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. 2014 Sep 11;36(1):213–225. doi: 10.1002/hbm.22624

Illness denial in schizophrenia spectrum disorders

A function of left hemisphere dominance

Philip Gerretsen 1,2, Mahesh Menon 1,3, M Mallar Chakravarty 2,4,5,6, Jason P Lerch 7,8, David C Mamo 1,2,9, Gary Remington 2,4, Bruce G Pollock 2,4, Ariel Graff‐Guerrero 1,2,4,✉
PMCID: PMC4268179  NIHMSID: NIHMS624188  PMID: 25209949

Abstract

Impaired illness awareness or anosognosia is a common, but poorly understood feature of schizophrenia that contributes to medication nonadherence and poor treatment outcomes. Here we present a functional imaging study to measure brain activity at the moment of illness denial. To accomplish this, participants with schizophrenia (n = 18) with varying degrees of illness awareness were confronted with their illness beliefs while undergoing functional MRI. To link structure with function, we explored the relationships among impaired illness awareness and brain activity during the illness denial task with cortical thickness. Impaired illness awareness was associated with increased brain activity in the left temporoparieto‐occipital junction (TPO) and left medial prefrontal cortex (mPFC) at the moment of illness denial. Brain activity in the left mPFC appeared to be a function of participants' degree of self‐reflectiveness, while the activity in the left TPO was associated with cortical thinning in this region and more specific to illness denial. Participants with impaired illness awareness had slower response times to illness related stimuli than those with good illness awareness. Increased left hemisphere brain activity in association with illness denial is consistent with the literature in other neuropsychiatric conditions attributing anosognosia or impaired illness awareness to left hemisphere dominance. The TPO and mPFC may represent putative targets for noninvasive treatment interventions, such as transcranial magnetic or direct current stimulation. Hum Brain Mapp, 36:391–414, 2015. © 2014 Wiley Periodicals, Inc.

Keywords: anosognosia, insight, cognitive insight, illness awareness, denial, functional MRI, cortical thickness

INTRODUCTION

Illness denial or impaired illness awareness is common among persons with schizophrenia [Jablensky et al., 1992] with close to 60% experiencing moderate to severe impaired illness awareness [Buckley et al., 2007]. Impaired illness awareness in schizophrenia contributes significantly to the illness' morbidity, leading to medication nonadherence and poor treatment outcomes [Amador et al., 1994; Buckley et al., 2007; Jablensky et al., 1992; Olfson et al., 2006].

The constructs of “denial” and “lack of illness awareness” represent two sides of the same coin [David, 1990]. The former implies an active psychological process, whereas the latter suggests a neurological deficit. Freud [1925] postulated that denial was a defense mechanism to prevent intolerable ideas or memories from gaining access to conscious awareness. Earlier, the renowned French neurologist Babinski [1914] coined the term anosognosia, which literally means lacking knowledge (gnosis) of disease (nosos). Although the neural mechanisms of illness denial are not understood [David, 1990], its counterpart anosognosia is commonly associated with right cerebral hemisphere damage secondary to stroke, neurodegeneration or brain injury [Orfei et al., 2008], particularly within the prefrontal and parietotemporal cortex [Orfei et al., 2007]. In cases of anosognosia secondary to stroke, patients are not only unaware of their condition but also when confronted with their deficits they deny their hemiparesis, confabulate, and may experience somatoparaphrenia—the delusional attribution of the paralyzed limb to someone else, such as the doctor, nurse, or family member.

Anosognosia in the context of right hemisphere brain lesions is thought to arise from interhemispheric rivalry. According to this theory, impaired illness awareness is attributable to left hemisphere dominance stemming from either right hemisphere dysfunction (e.g., stroke, dementia, or traumatic brain injury) or left hemisphere hyperactivity, serving as a model for understanding impaired insight in other neuropsychiatric disorders, such as schizophrenia [Ramachandran, 1995; Ramachandran et al., 2007; Shad et al., 2007]. Anosognosia in the absence of gross anatomical lesions, as in individuals with schizophrenia spectrum disorders, provides an opportunity to explore the functional neuroanatomy of illness denial especially given that anosognosia in schizophrenia has also been associated with volumetric reductions within right frontotemporoparietal regions [Flashman et al., 2001; Gerretsen et al., 2013; Shad et al., 2004, 2006, 2007]. A recent analysis of hemispheric asymmetry by our group found relatively reduced right hemisphere (or relatively increased left hemisphere) volume, specifically within the angular gyrus, medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DLPFC), insula, and anterior temporal lobe, in relation to impaired illness awareness in schizophrenia [Gerretsen et al., 2013].

As such, we aimed to test the hypothesis that illness denial would be characterized by a lateralized activity pattern, with the left hemisphere showing increased brain activity relative to the right in individuals with schizophrenia spectrum disorders. To accomplish this, we recruited participants with varying degrees of illness awareness and confronted them with their illness beliefs during fMRI. Based on the neurological literature, our structural imaging findings, and the volumetric studies in schizophrenia that used a region of interest approach, we expected to observe relatively increased brain activity, as measure by the BOLD response, in left versus right hemisphere in the mPFC, DLPFC, anterior temporal lobe, insula, and temporoparieto‐occipital junction (TPO) at the moment of illness denial.

In attempts to link structure with function, we had the additional aim of exploring the relationship among cortical thickness (CT), impaired illness awareness and brain activity during illness denial. To our knowledge, only one prior study has reported on the relationship between CT and impaired insight in a sample of patients with first episode psychosis, in which investigators found an association between impaired insight and cortical thinning in the left middle frontal and inferior temporal gyrus [Buchy et al., 2011].

METHOD

Participants

Participants with diagnoses of schizophrenia or schizoaffective disorder with varying degrees of illness awareness were recruited from the Schizophrenia Program at the Centre for Addiction & Mental Health (CAMH). Written informed consent was obtained after full explanation of the study procedures and risks. Capacity to consent was confirmed for all participants with the MacArthur Test of Competence [Appelbaum and Grisso, 1995]. An assessment of psychiatric disorders was performed using the MINI‐Plus structured interview [Sheehan et al., 1998]. Inclusion criteria for patients were as follows: (i) age 18–65; (ii) fluency in English; (iii) DSM‐IV diagnosis of schizophrenia or schizoaffective disorder; (iv) outpatients or inpatients with voluntary status; (v) able to undergo fMRI of approximately 50 min duration; and (vi) right handed. Handedness was assessed using the Edinburgh Handedness Inventory [Dragovic, 2004]. Exclusion criteria included: (i) serious, unstable medical illness, or any concomitant major medical or neurological illness; (ii) acute suicidal and/or homicidal ideation; (iii) DSM‐IV substance dependence (except caffeine and nicotine) within 3 months; (iv) current major depressive or manic episode; (v) metal implants, cardiac pacemaker, claustrophobia, or other limitations to participating in the MRI component of the study; and (vi) illegal psychoactive drug use in the last 2 weeks; (vii) severe head injury resulting in a loss of consciousness over 30 min; and, (viii) Scale for the Assessment of Positive Symptoms (SAPS) formal thought disorder rating of >2. Urine toxicology screens were done as part of the initial assessment. Those with good illness awareness were defined as having a Schedule for the Assessment of Insight—Expanded version (SAI‐E) score ≥20 (representing mild insight impairment) and those with impaired illness awareness an SAI‐E score <20 (representing moderate‐to‐severe insight impairment) [Kemp and David, 1997]. The study was approved by the Research Ethics Board of CAMH.

Study Measures

Illness awareness was measured using the SAI‐E [Kemp and David, 1997]. The SAPS and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia [Andreasen et al., 1995]. The Wide Range Achievement Test (WRAT‐3) reading subtest was used to measure Premorbid IQ [Wilkenson and Jastak, 1993]. Cognitive insight was evaluated with the Beck Cognitive Insight Scale (BCIS), which provides subscale scores for the concepts self‐reflectiveness and self‐certainty [Beck et al., 2004].

Statistical Analyses

Statistical analyses of clinical, demographic, and behavioral variables were carried out with PASW software (version 18.0). Means and standard deviations were calculated for the demographic and clinical data. Bivariate Pearson correlations were performed between illness awareness (SAI‐E) scores and relevant demographic and clinical variables. Independent t‐tests were used for group analyses. The significance level for tests was established at P ≤ 0.05.

Illness Denial Task

During scanning participants undertook an fMRI paradigm that confronted participants with their illness beliefs (Supporting Information Fig. 1). The paradigm was developed from previous paradigms that have explored the neuroanatomy of self‐relevance, and it involves the same procedure of a recently published paper by our group exploring the neural correlates of delusions of self‐reference [Menon et al., 2011; Schmitz et al., 2004]. The paradigm consisted of a bank of brief questions to which participants were to respond either “yes”/agree, or “no”/disagree. The brief statements are derived from four categories: illness awareness, symptom awareness, awareness of need for treatment, and illness independent/neutral. The symptom‐specific statements themselves were, in turn, derived from the participant's own experiences identified during the standardized assessment of his or her illness awareness with the SAI‐E; hence, the paradigm is intentionally tailored to the content of each participant's illness experience. On average ∼75% of the paradigm (i.e., neutral, general illness awareness and need for treatment awareness items) was common across all participants, whereas the symptom awareness items (25%) were individually specific, consisting of two distinct delusions and one hallucination (or three delusions if the participant had never had hallucinations).

Figure 1.

Figure 1

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Association with impaired illness awareness (i.e., negative association with SAI‐E scores) and brain activations for the contrasts: (A) General illness awareness > neutral, (B) Symptom awareness > neutral; (C) Awareness of Need for Treatment > neutral. Association with good illness awareness (i.e., positive association with SAI‐E scores) and brain activations for the contrasts: (D) General illness awareness > neutral (E) Symptom awareness > neutral; (F) Awareness of Need for Treatment > neutral. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Stimuli were presented using E‐Prime software (Psychology Software Tools, Pittsburgh, PA). Each statement was presented for 4 s, with a variable interstimulus interval of 2 s on average, where participants saw a fixation cross. Participants could respond up to 5 s following the presentation of the stimulus.

Following the task, participants were presented with the stimuli again to ensure the selections made in the scanner were consistent with their beliefs about their illness experiences.

MRI Data Acquisition

MRI scans were performed using a GE Signa 1.5 T scanner (General Electric, Waukesha, WI) equipped with standard head coils. An adjustable mirror located above the participant's eyes was used to view the back‐projected images on a screen placed at the foot of the scanner bed. In each functional imaging session, 217 volumes (28 contiguous axial 4.4‐mm‐thick slices) covering the whole brain were acquired using a T2*‐sensitive spiral sequence (TR = 2,300 ms; TE = 40 ms; flip angle 85°; matrix 64 × 64; FOV 200 × 200 mm). The first three volumes were discarded to allow for T1 equilibrium effects, and the data from the remaining 214 volumes were used in the analysis.

T1‐weighted IR‐Prepped 3D FSPGR anatomical images (120 contiguous axial 1.1‐mm‐thick slices) were acquired (TR = 12 ms; TE = 5.4 ms; flip angle 20°; matrix 256 × 256; FOV 200 × 200 mm) to assess brain structure.

Image Preprocessing

Functional Images

The data were preprocessed and analyzed using SPM8 (The Wellcome Department of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm/software/spm8). The functional images were realigned to the first volume using a six‐parameter rigid body transformation, and a mean image was created. Data from participants who showed movement of greater than two voxels on any axis were discarded. The mean image generated was spatially normalized into standard stereotactic space, using the Montreal Neurological Institute (MNI) echo planar imaging (EPI) template. Computed transformation parameters were applied to all functional images, interpolated to isotropic voxels of 3 mm3 and the resulting images were smoothed using an 8‐mm full‐width half‐maximum, isotropic Gaussian kernel.

Cortical Thickness Analyses

The CIVET processing pipeline was used to estimate CT (version 1.1.10; Montreal Neurological Institute). The T1‐weighted images were linearly aligned to the ICBM 152 average template using a nine‐parameter transformation (3 translations, rotations, and scales) [Collins et al., 1994] and preprocessed to minimize the effects of intensity nonuniformity [Sled et al., 1998]. Images were then classified into gray matter, white matter, and cerebrospinal fluid [Zijdenbos et al., 2002]. The hemispheres were then modeled as gray and white matter surfaces using a deformable model strategy that generates four separate surfaces each defined by 40,962 vertices [Kim et al., 2005]. CT was determined in native space through nonlinear surface‐based normalization that uses a midsurface between pial and white matter (WM) surfaces [Robbins et al., 2004]. Images were the smoothed with a 20‐mm surface‐based diffusion kernel and nonlinearly registered to a minimally biased surface‐based template [Boucher et al., 2009; Lyttelton et al., 2007]. Native‐space thicknesses were used in all analyses as normalizing for head or brain volume has little relationship to CT and risks introducing noise into the analyses [Ad‐Dab'bagh, et al., 2005; Sowell et al., 2007].

Functional Imaging Analysis

Whole Brain Analysis

A random‐effects analysis of the data was performed, first by creating first level contrasts for each participant's data between illness awareness stimuli (general illness awareness, symptom awareness, and awareness need for treatment) and neutral/illness‐independent items. These contrast images were then used for second level analyses—total illness awareness (general awareness + symptom awareness + awareness of need for treatment) > neutral, general illness awareness > neutral, symptom awareness > neutral, and awareness of need for treatment > neutral. We carried out both regression analyses using participants' illness awareness scores (SAI‐E score) as the covariate of interest and two sample t‐tests to assess for group differences (i.e., impaired illness awareness vs. good illness awareness).

As the a priori hypothesis was specific to the mPFC, DLPFC, insula, anterior temporal lobe, and TPO, we confined the statistical search to these regions of interest. The threshold for these a priori regions was set at P ≤ 0.001 level of significance (t > 3.69). A cluster was reported as significant if it was ≥20 voxels in size and the peak survived a familywise error (FWE) correction for multiple comparisons of P ≤ 0.05 [Friston et al., 1996].

As illness awareness may be influenced by hemisphere lateralization, participants' degree of right handedness, as measured by the Edinburgh Handedness Inventory, was included as a covariate in both the group and regression analyses.

Region of Interest analyses

To compare the brain activity between hemispheres within regions of interest in those with impaired and good illness awareness, we extracted the mean beta value from each region of interest and as a whole in each hemisphere. This was carried out using the REX toolbox (http://web.mit.edu/swg/software.htm) available for SPM. Paired t‐tests were then performed between regions of interest in each hemisphere both as a whole and then separately to assess for mean differences in activation.

Structural Imaging Analysis

Cortical Thickness Whole Brain Analysis

All vertexwise analyses were performed with the RMINC package (https://github.com/mcvaneede/RMINC). Using a general linear model, separate CT regression analyses were carried out using SAI‐E scores, peak left TPO activity and peak left mPFC activity from the illness denial task as the variables of interest, including age and gender as control variables. Analyses were corrected for multiple comparisons using a false discovery rate (FDR < 0.10) [Genovese et al., 2002].

Cortical Thickness Region of Interest Analysis

The mean CT was generated for the angular gyrus and medial orbitofrontal cortex regions of interest (ROI) (the regions that corresponded to the areas that showed the peak brain activity during the illness denial task) from the LONI Probabalistic Brain Atlas (LPBA40; http://www.loni.usc.edu/atlases/) in each hemisphere after resampling the atlas to fit to each subjects unique surface representation. Separate partial correlations were performed for SAI‐E scores and peak brain activity in the left TPO and left mPFC with the CT ROIs, controlling for age and gender. The significance level for tests was established at P ≤ 0.05. Bonferroni corrections for multiple comparisons were applied.

RESULTS

Demographic and Clinical Data

Data for three participants could not be used due to excess head motion. The final sample consisted of 18 patients. The demographic and clinical data are presented in Table 1. Differences were found between those with impaired and good illness awareness for SAI‐E scores (t = 9.41, P < 0.001) and for the Average SAPS score (t = 3.66, P < 0.002). SAI‐E scores were inversely correlated with Average SAPS scores (r = −0.731, P = 0.001), suggesting a strong association between active psychosis and impaired illness awareness. Although strongly correlated and different between groups, the positive symptom severity (SAPS Average Score) was in the absent‐to‐mild range for both those with impaired and good illness awareness. There was also a strong positive association between BCIS self‐reflectiveness and SAI‐E scores (r = 0.682, P = 0.002) and group differences in self‐reflectiveness (t = 3.58, P = 0.003). All patients were on antipsychotic medication (clozapine = 3; risperidone = 6; risperidone IM = 1; quetiapine = 3; olanzapine = 3; aripiprazole = 3; loxapine = 1; zuclopenthixol decanoate = 1; haldol decanoate = 1; mean chlorpromazine (CPZ) equivalent dose = 346.8 mg, SD = 211.1) [Atkins et al., 1997; Woods, 2003].

Table 1.

Demographic and clinical characteristics

Total sample SAI‐E Sig. Impaired awarenessc Good awarenessc Impaired v. good Sig.
Mean (SD) Score P Mean (SD) Mean (SD) t‐Value P
N 18 9 9 0.000, df = 1d 1.000
Male:female 11:7 4:5 7:2 2.104, df = 1d 0.147
Schizophrenia:schizoaffective 10:8 5:4 5:4 0.000, df = 1d 1.000
Mean (SD) r
Age, range 41.7 (12.2), 18–65 −0.329 0.182 45.8 (10.3), 30–65 37.7 (12.5), 18–56 1.50 0.153
Age of illness onset 25.5 (7.9) −0.197 0.433 26.4 (7.6) 22.1 (6.6) 1.29 0.214
Duration (years) of Illness 18.9 (13.6) −0.208 0.408 19.3 (12.7) 15.6 (11.5) 0.661 0.518
Antipsychotic CPZ equivalents 346.8 (211.1) −0.328 0.184 408.3 (230.4) 285.2 (181.7) 1.259 0.227
Test score
IQ (WRAT‐3) 107.5 (5.1) 0.251 0.314 107.6 (7.4) 112.3 (6.4) −1.47 0.162
Degree of Right Handednessd 88.0 (17.6) −0.255 0.306 92.2 (17.2) 83.8 (17.9) 1.025 0.321
SAI‐E score (max = 28), range 18.6 (7.5), 8.5–28 1.000 – 12 (3.2) 25.3 (2.8) −9.41 <0.001b
SAPS total average score (max = 5) 0.8 (0.7) −0.731 0.001b 1.3 (0.6) 0.3 (0.5) 3.66 0.002a
SANS total average score (max = 5) 1.2 (0.7) 0.342 0.165 1.0 (0.4) 1.4 (0.8) −1.29 0.214
BCIS Composite score 9.5 (7.5) 0.615 0.007a 5.1 (5.1) 13.9 (7.0) −3.03 0.008a
BCIS Self‐reflectiveness 15.6 (4.9) 0.682 0.002a 12.4 (3.7) 18.8 (3.8) −3.58 0.003a
BCIS Self‐certainty 6.1 (3.7) −0.340 0.168 7.3 (3.0) 4.9 (4.1) 1.44 0.169
Condition Response time (s)
Neutral/illness independent 1.79 (0.33) −0.122 0.641 1.87 (0.36) 1.73 (0.31) 0.88 0.395
Total illness‐related stimuli 2.74 (0.51) −0.550 0.022a 3.00 (0.42) 2.5 (0.48) 2.25 0.040a
General illness awareness 2.48 (0.53) −0.635 0.006a 2.83 (0.41) 2.17 (0.42) 3.30 0.005a
Symptom awareness 3.07 (0.51) −0.449 0.071 3.23 (0.42) 2.93 (0.57) 1.24 0.237
Need for treatment awareness 2.67 (0.58) −0.488 0.047a 2.95 (0.53) 2.42 (0.52) 2.05 0.056
General illness minus neutral 0.69 (0.36) −0.820 <0.001b 0.96 (0.21) 0.44 (0.28) 4.41 0.001b
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SCZ, schizophrenia; SCZ‐AFF, schizoaffective disorder; IQ, intelligence quotient; WRAT‐3, Wide Range Achievement Test, 3rd Edition; SAI‐E, Schedule for the Assessment of Insight ‐ Extended Version; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms, BCIS, Beck Cognitive Insight Scale

a

P ≤ 0.05

b

P ≤ 0.001, after Bonferroni correction for multiple comparisons

c

Impaired illness awareness, SAI‐E < 20; Good illness awareness, SAI‐E ≥ 20

d

Pearson's Chi square

Edinburgh handedness inventory

Functional Imaging Results

Whole Brain Analysis

Regression analysis

The results for the contrast total illness awareness (general illness + symptom + need for treatment) > neutral with participants' illness awareness (SAI‐E) scores as the covariate of interest revealed peak brain activity in the left TPO (t = 6.77, P = 0.003 FWE corr.) was negatively associated with SAI‐E scores (i.e., peak brain activity in the left TPO was positively associated with impaired illness awareness; Table 2). This region remained significant even after including positive symptoms (i.e., SAPS average total score) as a covariate (t = 4.74, P = 0.05 FWE corr.), which was anticipated to be strongly associated with impaired illness awareness [Gerretsen et al., 2013; Mohamed et al., 2009]. Intriguingly, activity in the left TPO was of greater significance after including BCIS self‐reflectiveness scores as a covariate (t = 7.13, P = 0.004 FWE corr.) and after including both positive symptom and self‐reflectiveness scores as covariates (t = 6.14, P = 0.017 FWE corr.). Although not an a priori region of interest, activity within the tail of the fornix bilaterally was also significant, even after including positive symptoms as a covariate (left t = 5.75, P < 0.001 uncorr., and right t = 4.51, P < 0.001 uncorr.), but not after including BCIS self‐reflectiveness.

Table 2.

Regional activations for the second‐level contrast Total Illness Awareness > Neutral

Voxels per Cluster maxima P value P value FWE
Brain region BA cluster x y z t Value uncorrected corrected
Regression
Impaired Illness Awareness a
Left TPO 19 47 −42 −80 30 6.77 <0.001 0.003
Good Illness Awareness b
Ventral striatum/mammillary bodies n/a 44 2 16 2 5.08 <0.001 n/a
Group comparison
Impaired Awareness > Good
Left TPO 19 47 −40 −82 32 5.42 <0.001 0.017
Left medial PFC 10 33 −4 50 6 4.40 <0.001 0.043
Good Awareness > Impaired
Ventral striatum/mammillary bodies n/a 37 2 16 2 4.72 <0.001 n/a
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BA, Brodmann area; FWE, Familywise error; TPO, Temporoparietooccipital junction; PFC, Prefrontal cortex

a

Negative correlation with SAI‐E scores

b

Positive correlation with SAI‐E scores

The results of the contrasts general illness awareness > neutral, symptom awareness > neutral and awareness of need for treatment > neutral (Supporting Information Tables 1–3, Fig. 1) with participants' illness awareness (SAI‐E) scores as the covariate of interest revealed similar peak brain activations negatively associated with SAI‐E scores (i.e., peak brain activations were positively associated with impaired illness awareness). Interestingly, the peak frontal activation for the contrast awareness of need for treatment > neutral was more lateralized than for the illness and symptom specific contrasts (Supporting Information Table 3, Fig. 1).

Table 3.

Partial correlationsb for illness awareness (SAI‐E), peak left TPO, and peak left mPFC brain activity during the functional MRI task with cortical thickness in regions of interest.

SAI‐E Left TPO Left mPFC
Brain region r p r p r p
Left angular gyrus 0.67 0.005 −0.87 <0.001 a −0.50 0.047
Left superior frontal gyrus −0.47 0.065 −0.53 0.033 −0.42 0.107
Right angular gyrus 0.46 0.075 −0.57 0.020 −0.57 0.021
Right superior frontal gyrus 0.42 0.108 −0.43 0.095 −0.44 0.091
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SAI‐E, Schedule for the Assessment of Insight—Expanded Version; TPO, Temporoparietooccipital junction; mPFC, medial prefrontal cortex

a

significant at alpha < 0.005, after Bonferroni correction for multiple testing (0.05/12)

b

controlling for age and gender

Group comparison

The results for the comparison between participants with impaired illness awareness versus good illness awareness for the same contrast used in the regression analysis, that is, total illness awareness (general illness + symptom + need for treatment) > neutral revealed a positive association between impaired illness awareness and brain activity in the left mPFC (t = 4.40, P = 0.043 FWE corr.) in addition to the left TPO (t = 5.42, P < 0.017 FWE corr.; Table 2, Figs. 2 and 3). Although activity in the left mPFC and left DLPFC appeared to represent the same cluster at lower thresholds, only the peak activation in the left mPFC survived correction for multiple comparisons within these regions of interest. As in the regression analysis, the significance of the peak activity within these regions increased with the inclusion of BCIS self‐reflectiveness scores as a covariate (mPFC, t = 4.65, P = FWE 0.030 corr.; TPO, t = 5.94, P = 0.017 FWE corr.)

Figure 2.

Figure 2

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Brain activations for the contrast total illness awareness > neutral in those with impaired illness awareness (impaired > good). Significant activations are presented in the PFC (−4, 50, 6) and temporoparieto occipital junction (−40, −82, 32). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3.

Figure 3

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Participants' peak brain activations in the (a) left mPFC and (b) left TPO for the contrast total illness awareness > neutral. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

The results of the contrasts general illness awareness > neutral, symptom awareness > neutral and awareness of need for treatment > neutral for the group comparison revealed similar peak brain activations positively associated with impaired illness awareness, which was in the same direction to that found in the regression analysis (Supporting Information Tables 1–3).

No associations were found in regions of interest in association with good illness awareness, however, a positive relationship between activity within the ventral striatum/mamillary bodies and good illness awareness was a consistent finding in both the regression and group analyses (t = 5.08, P < 0.001 uncorr. and t = 4.72, P < 0.001 uncorr., respectively, Fig. 1). This finding disappeared when including BCIS self‐reflectiveness as a covariate.

Region of Interest Analysis

The mean brain activity within the left DLPFC, mPFC, insula, anterior temporal lobe, and TPO was larger compared to the right in participants with impaired illness awareness (t = 4.35, P = 0.002; Supporting Information Fig. 2A). In specific regions of interest, only the mean brain activity in the left mPFC was larger than the right (t = 4.45, P = 0.02). Trend level differences were found for left greater than right hemisphere activity in the DLPFC (t = 1.63, P = 0.142), insula (t = 2.00, P = 0.08), and TPO (t = 2.16, P = 0.063). No difference was observed between hemispheres in participants with good illness awareness (Supporting Information Fig. 2B).

Behavioral Results

Participants' responses during scanning were highly consistent with their post scan responses (95.1% consistent, 76.1/80 stimuli, SD = 4.2). Similarly, the score generated for the number of correct responses (reflecting illness acceptance) to stimuli during scanning was highly correlated with participants' SAI‐E scores (r = 0.898, P < 0.001), suggesting participants' responses accurately reflected their level of illness awareness.

Participants with impaired illness awareness had higher response latencies for illness‐related stimuli as a whole and for the general illness awareness condition compared to those with good illness awareness (Table 1). Pearson correlations performed between SAI‐E scores and total illness related and neutral condition response times were r = −0.550, P = 0.022 and r = −0.122, P = 0.641, respectively, and did not change significantly after controlling for CPZ equivalents (r = −0.585, P = 0.017; r = −0.235, P = 0.380). Stronger correlations were observed between SAI‐E scores and scores calculated from the general illness awareness minus neutral condition response times (r = −0.820, P < 0.001), even after controlling for CPZ equivalents (r = −0.841, P < 0.001) and active psychotic symptoms (average SAPS score; r = −0.622, P = 0.013). Intriguingly, this score (general illness awareness – neutral condition response time) when set at >0.6 s was 100% sensitive and 100% specific for identifying participants with any impairment in illness awareness (SAI‐E < 25), while a cutoff of >0.7 s was 100% sensitive and 89% specific for identifying those with moderate to severe impaired illness awareness (SAI‐E<21). These findings suggest higher response latencies to illness‐related stimuli may be a surrogate behavioral marker of impaired illness awareness in schizophrenia.

Structural Imaging Results

Cortical Thickness Whole Brain Analysis

Increased peak left TPO brain activity during the illness denial task was significantly associated with decreased CT in the left angular gyrus (t = −5.0; −37, −35, 42), left parieto‐occipital junction (t = −5.3, −23, −60, 12), and along the left medial superior frontal gyrus (t = −5.2, −14, 34, 42) after correcting for multiple comparisons (surviving 10% FDR; Fig. 4). No associations were found for SAI‐E score or left mPFC activity and CT.

Figure 4.

Figure 4

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T‐statistic map showing the association between peak left temporoparieto occipital junction brain activity during the illness denial task and decreased CT in the left angular gyrus (t = −5.0, −37, −35, 42), parieto occipital junction (t = −5.3, −23, −60, 12), and along the medial superior frontal gyrus (t = −5.2, −14, 34, 42) (not shown). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

CT ROI Analysis

As with the whole brain CT analysis, left hemisphere peak TPO brain activity for the illness denial task was correlated with reduced mean CT in the left angular gyrus (Table 3). Impaired illness awareness (i.e., lower SAI‐E scores) was also strongly correlated with reduced mean CT in the left angular gyrus; however, the correlation (r = 0.67, P = 0.005) marginally failed to achieve significance when correcting for multiple comparisons (P < 0.005). The relationship of reduced mean CT in the left angular gyrus with peak TPO brain activity was stronger than with impaired illness awareness (left peak TPO activity and mean left angular gyrus CT, r = −0.87 vs. SAI‐E and mean left angular gyrus CT, r = 0.67, Steiger's Z = 2.44, P = 0.01).

DISCUSSION

Here we present evidence in support of the functional neuroanatomy of anosognosia in schizophrenia spectrum disorders at the moment of illness denial. Our results indicate that left hemisphere dominant brain activity, particularly within the TPO and PFC regions, may be a neural correlate of illness denial and anosognosia in schizophrenia spectrum disorders. Linking structure and function, our results revealed an association between left TPO activity and cortical thinning within this region.

The association of left hemisphere dominant brain activity with illness denial in schizophrenia provides further evidence for the theory of interhemispheric rivalry as a mechanism of anosognosia in neuropsychiatric conditions [Mintz et al., 2003; Ramachandran, 1995]. According to this theory, impaired illness awareness is attributable to left hemisphere dominance secondary to either right hemisphere dysfunction (e.g., stroke) or left hemisphere hyperactivity. In support of this concept, a number of noninvasive strategies, including transcranial magnetic stimulation (TMS), caloric vestibular stimulation, and transcranial direct current stimulation (tDCS), have been used to induce unilateral visuospatial neglect in healthy controls, transiently reverse anosognosia in stroke patients, and improve illness awareness in schizophrenia spectrum and bipolar disorders through unilateral hemispheric excitation or inhibition [Cappa et al., 1987; Kortte and Hillis, 2011; Levine et al., 2012; Miller and Ngo, 2007; Oliveri et al., 2001; Sparing et al., 2009]. In a recent fMRI study [Raij et al., 2012] that used a design similar to our own, increased right frontopolar activity was associated with greater clinical insight when illness‐related stimuli were contrasted with a comparison condition. The findings of this study provide further evidence for the theory of interhemispheric rivalry of illness awareness, whereby those with good clinical insight activated the right frontal cortex more than those with impaired insight; however, the authors did not report on the relationship between brain activity during their ‘clinical insight’ task and impaired illness awareness.

The mPFC, and to a lesser degree the inferior parietal area, are regions associated with self‐ and other‐reflective processing both in healthy controls [Murray et al., 2012; van der Meer et al., 2010, 2012] and individuals with schizophrenia [Raij et al., 2012; van der Meer et al., 2012]. In the aforementioned study [Raij et al., 2012], the investigators found increased cortical midline structure brain activity during self‐referential processing, namely the left mPFC and left posterior cingulate cortex. In another recent study [van der Meer et al., 2012], persons with schizophrenia and healthy controls showed similar patterns of activation in self‐reflection areas, which included the mPFC, the anterior pole of the medial‐superior temporal gyrus, insula, and inferior parietal area. Intriguingly, among schizophrenia participants, there was a positive association between good insight and activity in the left inferior frontal lobe/anterior insula (peak = −38, 18, 12) and left inferior parietal lobe—defined as the temporoparietal junction, angular gyrus, and inferior parietal lobule (peak = −36, −64, 42), during a self‐reflection task. In a post hoc analysis, we confirmed their study's findings [van der Meer et al., 2012], observing similar brain activations in association with good illness awareness for our neutral condition (Left TPO: −42, −82, 30, t = 3.45, P = 0.002 uncorr.; left PFC: −24, 52, 14, t = 3.17, P = 0.003; Supporting Information Fig. 3A), which closely resembles that study's self‐condition. In van der Meer et al. study's self‐condition, statements reportedly included “I am a good friend” or “I smell bad,” which are similar to many of the statements used in our neutral condition, such as “I am right handed” or “I am a smoker.” Moreover, consistent with their study's [van der Meer et al., 2012] results, when we performed the same analysis for our neutral condition to determine the unique contribution of BCIS self‐reflectiveness as the covariate of interest, brain activity was predominant in the left mPFC (Neutral: t = 3.48, P = 0.002 uncorr.) and not the left TPO (Supporting Information Fig. 3B).

The positive relationship between greater illness awareness and left frontoparietal activity during self‐reflection, in conjunction with our principal finding of an association between impaired illness awareness and greater activity in similar areas for illness related stimuli, suggests the following: At baseline, individuals with impaired illness awareness appear to under‐recruit left frontoparietal areas during self‐reflective processing, but will over‐recruit these regions when thinking about their illness‐related beliefs. The left TPO has been implicated in a left lateralized ventral attention network that reorients attention toward relevant, salient, nonvisuospatial, or autobiographical stimuli [see DiQuattro and Geng, 2011 for a review of left TPO functions]. The left TPO is also more active during first person perspective taking [Ruby and Decety, 2001] and when one is certain a stimulus is either ‘new’ (i.e., encountered for the first time) or ‘old’ (i.e., remembered) [Ciaramelli et al., 2008]. In light of our findings, this may explain why participants with impaired illness awareness are generally less certain about their sense of self (as indicated by left TPO hypoactivation to the illness independent/neutral self‐relevant condition), but more erroneously convinced of their mental health and ‘veracity’ of their delusions. In other words, persons with schizophrenia and impaired illness awareness may lose their sense of self to their illness and delusional experiences.

To our knowledge, this is the first study to explore the interaction between CT, illness awareness, and brain activity in relation to an illness denial task. We found that CT was reduced in the left angular gyrus and parieto‐occipital junction in relation to peak brain activity within this region during the illness denial task (Fig. 4 and Table 3). Although preliminary, reduced CT may represent a structural correlate of brain function during illness denial. These results, taken together with the findings of our previous study in which we reported an association between impaired illness awareness and relatively increased brain volume in left hemisphere regions, seem to suggest increased volume and decreased CT in the left angular gyrus/TPO may underlie impaired illness awareness in schizophrenia [Gerretsen et al., 2013]. At first glance, these findings appear contradictory, however, the discrepancy may be attributable to methodological differences. First, CT and gray matter volume appear to be independent markers of brain structure and are only modestly correlated with one another [Hutton et al., 2009; Winkler et al., 2010]. Second, MR voxel‐based methods of whole brain volume may not be sensitive enough to reliably determine associations with clinical features, such as impaired illness awareness. It was this notion based on the inconsistent findings in previous studies that had used a voxel‐based whole brain approach that led us to perform analyses of hemispheric asymmetry with the premise that asymmetry may be a more sensitive structural marker of impaired illness awareness than gray matter volume [Gerretsen et al., 2013]. Moreover, in the same study, we found no relationship between gray matter volume and impaired illness awareness. Lastly, in the present study, we found CT was more strongly correlated with brain activity during the illness denial task than with impaired illness awareness (i.e., SAI‐E scores; Table 3). In summary, our results implicate posterior parietal regions (i.e., angular gyrus/TPO) as structural and functional correlates of illness denial and impaired illness awareness in schizophrenia spectrum disorders. The specific relationship between various measures of brain structure (e.g., gray and white matter volume, CT, diffusion tensor imaging, and so forth) and function (e.g., resting state and task fMRI) requires further study with larger sample sizes.

Another finding that emerged from our study was that participants with impaired illness awareness showed longer response times to illness related versus neutral stimuli compared to those with good illness awareness. In a study mentioned previously [van der Meer et al., 2012], both participants with schizophrenia and healthy controls responded faster to self‐related stimuli during self‐reflection tasks than to other or semantic stimuli. By comparison, we did not observe any differences in response times between those with good versus impaired illness awareness for our neutral condition. This suggests that illness‐related stimuli may be perceived of as foreign (i.e., other related) and less self‐relevant to those with impaired illness awareness. Increased response time to illness‐related stimuli may be a behavioral marker of impaired illness awareness in schizophrenia spectrum disorders.

The results of our study are limited by two main factors. First, our sample population was restricted to stable patients with schizophrenia, excluding those who were acutely psychotic and unable to provide consent to participate in the study. This was done by design to better control for illness severity (i.e., psychosis), which is highly associated with impaired illness awareness; and second, due to lack of guidance from the literature, we arbitrarily defined those with impaired and good illness awareness for the purpose of carrying out our group comparisons. To overcome this limitation, we recruited participants with a wide range of illness awareness and performed regression analyses in which participants' illness awareness scores were used as the covariate of interest. Another possible limitation of this study was the lack of a healthy control comparison group. In the original design of this study, however, we felt healthy controls would not be a valid comparison group, primarily as they do not have a schizophrenia spectrum disorder, and thus, do not have a neuropsychiatric illness or psychotic symptoms to deny. We believe that the only true valid comparison is between those with impaired and intact illness awareness using a task fMRI design. Additional methodological limitations include: the small sample size; the participants' use of antipsychotic medications (we controlled for CPZ equivalents); and the spiral acquisition slice thickness (4.4 mm), which may have reduced the functional imaging resolution.

Many other mental illnesses and nonpsychiatric disorders beyond those described in this study can feature varying degrees of impaired illness awareness or illness denial, including other psychotic disorders, mood disorders with psychotic features, obsessive compulsive disorder, eating disorders, addictions, and medical conditions in which the severity of one's illness or need for treatment is minimized (e.g., heart disease, hypertension, and diabetes). Generally, impaired illness awareness across these conditions can be envisioned both on a spectrum of severity and degree of structural involvement. To one end, there is clear evidence of structural lesions, as in strokes, neurodegeneration or brain injury; while to the other, there is arguably less structural brain damage (e.g., eating disorders, addictions, hypertension, and diabetes), where illness denial may be comparatively more malleable—attributable to dysfunction on a neurocircuit, synaptic or molecular level. In each instance, whether “structural” or “functional,” the same brain regions or circuits may be involved. Further investigation is required to replicate the findings of our study and to determine if the model of interhemispheric rivalry is generalizable to other psychiatric and nonpsychiatric disorders that can feature illness denial or minimization of the need for treatment. Lastly, the brain regions identified in this study may also represent putative targets for treatment intervention with noninvasive techniques, such as TMS and tDCS.

Disclosures

P.G. has received fellowship awards from the Centre for Addiction and Mental Health and the Ontario Mental Health Foundation.

M.M. reports no competing interests.

MMC received support from the W. Garfield Weston Foundation

J.P.L. reports no competing interests.

D.M. receives research support from the National Institute of Health and the Canadian Institutes of Health Research. He has received investigator‐initiated research support from Pfizer Canada over the past three years.

G.R. has received research support from the Canadian Diabetes Association, the Canadian Institutes of Health Research, Medicure, Neurocrine Biosciences, Novartis, Research Hospital Fund‐Canada Foundation for Innovation, and the Schizophrenia Society of Ontario and has served as a consultant or speaker for Novartis, Laboratorios Farmacéuticos Rovi, Synchroneuron, and Roche.

B.G.P. receives research support from the National Institute of Health and the Canadian Institutes of Health Research. Within the past 5 years, he has been a member of the advisory board of Lundbeck Canada (final meeting was May 2009) and Forest Laboratories (final meeting was March 2008). He has served one time as a consultant for Wyeth (October 2008) and Takeda (July 2007). He was also a faculty member of the Lundbeck International Neuroscience Foundation (LINF) (final meeting was April 2010).

A.G. receives grant support from National Institute of Health, Canadian Institute of Health Research, Ontario Mental Health Foundation, CONACyT, ICyTDF and Janssen. He has served as consultant for Abbott Laboratories, Gedeon Richter Plc, and Eli Lilly.

Supporting information

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ACKNOWLEDGMENT

The authors would like to thank Wanna Mar, research coordinator and Kathryn Kalahani, research student for their contribution to this work.

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