Skip to main content
Full access
Letters to the Editor
Published Online: 1 July 2020

Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: Response to Rasetti et al.

To the Editor: We read with interest the letter from Rasetti et al. and thank them for further discussing the potential implications of the results of our meta-analysis. The first part of their letter raised concerns about the concept of neutral stimuli in an MRI environment. Although we understand their comment, we would like to reiterate that the rationale of our meta-analysis was based on a legitimate question that was raised initially by Anticevic and colleagues (1). In that article, the investigators performed a meta-analysis of functional neuroimaging studies on emotion processing in schizophrenia that focused on the amygdala as a region of interest. In studies using the “negative emotion minus neutral” contrast, they found that amygdala activity was reduced in schizophrenia and that there were no between-group differences in studies examining the “negative emotion” condition only. Indirectly, these results raised the possibility that the reduced activations observed in schizophrenia using traditional contrasts (e.g., negative minus neutral) may actually be driven by significant differences during what the authors reported to be the “neutral condition.” Unfortunately, at the time, the data were not available to directly test this assumption. Since then, several studies have been published that allowed our research team to test and support the untested assumption of Anticevic and colleagues. Indeed, 23 functional neuroimaging studies on emotion processing were identified and analyzed, and these showed that there are increased activations in limbic regions (e.g., amygdala, hippocampus, insula) in schizophrenia during the neutral control condition (compared with an at-rest condition or baseline). In their critique, Rasetti and colleagues argued that our results may simply be explained by different levels of exposure to the MRI environment among schizophrenia patients and healthy control subjects and by the discomfort experienced by patients in the scanner. However, this possibility seems unlikely to explain our results. The main empirical reason is that several experimental studies using emotion induction paradigms (e.g., affective pictures and faces, film clips) have been performed in patients with schizophrenia on emotion processing outside the scanner, and these have shown results in line with the results observed inside the MRI machine. That is, patients report greater levels of aversion and arousal than control subjects in response to stimuli validated as being emotionally neutral. This finding has been demonstrated by two meta-analyses (2, 3). That said, we agree with Rasetti and colleagues that the increased limbic activity observed in schizophrenia during the processing of neutral stimuli needs to be better explained (as long as the phenomenon is replicated). Precisely because of that, we mentioned in the Discussion section of our article that (at least) two options proposed by other investigators deserve further investigation using proper experimental paradigms. A first possibility is that neutral stimuli may acquire aberrant emotional significance in schizophrenia as the result of abnormal associative learning (4). Another option has to do with the spontaneous social judgments people make when watching nonemotional faces (about their attractiveness, trustworthiness, etc.) (5), and this perception may be impaired in schizophrenia (6).
In the second part of their letter, Rasetti and colleagues reported that we omitted key neuroimaging investigations on emotion processing performed in individuals at risk for psychosis. Here it is important to clarify that psychosis risk was not part of the meta-analysis. The main focus was to review neuroimaging studies on emotion processing in schizophrenia, having examined the control condition (e.g., neutral stimuli) specifically. Psychosis risk was evoked only in the Discussion section, and we acknowledged that the studies examining the control condition have produced mixed results thus far (79). As for the functional neuroimaging studies using traditional contrasts (e.g., negative emotion minus neutral), which were not reviewed in the article, our understanding of the literature is that results also have been mixed. While some studies have shown significant neurobiological differences between individuals at risk for psychosis and control subjects (1012), other studies, such as the important ones described by Rasetti and colleagues (13, 14), have not found differences. Finally, we would like to reiterate that regardless of the contrast used for the neuroimaging analyses, the comparison of results across studies has not been facilitated owing to the fact that the definitions of psychosis risk vary considerably from one study to another (e.g., psychotic experiences compared with at-risk mental state, first-degree relatives, polygenic risk score, etc.).
In sum, our meta-analysis sought to answer a scientifically valid question first raised by Anticevic and colleagues. We found increased activations of limbic regions during the processing of nonemotional stimuli in schizophrenia. Such results may encourage investigators to prudently interpret some of the results based on the contrast between emotional and neutral stimuli when investigating emotion processing in schizophrenia, and to pursue functional MRI studies on emotional disturbances in schizophrenia using more complex experimental paradigms and analytical strategies. As for psychosis risk, we agree that results have been mixed thus far.


Anticevic A, Van Snellenberg JX, Cohen RE, et al: Amygdala recruitment in schizophrenia in response to aversive emotional material: a meta-analysis of neuroimaging studies. Schizophr Bull 2012; 38:608–621
Cohen AS, Minor KS: Emotional experience in patients with schizophrenia revisited: meta-analysis of laboratory studies. Schizophr Bull 2010; 36:143–150
Llerena K, Strauss GP, Cohen AS: Looking at the other side of the coin: a meta-analysis of self-reported emotional arousal in people with schizophrenia. Schizophr Res 2012; 142:65–70
Jensen J, Willeit M, Zipursky RB, et al: The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 2008; 33:473–479
Oosterhof NN, Todorov A: The functional basis of face evaluation. Proc Natl Acad Sci USA 2008; 105:11087–11092
Trémeau F, Antonius D, Todorov A, et al: Implicit emotion perception in schizophrenia. J Psychiatr Res 2015; 71:112–119
Bourque J, Spechler PA, Potvin S, et al: Functional neuroimaging predictors of self-reported psychotic symptoms in adolescents. Am J Psychiatry 2017; 174:566–575
Modinos G, Ormel J, Aleman A: Altered activation and functional connectivity of neural systems supporting cognitive control of emotion in psychosis proneness. Schizophr Res 2010; 118:88–97
van Buuren M, Vink M, Rapcencu AE, et al: Exaggerated brain activation during emotion processing in unaffected siblings of patients with schizophrenia. Biol Psychiatry 2011; 70:81–87
Spilka MJ, Arnold AE, Goghari VM: Functional activation abnormalities during facial emotion perception in schizophrenia patients and nonpsychotic relatives. Schizophr Res 2015; 168:330–337
Modinos G, Tseng H-H, Falkenberg I, et al: Neural correlates of aberrant emotional salience predict psychotic symptoms and global functioning in high-risk and first-episode psychosis. Soc Cogn Affect Neurosci 2015; 10:1429–1436
Wolf DH, Satterthwaite TD, Calkins ME, et al: Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms. JAMA Psychiatry 2015; 72:456–465
Rasetti R, Mattay VS, Wiedholz LM, et al: Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk. Am J Psychiatry 2009; 166:216–225
Pardiñas AF, Holmans P, Pocklington AJ, et al: Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet 2018; 50:381–389

Information & Authors


Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 640 - 641


Accepted: 27 January 2020
Published online: 1 July 2020
Published in print: July 01, 2020


  1. Schizophrenia
  2. Psychosis
  3. Amygdala
  4. fMRI



Jules R. Dugré, M.Sc.
Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, Montreal (all authors); Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Montreal (all authors); Institut Philippe-Pinel de Montréal, Montreal (Dumais).
Alexandre Dumais, M.D., Ph.D.
Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, Montreal (all authors); Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Montreal (all authors); Institut Philippe-Pinel de Montréal, Montreal (Dumais).
Stéphane Potvin, Ph.D. [email protected]
Centre de Recherche de l’Institut Universitaire en Santé Mentale de Montréal, Montreal (all authors); Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal, Montreal (all authors); Institut Philippe-Pinel de Montréal, Montreal (Dumais).


Send correspondence to Dr. Potvin ([email protected]).

Funding Information

The authors’ disclosures accompany the original article.

Metrics & Citations



Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Citation style
Copy to clipboard

There are no citations for this item

View Options

View options


View PDF/ePub

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login
Purchase Options

Purchase this article to access the full text.

PPV Articles - American Journal of Psychiatry

PPV Articles - American Journal of Psychiatry

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).







Share article link