Search

This article has been retracted at the request of John H. Krystal, MD, Editor of Biological Psychiatry, with agreement from all authors. See Elsevier Policy on Article Withdrawal ( https://www.elsevier.com/about/policies/article-withdrawal ). The authors discovered an error in the scoring of the ERP data in this article. Specifically, the ERP in the authors' acquisition and processing stream is live referenced to CZ, and then should be re-referenced in post-processing to TP9 and TP10, as described in the paper. However, the authors discovered that they had accidentally continued to include Cz along with TP9 and TP10 in the template to re-reference the ERP data in post-processing. The authors reprocessed all of the data with only TP9 and TP10 in the referencing, as originally described in the manuscript, and then re-ran all of the analyses. The majority of the key results remained the same in terms of significance and interpretation. The results continue to show that children in PCIT_ED show a greater increase in RewP as a function of treatment than the waitlist group; however, the correlation with the corrected data is in the same direction, but reduced in magnitude and no longer significant. Thus, a greater change in RewP is no longer significantly associated with a greater reduction in MDD symptoms. This error affects the abstract, the results, Table 2, Figures 1-3, discussion, and supplement. The authors voluntarily informed the Journal of this honest error upon its discovery. Because of the extent and nature of the changes to the paper, the editors and authors concluded that, to ensure maximum clarity and transparency, the only course of action was to retract this version of the paper. The authors revised the paper, which the Journal had re-reviewed. The new version was accepted and has been published: 10.1016/j.biopsych.2020.06.032.

Background: \ud Numerous behavioral studies have highlighted the contribution of visual perceptual deficits to the nonverbal cognitive profile of individuals with 22q11.2 deletion syndrome. However, the neurobiological processes underlying these widespread behavioral alterations are yet to be fully understood. Thus, in this paper, we investigated the role of neural oscillations toward visuoperceptual deficits to elucidate the neurobiology of sensory impairments in deletion carriers.\ud \ud Methods: \ud We acquired 125 high-density electroencephalography recordings during a visual grating task in a group of 62 deletion carriers and 63 control subjects. Stimulus-elicited oscillatory responses were analyzed with 1) time-frequency analysis using wavelets decomposition at sensor and source level, 2) intertrial phase coherence, and 3) Granger causality connectivity in source space. Additional analyses examined the development of neural oscillations across age bins.\ud \ud Results: \ud Deletion carriers had decreased theta-band (4–8 Hz) and gamma-band (58–68 Hz) spectral power compared with control subjects in response to the visual stimuli, with an absence of age-related increase of theta- and gamma-band responses. Moreover, adult deletion carriers had decreased gamma- and theta-band responses but increased alpha/beta desynchronization (10–25 Hz) that correlated with behavioral performance. Granger causality estimates reflected an increased frontal-occipital connectivity in the beta range (22–40 Hz).\ud \ud Conclusions: \ud Deletion carriers exhibited decreased theta- and gamma-band responses to visual stimuli, while alpha/beta desynchronization was preserved. Overall, the lack of age-related changes in deletion carriers implicates developmental impairments in circuit mechanisms underlying neural oscillations. The dissociation between the maturation of theta/gamma- and alpha/beta-band responses may indicate a selective impairment in supragranular cortical layers, leading to compensatory top-down connectivity.

Traumatic brain injury (TBI) is associated with a host of psychiatric and neurobehavioral problems. As mortality rates have declined for severe TBI, attention has turned to the cognitive, affective, and behavioral sequelae of injuries across the severity spectrum, which are often more disabling than residual physical effects. Moderate and severe TBI can cause personality changes including impulsivity, severe irritability, affective instability, and apathy. Mild TBI, once considered a largely benign phenomenon, is now known to be associated with a range of affective symptoms, with suicidality, and with worsening or new onset of several psychiatric disorders including posttraumatic stress disorder (PTSD) and major depressive disorder. Repetitive head impacts, often in athletic contexts, are now believed to be associated with a number of emotional and behavioral sequelae. The nature and etiology of mental health manifestations of TBI (including a combination of brain dysfunction and psychological trauma and interrelationships between cognitive, affective, and physical symptoms) are complex and have been a focus of recent epidemiologic and mechanistic studies. This paper will review the epidemiology of psychiatric and neurobehavioral problems after TBI in military, civilian, and athletic contexts.

Background: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age. Methods: Individual participant data for 11,870 mother-child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method. Results: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95-0.99; OR 0.97, 95% CI, 0.94-0.99; OR 0.97, 95% CI, 0.95-0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03-1.11; OR 1.07, 95% CI, 1.02-1.13; OR 1.07, 95% CI, 1.01-1.13, respectively. Conclusions: Our findings suggest that a maternal low-quality and proinflammatory diet may increase the risk of emotional and behavioral symptoms in children. This work was supported by an award from the European Union’s Horizon 2020 research and innovation programme under the ERA-Net Cofund of the Joint Programming Initiative Healthy Diet for Healthy Life (JPI-HDHL) (http://www.healthydietforhealthylife.eu) action number 696295 (Biomarkers for Nutrition and Health). Cofunding was provided by Science Foundation Ireland, Ireland (Grant No. SFI/16/ERA-HDHL/3360 [to CMP]), the UK Biotechnology and Biological Sciences Research Council (ERA-HDHL Biomarkers: BBSRC BB/P028187/1 [to CR]), the Polish National Centre for Research and Development (ERA-HDHL/01/ALPHABET/1/2017 [to KP]), the ZonMw The Netherlands (Grant No. 529051014; 2017) ALPHABET project (Grant No. 696295; 2017 [to LD]) and the French National Agency of Research (reference AnrR16227KK [to BH]). ALSPAC: This work was supported by the UK Medical Research Council and Wellcome (Grant No. 102215/2/13/2) and the University of Bristol. This publication is the work of the authors and Matthew Suderman will serve as guarantors for the contents of this paper. EDEN: This work was supported by the Foundation for Medical Research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR Cohorte Santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale, a complementary health insurance (MGEN), French National Agency for Food Security, French-speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM). Generation R: This work was supported by the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. Dr Liesbeth Duijts received funding from the European Union's Horizon 2020 cofunded programme ERA-Net on Biomarkers for Nutrition and Health (ERA HDHL) (ALPHABET project (Grant No. 696295; 2017), ZonMW The Netherlands (Grant No. 529051014; 2017). Dr. Hanan El Marroun was supported by Stichting Volksbond Rotterdam, the Dutch Brain Foundation (De Hersenstichting, project number GH2016.2.01), and NARSAD Young Investigator Grant No. 27853 from the Brain & Behavior Research Foundation. The project received funding from the European Union’s Horizon 2020 Research and Innovation Programme (LIFECYCLE project, Grant No. 733206; 2016). REPRO_PL: This work was supported by the Ministry of Science and Higher Education, Poland (PBZ-MEiN-/8/2//2006; Contract No. K140/P01/2007/1.3.1.1); by the grant PNRF-218-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund, National Science Centre under the call of JPI HDHL Nutrition and Cognitive Function (2015/17/Z/NZ7/04273), and the National Science Centre, Poland (DEC-2014/15/B/NZ7/00998). Mònica Guxens (CPII18/00018) and Maribel Casas (CP16/00128) are funded by a Miguel Servet fellowship (from the Spanish Institute of Health Carlos III). We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Programme.

BACKGROUND: Research documents bidirectional pathways linking peripheral inflammation and neural circuitries subserving emotion processing and regulation. To extend this work, this paper presents results from two independent studies examining the relationship between inflammation and resting state functional connectivity (rsFC), as measured by fMRI. METHODS: Study 1 involved 90 rural African-American young adults, age 25 years (52% female), and Study 2 involved 82 urban African-American youth, ages 13–14 (66% female). Both studies measured circulating inflammatory biomarkers (CRP, IL6, IL10, TNFα), which were averaged to form a composite. Study 2 also enumerated classical monocytes, a key leukocyte sub-population involved in immune-to-brain signaling. All participants completed a resting state fMRI scan. RESULTS: Consistent with prediction, higher scores on the inflammatory composite were associated with lower rsFC within an emotion regulation network in Study 1, controlling for sex. Study 2 replicated Study 1, showing that higher scores on the inflammatory composite were associated with lower rsFC within the emotion regulation network, controlling for sex, age and pubertal status, and found a similar pattern for rsFC within a central executive network. Study 2 also found that higher numbers of classical monocytes were associated with lower rsFC within both the emotion regulation and central executive networks. There was no relationship between rsFC in the anterior salience or default mode networks with inflammation in either study. CONCLUSIONS: These findings document relationships between peripheral inflammation and rsFC within an emotion regulation and central executive network, and replicate these associations with the emotion regulation network across two independent samples.

This paper proposes a heuristic framework for an Addictions Neuroclinical Assessment (ANA) that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (AD) are presently diagnosed, and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of AD, challenges to current classification systems, and prior attempts to subtype individuals with AD are described. Complementary initiatives, including the Research Domain Criteria (RDoC) project, which have established frameworks for the neuroscience of psychiatric disorders, are discussed. Three domains, executive function, incentive salience, and negative emotionality, tied to different phases in the cycle of addiction, form the core functional elements of AD. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of AD on the basis of process and etiology, an advance that can lead to improved prevention and treatment.

In their recent paper, “Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking,” Polter and colleagues showed that cold-water swim stress exposure blocks LTP of GABAergic synaptic input recorded in ventral tegmental area (VTA) dopamine neurons of male Sprague-Dawley rats (1). The effects of stress exposure on LTPGABA were blocked by pretreatment with the glucocorticoid antagonist RU-486 or the kappa opioid receptor (KOR) antagonist norbinaltorphimine (norBNI). Importantly, norBNI given 4 days after stress exposure could reverse the effects of swim-stress on LTPGABA and block stress-induced reinstatement of cocaine self-administration. Because stress-exposure is such a well-recognized risk factor for the development of compulsive drug abuse and relapse during intervals of abstinence, the demonstration that norBNI given after stress exposure could promote stress-resilience and reverse the adverse effects of prior stress exposure are important preclinical advances in the development of addiction therapeutics. The Polter study also increases our understanding of the complex effects of stress on the reward circuitry controlling addictive drug effects. Multiple synaptic inputs converge on the VTA dopaminergic neurons to regulate their excitability, and these neurons, in turn, project broadly to critical targets in the brain to coordinate the drug seeking behaviors initiated by addictive drugs (2) (Figure 1). Understanding this circuit and defining the effects of stress-mediators on the functioning of these neurons seems vital in the development of novel treatments for addiction, which has appropriately been described as a ‘stress-surfeit’ disorder by Koob and colleagues (3). The intimate relationship between stress vulnerability and addiction risk was summarized there and in other reviews on this topic, and the reciprocal concepts that stress exposure increases addiction risk and that addictive drug exposure increases stress vulnerability have now been supported by an extensive literature. Breaking this cycle by blocking the actions of the stress-mediators holds great promise, but understanding how these antagonists act on the reward circuit requires the kind of high-resolution circuit analysis described by Polter and colleagues (1). Figure 1 The ventral tegmental area (VTA) is a key player in the brain’s reward system, and the stress-mediators CRF, corticosterone, and dynorphin have dramatic effects on the neurophysiology of this brain region. Some of the principal actions of dynorphin ... Stress exposure produces adaptive physiological responses vital for the individual’s survival. As such, some mildly stressful experiences can be perceived as ‘exciting’ and positive when controlled by the individual, but persistent uncontrolled stressful experiences are aversive and can cause lasting changes in the reward circuitry (4). Corticotrophin releasing factor (CRF) orchestrates the classically recognized stress response by activating the hypothalamic-pituitary-adrenal glucocorticoid response, but CRF also acts intracerebrally to produce some of the cognitive and emotional responses to stress. These can be adaptive by promoting escape behaviors, but can be maladaptive when promoting mood and cognitive disorders. The mechanisms of these maladaptive responses are being actively studied by many research groups, but a key role of CRF-induced activation of the endogenous dynorphin opioid peptides and their cognate kappa opioid receptors has been implicated as essential mediators of these adverse responses (5). Dynorphins have been shown to encode the dysphoric effects of stress (6); stress-induced release of dynorphins potentiates the rewarding effects of drugs of abuse including cocaine, ethanol, and nicotine (7); and the dynorphins mediate stress-induced reinstatement of drug seeking behaviors (5). Mice lacking the prodynorphin or KOR genes or pretreated with the KOR antagonists norBNI or JDtic demonstrate stress-resilience in assays of anxiety-like, aversion, and reinstatement behaviors (5). This preclinical research suggests that KOR antagonists may have therapeutic potential, and results from early clinical studies support this conception (8). Nevertheless, understanding of how dynorphin acts in brain to increase addiction and mood disorder risk is still incomplete. Kappa opioid regulation of serotonergic inputs from dorsal raphe to nucleus accumbens (NAc) has been described (9). Dynorphin released during stress exposure within the NAc (presumably by prodynorphin-expressing medium spiny neurons) activates KOR expressed on serotonergic nerve terminals; KOR stimulation activates p38 MAPK to increase cell surface expression of the serotonin transporter SERT; and the resulting transient hyposerotonergic state in the NAc is necessary for stress-induced aversion, social avoidance and reinstatement of extinguished cocaine place preference (9). The Kauer lab has previously demonstrated that stress can block long-term potentiation of GABAergic inputs onto dopamine neurons (10). They further demonstrated that this effect of stress requires KOR activation, as it is blocked by pretreatment with either the mixed opiate antagonist naloxone or the selective KOR antagonist norBNI. Intriguingly, they also showed that selective injection of norBNI into the VTA attenuates stress-induced reinstatement to cocaine self-administration. This suggests that the potentiation of GABAergic signaling onto dopaminergic neurons may play a key role in reinstatement of cocaine-seeking behavior. In this issue, Polter et al follow-up on that observation by probing the duration of stress-induced blockade of LTPGABA (1). They find that stress blocks LTPGABA at 1 and 5, but not 10 days after exposure to a single cold water forced swim. They further find that norBNI administered after stress still blocks its effects on GABAergic signaling, whether administered at 2 hr, 24 hr, or 4 days after stress exposure. This is independent of any effect on glucocorticoid signaling, as the authors confirmed results reported previously showing that norBNI pretreatment fails to alter serum corticosterone after stress exposure. Further, although the glucocorticoid receptor antagonist RU-486 can also block the effects of stress on LTPGABA induction, it only does so if administered within one hour of stress exposure. But most dramatically, they demonstrate that after extinction of cocaine self-administration, norBNI can block stress-induced reinstatement of cocaine-seeking even if administered subsequent to stress. These two results combined strongly suggest that in cocaine-experienced animals, a single stress exposure can induce a long-lasting state of dynorphin release and/or KOR activation that can mediate substantial alterations to behavior. Future studies are needed to further define the key elements of this neural circuit and the sites of stress-induced regulation. The Polter et al study used systemic norBNI administration, and subsequent studies using cell-specific activation and inactivation methods will be revealing. For instance, it has also been demonstrated that KOR activation in the dorsal raphe nucleus is required for stress-induced reinstatement of place preference for cocaine (6). KOR-induced activation of p38 MAPK is also required for CPP reinstatement, an effect that may be mediated specifically by KORs located on serotonergic terminals within the nucleus accumbens (9). If stress acts by inducing a long-lasting state of ongoing dynorphin release, it is also possible that the effect may be mediated by inhibition of dopamine release via action at terminals in the nucleus accumbens, medial prefrontal cortex or even via direct inhibition of dopamine neurons in the VTA. The development of better treatments for drug use relapse and its exacerbation by stress after prolonged abstinence from drug abuse in vulnerable individuals is urgently needed. Addictive disorders may have well documented pathologies, but the specific role of dynorphin in the human syndromes remains poorly defined. Kappa antagonists developed for human use will hopefully have beneficial effects in stress-vulnerable individuals, but a better understanding of dynorphin’s functions seems essential if we are to properly anticipate the range of beneficial and possibly adverse consequences that a KOR antagonist might clinically produce.

Suicide is a major public health problem as about 40,000 people die by suicide in the U.S. annually. Prevention and treatment of suicidal behavior is therefore very important. The major problem in the prevention of suicide is early identification and treatment of suicide-prone patients. Suicide is a multifactorial problem involving clinical, genetic and neurobiological risk factors. The identification of risk factors that could accurately predict completed suicide has been therefore investigated by many researchers. An important risk factor for completed suicide is a history of previous suicide attempts and presence of suicidal ideation, and these have been suggested as major predictors of subsequent suicide attempt or suicide. Since clinical risk factors by themselves are not strong predictors of suicide, a combination of clinical and neurobiological risk factors may improve the ability to predict suicide. In that context, several biological markers have been studied in suicidal behavior. These include 5-hydroxytryptamine (5HT)2A receptors, 5-hydroxyindoleacetic acid (5HIAA), serotonin transporter (5HTT) and the dexamethasone suppression test (DST; an index of hypothalamic pituitary adrenal [HPA] axis function), for prediction of suicidal behavior or completed suicide (1). Several studies suggest dysregulation of the immune system and cytokines in suicidal behavior. Steiner et al. (2) found increased microgliosis in the postmortem brain of suicide victims with affective disorders and schizophrenia compared with normal control subjects. Some investigators observed that the administration of proinflammatory cytokines like interferon (IFN)-α to cancer patients causes symptoms known as sickness behavior. These symptoms appear to be similar to depression, psychosis, mania and sometimes suicidal behavior. A review of IFN-α treatment of chronic hepatitis-C patients (3) showed the emergence of suicidal ideation and attempts during IFN-α treatment also suggesting that cytokines may be involved in suicide. In order to examine if cytokine dysregulation is associated with suicide, several investigators determined cytokines and chemokines levels in plasma, cerebrospinal fluid (CSF), and postmortem brain of suicidal patients. In general, these studies indicate abnormalities of several cytokines in suicide. However, single studies do not provide adequate evidence either about their role in suicide or as potential risk factors for suicide, as they are generally of low power. Meta-analysis is an important tool to clarify these findings and improve the strength of evidence, taking into account the sources of heterogeneity among various studies. The accompanying paper by Black and Miller (4), who performed a meta-analysis of these studies to examine if any of the cytokines or chemokines were abnormally expressed in suicidal patients compared to non-suicidal patients or normal controls, is therefore important in identifying the role of cytokines in suicide and their potential as biomarkers. The cytokines have been widely studied in mood disorders, schizophrenia and alcohol abuse, but there are not many studies of cytokines in suicidal patients. The cytokines in suicide have been studied in plasma, CSF and postmortem brain. In addition, in vivo studies of cytokines have also been conducted. In order to examine if alterations in cytokine levels are specific and/or are risk factors for suicide the comparisons of cytokine levels between suicidal patients, non-suicidal patients and normal controls were performed. Using these criteria in the meta-analysis performed by Black and Miller (4) some important findings emerged. The most significant observation of cytokine abnormalities was that interleukin (IL)-1β was higher in suicidal patients compared with non-suicidal patients. IL-6, but not tumor necrosis factor (TNF)-α, was higher only after the removal of one study. A different pattern emerged when they (4) compared the suicidal patients against normal controls. In this case, they found that the blood levels of IL-6, IL-10, and C-reactive protein (CRP) were significantly increased in suicidal patients compared with normal controls. No differences were observed in the levels of IL-1β and TNF-α between suicidal patients and normal controls. The results of the comparison between suicidal patients and normal controls are thus intriguing as they are not consistent with the results obtained by comparing suicidal and non-suicidal patients and raise the possibility that observed differences between suicidal patients and normal controls may be related to diagnosis, rather than to suicide. Since different diagnoses may have different risks of suicidal ideation and attempt (5), it will be important to examine the effect of diagnosis in these cases, as they rightly pointed that out (4). IL-2 may be another cytokine with a potential of distinguishing suicidal patients vs. non-suicidal patients as in this meta-analysis a decrease in IL-2 (in vitro) was observed in suicidal patients compared to both non-suicidal patients and controls. Also, an interesting observation by Black and Miller (4) was that the in vivo blood levels of these cytokines distinguished psychiatric suicidal patients from both psychiatric patients without suicidality and also from normal controls. Another reason for this robust finding was that relatively more studies were available for the meta-analysis as opposed to single or fewer studies for other cytokines. The role of chemokines in suicide is less clear as there were only a few studies of chemokines in suicidal patients. An issue is the suitability of peripheral cytokine measures as a function of CNS cytokines. To address this issue levels of cytokines have been studied in the CSF and postmortem brain of suicides. Although these are only single studies available for this meta-analysis, they suggest similar changes in postmortem brain of suicide subjects at least for IL-6. Most of the studies in CSF, postmortem brain or in vitro were either single studies or few studies for a meaningful analysis. Nonetheless, several of these studies in CSF and postmortem brain show differences between suicidal subjects compared to non-suicidal patients or normal controls for IL-1β, IL-6, TNF-α and IL-8. The studies in postmortem brain and CSF suggest that peripheral cytokines may be a good measure of cytokine levels in the brain. Although cytokines are also synthesized in the brain, bidirectional movements of cytokines between periphery and the CNS through several mechanisms have been suggested. Thus, peripheral cytokines could not only be suitable biomarkers for suicide, but may also mirror similar changes in the brain.

Cotard syndrome is a fascinating entity, in which the patient lingers under extreme nihilistic delusions. While its etiology is still unclear, modern imaging techniques have revealed interesting possibilities regarding the role of insular cortex in mediating interoception and selfperception. Our paper reports development of Cotard syndrome in a 65-years old female suffering from symptoms of dementia and depression, who’s subsequent MRI revealed atrophy of bilateral insular cortices. We propose that etiology of Cotard syndrome in this case may be a reduction in her ability to validate internal perception against external information and subsequent coloring of anomalous perceptions by depressive cognitions.