , J Hootnick , S Heckers (2006). Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia. Schizophrenia Research 82, 153162.

R Honea , TJ Crow , D Passingham , CE Mackay (2005). Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. American Journal of Psychiatry 162, 22332245.

K Hoschel , E Irle (2001). Emotional priming of facial affect identification in schizophrenia. Schizophrenia Bulletin 27, 317327.

S Iritani (2007). Neuropathology of schizophrenia: a mini review. Neuropathology 27, 604608.

SR Kay , A Fiszbein , LA Opler (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.

H Kosaka , M Omori , T Murata , T Iidaka , H Yamada , T Okada , T Takahashi , N Sadato , H Itoh , Y Yonekura , Y Wada (2002). Differential amygdala response during facial recognition in patients with schizophrenia: an fMRI study. Schizophrenia Research 57, 8795.

AM Kring , SL Kerr , DA Smith , JM Neale (1993). Flat affect in schizophrenia does not reflect diminished subjective experience of emotion. Journal of Abnormal Psychology 102, 507517.

I Liberzon , SF Taylor , LM Fig , LR Decker , RA Koeppe , S Minoshima (2000). Limbic activation and psychophysiologic responses to aversive visual stimuli. Interaction with cognitive task. Neuropsychopharmacology 23, 508516.

RK McClure , I Phillips , R Jazayerli , A Barnett , R Coppola , DR Weinberger (2006). Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment. Psychiatry Research 148, 121132.

I Myin-Germeys , PA Delespaul , MW deVries (2000). Schizophrenia patients are more emotionally active than is assumed based on their behavior. Schizophrenia Bulletin 26, 847854.

KN Ochsner , JJ Gross (2005). The cognitive control of emotion. Trends in Cognitive Science 9, 242249.

L Pezawas , A Meyer-Lindenberg , EM Drabant , BA Verchinski , KE Munoz , BS Kolachana , MF Egan , VS Mattay , AR Hariri , DR Weinberger (2005). 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neuroscience 8, 828834.

ML Phillips , WC Drevets , SL Rauch , R Lane (2003 a). Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biological Psychiatry 54, 504514.

ML Phillips , WC Drevets , SL Rauch , R Lane (2003 b). Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biological Psychiatry 54, 515528.

ML Phillips , L Williams , C Senior , ET Bullmore , MJ Brammer , C Andrew , SC Williams , AS David (1999). A differential neural response to threatening and non-'threatening negative facial expressions in paranoid and non-paranoid schizophrenics. Psychiatry Research 92, 1131.

JC Pruessner , K Dedovic , N Khalili-Mahani , V Engert , M Pruessner , C Buss , R Renwick , A Dagher , MJ Meaney , S Lupien (2008). Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic resonance imaging studies. Biological Psychiatry 63, 234240.

R Rasetti , VS Mattay , LM Wiedholz , BS Kolachana , AR Hariri , JH Callicott , A Meyer-Lindenberg , DR Weinberger (2009). Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk. American Journal of Psychiatry 166, 216225.

RL Repetti , SE Taylor , TE Seeman (2002). Risky families: family social environments and the mental and physical health of offspring. Psychological Bulletin 128, 330366.

J Sanjuan , JJ Lull , EJ Aguilar , L Marti-Bonmati , D Moratal , JC Gonzalez , M Robles , MS Keshavan (2007). Emotional words induce enhanced brain activity in schizophrenic patients with auditory hallucinations. Psychiatry Research 154, 2129.

M Scazufca , E Kuipers , PR Menezes (2001). Perception of negative emotions in close relatives by patients with schizophrenia. British Journal of Clinical Psychology 40, 167175.

F Schneider , U Weiss , C Kessler , JB Salloum , S Posse , W Grodd , HW Muller-Gartner (1998). Differential amygdala activation in schizophrenia during sadness. Schizophrenia Research 34, 133142.

JL Stein , LM Wiedholz , DS Bassett , DR Weinberger , CF Zink , VS Mattay , A Meyer-Lindenberg (2007). A validated network of effective amygdala connectivity. Neuroimage 36, 736745.

S Surguladze , T Russell , K Kucharska-Pietura , MJ Travis , V Giampietro , AS David , ML Phillips (2006). A reversal of the normal pattern of parahippocampal response to neutral and fearful faces is associated with reality distortion in schizophrenia. Biological Psychiatry 60, 423431.

T Suslow , C Roestel , V Arolt (2003). Affective priming in schizophrenia with and without affective negative symptoms. European Archives of Psychiatry and Clinical Neurosciences 253, 292300.

SE Taylor , NI Eisenberger , D Saxbe , BJ Lehman , MD Lieberman (2006). Neural responses to emotional stimuli are associated with childhood family stress. Biological Psychiatry 60, 296301.

SE Taylor , JS Lerner , RM Sage , BJ Lehman , TE Seeman (2004). Early environment, emotions, responses to stress, and health. Journal of Personality 72, 13651393.

SF Taylor , I Liberzon , LR Decker , RA Koeppe (2002). A functional anatomic study of emotion in schizophrenia. Schizophrenia Research 58, 159172.

SF Taylor , KL Phan , JC Britton , I Liberzon (2005). Neural response to emotional salience in schizophrenia. Neuropsychopharmacology 30, 984995.

SF Taylor , KL Phan , LR Decker , I Liberzon (2003). Subjective rating of emotionally salient stimuli modulates neural activity. Neuroimage 18, 650659.

MC Tompson , MJ Goldstein , MB Lebell , LI Mintz , SR Marder , J Mintz (1995). Schizophrenic patients' perceptions of their relatives' attitudes. Psychiatry Research 57, 155167.

R van Winkel , NC Stefanis , I Myin-Germeys (2008). Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene–stress interaction. Schizophrenia Bulletin 34, 10951105.

D Velakoulis , SJ Wood , MT Wong , PD McGorry , A Yung , L Phillips , D Smith , W Brewer , T Proffitt , P Desmond , C Pantelis (2006). Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Archives of General Psychiatry 63, 139149.

T White , K Cullen , LM Rohrer , C Karatekin , M Luciana , M Schmidt , D Hongwanishkul , S Kumra , S Charles Schulz , KO Lim (2008). Limbic structures and networks in children and adolescents with schizophrenia. Schizophrenia Bulletin 34, 1829.

LM Williams , P Das , AW Harris , BB Liddell , MJ Brammer , G Olivieri , D Skerrett , ML Phillips , AS David , A Peduto , E Gordon (2004). Dysregulation of arousal and amygdala–prefrontal systems in paranoid schizophrenia. American Journal of Psychiatry 161, 480489.

LM Williams , P Das , BJ Liddell , G Olivieri , AS Peduto , AS David , E Gordon , AW Harris (2007). Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes. Psychiatry Research 155, 2944.

SJ Wood , C Pantelis , D Velakoulis , M Yucel , A Fornito , PD McGorry (2008). Progressive changes in the development toward schizophrenia: studies in subjects at increased symptomatic risk. Schizophrenia Bulletin 34, 322329.

P Wright , D Albarracin , RD Brown , H Li , G He , Y Liu (2008). Dissociated responses in the amygdala and orbitofrontal cortex to bottom-up and top-down components of emotional evaluation. Neuroimage 39, 894902.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *