0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Functional, Structural, and Emotional Correlates of Impaired Insight in Cocaine Addiction FREE

Scott J. Moeller, PhD1; Anna B. Konova, MA1,2; Muhammad A. Parvaz, PhD1; Dardo Tomasi, PhD3; Richard D. Lane, MD, PhD4; Carolyn Fort, BA4; Rita Z. Goldstein, PhD1
[+] Author Affiliations
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York
2Department of Psychology, Stony Brook University, Stony Brook, New York
3National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland
4Department of Psychiatry, University of Arizona, Tucson
JAMA Psychiatry. 2014;71(1):61-70. doi:10.1001/jamapsychiatry.2013.2833.
Text Size: A A A
Published online

Importance  Individuals with cocaine use disorder (CUD) have difficulty monitoring ongoing behavior, possibly stemming from dysfunction of brain regions mediating insight and self-awareness.

Objective  To investigate the neural correlates of impaired insight in addiction using a combined functional magnetic resonance imaging and voxel-based morphometry approach.

Design, Setting, and Participants  This multimodal imaging study was performed at the Clinical Research Center at Brookhaven National Laboratory. The study included 33 CUD cases and 20 healthy controls.

Main Outcomes and Measures  Functional magnetic resonance imaging, voxel-based morphometry, Levels of Emotional Awareness Scale, and drug use variables.

Results  Compared with the other 2 study groups, the impaired insight CUD group had lower error-induced rostral anterior cingulate cortex (rACC) activity as associated with more frequent cocaine use, less gray matter within the rACC, and lower Levels of Emotional Awareness Scale scores.

Conclusions and Relevance  These results point to rACC functional and structural abnormalities and diminished emotional awareness in a subpopulation of CUD cases characterized by impaired insight. Because the rACC has been implicated in appraising the affective and motivational significance of errors and other types of self-referential processing, functional and structural abnormalities in this region could result in lessened concern (frequently ascribed to minimization and denial) about behavioral outcomes that could potentially culminate in increased drug use. Treatments that target this CUD subgroup could focus on enhancing the salience of errors (eg, lapses).

Figures in this Article

Drug-addicted individuals often take drugs despite conscious, well-intentioned plans to abstain. Although this practice is often viewed as a deficiency in will power, we recently suggested that a core symptom of drug addiction is dysfunction of brain regions that underlie insight and self-awareness.1 Because impaired insight is marked by reduced sensitivity to negative outcomes, poorer treatment outcome, and lowered treatment adherence across various neuropsychiatric disorders (eg, schizophrenia and neurologic insults),2 we reasoned that this deficit could also have important implications for addiction. Discrepancies between self-reports and objective indices of behavior35 and compromised monitoring of ongoing behavior6,7 as associated with more severe drug-seeking behavior7 provided the preliminary evidence for impaired insight in addiction. We investigated the neural correlates of impaired insight in addiction using a combined functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) approach.

We hypothesized key roles for brain regions underlying self-monitoring, self-awareness, interoception, and error-related processing, especially the anterior cingulate cortex (ACC) and the anterior insula. The ACC is classically implicated in the neural response to errors8 and in cognitive control more generally,9 subserving functions that include performance monitoring,10 conflict monitoring,11 error detection,12 and the prediction of posterror slowing.13 Abnormal (especially, hypoactive) ACC activity has been documented on selective attention and inhibitory control tasks in users of various addictive substances.14 We recently found that ACC deficits extend to emotionally salient tasks in addiction, with individuals with cocaine use disorder (CUD) showing hypoactivations in the dorsal ACC (dACC) and rostral ACC (rACC) during a drug Stroop task.15 Of particular relevance, the ACC also participates in consciously mediated behavior. The ACC forms part of a network that is hypoactive during vegetative states, minimally conscious states, seizures, and sleep,16 and damage to the ventromedial prefrontal cortex (PFC) and adjacent ACC is associated with unawareness of one’s social impairment.17 In cannabis users, dACC (extending into the rACC) hypoactivity was associated with unaware errors on an error awareness task.18 In further agreement, a study of Alzheimer disease19 found that patients unaware of their illness-related deficits had reduced activity in the dACC and rACC-PFC region during a go/no-go task. Insula involvement was hypothesized because of its central role in interoception,20,21 implicated in conscious drug craving in addicted individuals2224 and error awareness in health.25,26 In one study27 that targeted both regions, insula and ACC error-related activity during a go/no-go task was associated with individual differences in absentmindedness, a concept related to self-monitoring and awareness.

Using a previously developed choice task that assesses self-monitoring of behavior,7,28 participants in the current study were grouped by insight. In parallel, participants underwent fMRI while performing an event-related color-word Stroop task.29 Errors on this classic inhibitory control task could have implications for insight because of the need to self-monitor behavior (eg, on error commission); of additional relevance, errors reliably engage the ACC and insula, including during Stroop tasks3035 and other inhibitory control tasks.3641 During these same scanning sessions, structural MRI was collected. Compared with healthy controls and unimpaired insight CUD (uCUD) cases, we hypothesized that impaired insight CUD (iCUD) cases would show abnormal ACC and insula functional activity during error processing and gray matter integrity (with the latter resting on previous studies4245 in which CUD had reduced gray matter volume in the ACC and/or insula) and that these functional and/or structural abnormalities would correlate with increased drug use. We further hypothesized that iCUD would show diminished self-awareness of one’s own emotional experiences, assessed with the Levels of Emotional Awareness Scale (LEAS).46 Inclusion of the LEAS was important to validate our insight measure; it was also intended to extend the insight concept in addiction beyond compromised behavioral monitoring (eg, error or choice awareness) and into more complex socioemotional and interpersonal scenarios.

Participants

The Institutional Review Board of Stony Brook University approved this project. Our main sample included 33 CUD cases and 20 controls, all right-handed and native English speakers; all provided written informed consent to participate. A psychiatric interview (see the eAppendix in the Supplement) determined that all CUD cases met DSM-IV criteria for current cocaine dependence (n = 28) or cocaine dependence in early (n = 3) or sustained (n = 2) remission4749 (Table 1 provides current dependence and remission partitioning; the eAppendix in the Supplement provides current and past comorbidities). A triage urine panel for drugs of abuse was conducted in all participants immediately before all other study procedures (ie, not on a separate screening day) (Table 1 provides cocaine urine status partitioning). Urine test results positive for drugs other than cocaine in CUD cases and positive urine screen results for any drugs in controls were exclusionary (see the eAppendix in the Supplement for additional discussion of this variable and for additional exclusion criteria).

Table Graphic Jump LocationTable 1.  Demographic Characteristics and Drug Use of All Study Participantsa
Study Procedures
Insight Assessment

Insight was assessed using established, validated procedures7,28 (the eAppendix in the Supplement provides a comprehensive description). In brief, participants performed a probabilistic learning choice task, providing their objective preference for viewing standardized50 pleasant (eg, infants), unpleasant (eg, disfigurement), neutral (eg, household objects), and in-house5 cocaine images. After the task, participants’ most selected picture category (actual choice) was compared with participants’ awareness of this choice (self-report of which picture category was chosen most frequently). The CUD cases who showed agreement between their behavior and self-reports formed the uCUD group (n = 18); those showing disagreement between these measures formed the iCUD group (n = 15). All included controls (n = 20) were selected to have intact insight (only 7 controls with completed study procedures had impaired insight, requiring future investigation with larger samples; see the eAppendix in the Supplement for additional discussion of these controls). This task’s relevance to insight is in assessing whether CUD cases have explicit knowledge (awareness) about their drug-seeking behavior. Because human instrumental learning (under conditions similar to the current task) is encoded as explicit causal knowledge,5153 choice on this task is likely goal driven (ie, not governed by habitual, implicit responding) (see the eAppendix in the Supplement for additional discussion).

Inhibitory Control Task

Participants performed 3 runs of an event-related fMRI color-word Stroop task, with instructions to press for the ink color of color-words (red, blue, yellow, and green) printed in their congruent or incongruent colors. Each task run contained 12 incongruent events (totaling 36 such events per participant) and 188 congruent events (totaling 564 such events per participant). Participants committed a mean of 20.4 (range, 1-74), 25.6 (range, 2-119), and 24.0 (range, 1-73) total errors (ie, summed across congruent and incongruent trials) during runs 1, 2, and 3, respectively (combined mean [SD], 23.4 [16.6]). No word or color of an incongruent stimulus mirrored the preceding congruent color-word; otherwise, stimuli were presented randomly. Each word was presented for 1300 milliseconds, which was also the time allotted for response (intertrial interval, 350 milliseconds); participants were not given performance feedback. Remuneration for task completion was $25 (fixed). This Stroop task version was adapted from a previous neuroimaging study54 and is comprehensively described elsewhere (including a descriptive task schematic).30,55Table 2 gives the behavioral data.

Table Graphic Jump LocationTable 2.  Performance on the Color-Word Stroop fMRI Task Across All Study Participantsa
MRI Data Acquisition

The MRI scanning was performed on a 4-T whole-body scanner (Varian/Siemens MRI scanner). The blood oxygenation level–dependent (BOLD) fMRI responses were measured as a function of time using a T2*-weighted, single-shot, gradient-echo planar sequence (echo time, 20 milliseconds; repetition time, 1600 milliseconds; in-plane resolution, 3.125 × 3.125 mm2; slice thickness, 4 mm; gap, 1 mm; typically 33 coronal slices; field of vision, 20 cm; matrix size, 64 × 64; flip angle, 90°; bandwidth with ramp sampling, 200 kHz; 207 time points; and 4 dummy scans to avoid nonequilibrium effects in the fMRI signal). Anatomical images were collected using a T1-weighted 3-dimensional modified driven equilibrium Fourier transform sequence57 and a modified T2-weighted hyperecho sequence.58

MRI Data Processing

Image processing and analysis were performed with Statistical Parametric Mapping, version 8 (SPM8) (Wellcome Trust Centre for Neuroimaging). Image reconstruction was performed using an iterative phase correction method that produces minimal signal-loss artifacts in echoplanar images.59 A 6-parameter rigid body transformation (3 rotations and 3 translations) was used for image realignment and correction of head motion. Criteria for acceptable motion were 2-mm displacement and 2° rotation. The realigned data sets were spatially normalized to the standard Montreal Neurological Institute stereotactic space using a 12-parameter affine transformation60 and a voxel size of 3 × 3 × 3 mm. An 8-mm full width at half maximum gaussian kernel spatially smoothed the data.

BOLD-fMRI Analyses

A general linear model,61 which included 6 motion regressors (3 translations and 3 rotations) and 1 task condition regressor convolved with a canonical hemodynamic response function and a high-pass (cutoff frequency, 1/90 seconds) filter, was used to calculate individual BOLD-fMRI maps. Specifically, our design matrix included 1 regressor collapsed across both error trials (congruent incorrect and incongruent incorrect), leaving both correct trials (congruent correct and incongruent correct) to serve as the active, implicit baseline; this implicit baseline was chosen because the task contained mostly correct events. Thus, the β-weights for this incorrect (error) regressor equated to a contrast functionally equivalent to incorrect greater than “everything else” (insofar as everything else consisted entirely of correct events), reflecting task-related error processing remaining after the variance related to correct events was removed. For analyses pertaining to a second design matrix that modeled the incongruent events, see eFigure 2 in the Supplement. Because error is contrasted with an active baseline (correct) and not a neutral baseline (eg, fixation), BOLD signal values below 0 do not necessarily reflect deactivations.

At the second level, we conducted a whole-brain 1-way analysis of variance (ANOVA) in SPM8. Because our regions of interest (ROIs) were relatively large (ACC and insula) and following the recommendation that broader, more diffuse activations are best detected by lower thresholds,62 we specified a height threshold of P < .005 voxel level–uncorrected threshold (T = 2.68), a common threshold in psychiatric neuroscience research. We then used a Monte Carlo procedure63 (similar to AlphaSim) to identify the number of contiguous voxels necessary for a P < .05 cluster-corrected threshold (ie, given our imaging parameters and a height threshold of T = 2.68), which was calculated to be 26 contiguous voxels. One-sample t tests were then conducted on the same first-level contrasts to confirm that the regions that differed between groups were indeed engaged during the task. To focus these latter analyses, results were masked by the respective between-group ANOVA contrasts (for results of unmasked 1-sample t tests across all participants, see eTable 1 and eTable 2 in the Supplement). Nevertheless, to protect against type I error, statistical significance for these 1-sample t tests was set at P < .05 family-wise voxel level–corrected threshold. The mean BOLD signals from peaks that met both criteria were extracted as spherical volumes (3-mm radius) to inspect for outliers and for use in correlation analyses (see below). MRIcron corroborated anatomical specificity.

Structure

A VBM analysis was conducted with the VBM toolbox (version 8) (C. Gaser, Department of Psychiatry, University of Jena, Jena, Germany; http://dbm.neuro.uni-jena.de/vbm/), which combines spatial normalization, tissue segmentation, and bias correction into a unified model. The modified driven-equilibrium Fourier transform scans, which produce especially precise characterization of gray matter tissue,64 were first spatially normalized to standard proportional stereotaxic space (voxel size, 1 × 1 × 1 mm) and segmented into gray matter, white matter, and cerebrospinal fluid tissue classes according to a priori tissue probability maps.65,66 A hidden Markov random field67 maximized segmentation accuracy. Jacobian modulation compensated for the effect of spatial normalization and restored the original absolute gray matter volume in the gray matter segments. Three uCUD cases had unusable structural scans; for these participants, structural scans during a 6-month follow-up session were substituted (note that removing these 3 participants did not change any VBM results). After smoothing the normalized and modulated gray matter segments with a 10-mm3 full width at half maximum gaussian kernel, we estimated a 1-way analysis of covariance, with age and total brain volume included as covariates of no interest.42,43,6871 We first performed whole-brain analyses, consistent with the functional approach. As an additional test of group differences, we defined spherical ROIs (3-mm radius) at the coordinates from the functional data that were observed for both the between-group ANOVA and 1-sample t tests. These firmly a priori ROIs were then analyzed in SPSS statistical software (SPSS Inc).

LEAS Scores

Participants were presented with 20 emotionally charged interpersonal scenarios and answered how each person involved would likely feel. For example, “You and your best friend are in the same line of work. There is a prize given annually to the best performance of the year. The two of you work hard to win the prize. One night the winner is announced: your friend. How would you feel? How would your friend feel?” Scoring followed a validated coding scheme (higher scores equal higher self-awareness of one's own emotion).46 Previously, lower LEAS scores were associated with reduced rACC activity during trauma recall in patients with posttraumatic stress disorder relative to controls who had also experienced trauma.72 Because only 15 participants from our main sample had LEAS data (ie, this measure was not yet in place when the fMRI protocol commenced), data from 20 additional participants (who did not complete the fMRI component) were included in the LEAS analyses to maximize sample size. Importantly, the 15 participants overlapping between both protocols did not differ from the rest of the main sample and did not differ from these new 20 participants on any Table 1 demographics (all P > .05), suggesting that these 20 new participants were comparable to the main sample. An analysis of covariance tested for between-group differences while controlling for age (ie, one anticipates LEAS scores to increase with age and development73) and verbal IQ (ie, to produce effective written responses, one anticipates LEAS scores to increase with higher verbal IQ46). The LEAS scorer was masked to insight and participant grouping.

Correlation Analyses

We first tested for functional-structural correspondence (correlations) among regions that showed parallel between-group differences for both methods. We then tested correlations between functional activations or gray matter (that also first showed between-group differences) with the 12 cocaine use variables from Table 1. Significance for these drug use correlations was set at P < .01 to minimize type I error. Because only 15 total participants from our main sample had LEAS data as described above, we were unable to inspect correlations with this measure.

Function

Whole-brain SPM8 analyses revealed iCUD cases to have less error  greater than correct activations compared with the other 2 study groups in the rACC (Figure 1A). Although this cluster extended dorsally to include additional ACC subregions (Table 3), a 1-sample t test in the iCUD group revealed that this between-group difference was driven by error greater than correct lower activations in this group specifically in the rACC (ie, not in the entire ACC cluster; note that one peak coordinate overlapped across both analytical approaches [x = 12, y = 44, z = 13; Table 3]). No other between-group differences reached significance.

Place holder to copy figure label and caption
Figure 1.
Brain and Levels of Emotional Awareness Scales Analyses

A, Reduced error greater than correct rostral anterior cingulate cortex (rACC) mean blood oxygenation level–dependent (BOLD) signal change in the 15 impaired insight cocaine use disorder (iCUD) cases compared with the other 2 study groups (18 unimpaired insight cocaine use disorder cases and 20 healthy controls) during the color-word Stroop task (with corresponding image, which for display purposes only was thresholded at 2.4 ≤ T ≤ 7.0 and masked by an anatomical ACC region of interest) (Pcorrected < .05 for impaired less than others). B, This reduced error-related rACC activity correlated with more frequent drug use in the last 30 days in all CUD participants (r = −0.50, P = .007). In parallel and compared with the other study groups, impaired iCUD cases had lower (C) voxel-based morphometry (VBM) gray matter volume in the same rACC region and (D) emotional awareness (Levels of Emotional Awareness Scale [LEAS] scores) (P < .05 for impaired less than others) for both (C) and (D). Error bars indicate SEs. Note that BOLD signal values below 0 do not necessarily reflect deactivations (because the contrast with error is not with a fixation baseline but rather with an implicit, active baseline of correct trials; see Methods).

Graphic Jump Location
Table Graphic Jump LocationTable 3.  Color-Word Stroop Task Between-Group Differences During Errora
Structure

Although whole-brain between-group differences were nonsignificant, we extracted 2 ROIs corresponding to the peak rACC functional coordinate that emerged using both the whole-brain between-group ANOVA and 1-sample t tests (x = 12, y = 44, z = 13; Table 3; extracted on both the ipsilateral and contralateral sides). The iCUD group had reduced gray matter compared with the other study groups in the contralateral rACC ROI (planned comparison: F1,50 = 4.7, P = .04) (Figure 1C).

LEAS Scores

The iCUD group scored lower on the LEAS (total score) than the other 2 study groups (planned comparison: F1,31 = 4.3, P = .048) (Figure 1D), suggesting decreased self-awareness of one's own emotion in the iCUD group.

Correlations

The lower the error greater than correct activity in the extracted rACC cluster, the more frequently (days per week in the last 30 days) cocaine was used in all CUD cases (Figure 1B). The other drug use variables did not correlate with rACC activity or structure; structure and function also did not correlate.

Our data provide novel evidence that impaired insight is associated with rACC dysfunction in cocaine addiction. Compared with controls and even uCUD cases (both with intact insight), iCUD cases had lowered rACC error greater than correct activity during a classic inhibitory control task (the pattern of response in the uCUD group more closely resembled that of controls) and gray matter volume, effects not attributable to between-group differences in demographic characteristics and drug use (see the eAppendix in the Supplement). Given the task’s active task baseline (correct trials), our functional results indicate that the iCUD group had disproportionately reduced activity to error events; in contrast, the other 2 groups had relative equivalence of these trial types (see eFigure 1 in the Supplement for time-series plots, which provide visual evidence that rACC error–related activity, even when not directly contrasted with correct responses, is decreased in iCUD cases). Interestingly, the rACC (extending into medial PFC) has been previously associated with insight-related compromises in patients with schizophrenia,74 cannabis use disorder,18 and Alzheimer disease19; notably, only the rACC extending to the medial PFC was implicated in all 3 disorders (Figure 2). Also potentially relevant to insight, this brain area is activated during the experience of negative self-conscious emotions7577 and during other activities relevant to social cognition (eg, self-knowledge, person perception, and mentalizing78,79).

Place holder to copy figure label and caption
Figure 2.
Rostral Anterior Cingulate Cortex Involvement in Neuropsychiatric Illnesses Characterized by Impaired Insight

A, Current results. B, Activations during reality monitoring (the ability to distinguish internally generated information from externally generated information) in health (that do not emerge under the same task conditions in schizophrenia)74 (adapted with permission from Elsevier). C, Activity during a go/no-go task in patients with Alzheimer disease with unimpaired insight relative to those with impaired insight19 (adapted with permission from Oxford University Press). D, Activity during error on an error awareness task, which was lower during unaware errors in cannabis abusers18 (note that although peak anterior cingulate cortex activity in this cannabis study is more caudal and dorsal, the cluster indeed extends to the rostral anterior cingulate cortex) (adapted with permission from Nature Publishing Group).

Graphic Jump Location

Another notable finding was a correlation between lower rACC functional activity to error and more frequent cocaine use. Because iCUD and uCUD did not differ on days of current abstinence, current use frequency, or cocaine urine status (Table 1), this association is unlikely attributable to the residual effects of recent cocaine use (ie, acute drug effects) and might instead reflect addiction-related symptoms—an interpretation consistent with previous research. In one relevant study,80 less cocaine use per week correlated with greater activation in the rACC during a modified Stroop task; because this study was conducted in CUD participants who had approximately 23 days of cocaine abstinence, results suggest that, similarly to the current study, the rACC–drug use association is more likely marking an addiction-related deficit (not short-term drug use). If future studies determine that iCUD cases (with associated rACC dysfunction) also have worse clinical outcomes as we anticipate, then treatments targeting rACC functioning could have clinical viability. This region showed cue-reactivity reductions to pharmacotherapeutic interventions in cigarette smokers81,82 and was suggested through meta-analysis as a marker of treatment response in major depression.83 Conversely, future studies should also uncover the mechanisms of continued drug use in uCUD cases, themselves a highly interesting CUD subgroup insofar as they had preserved rACC function and structure while still meeting criteria for addiction. One potential explanation could be that, although uCUD cases report lower craving overall (Table 1), there is tighter correspondence between their craving and drug-seeking behavior (see eFigure 3 in the Supplement).

In parallel to these rACC results, the dACC and insula had informative null results, which were not attributable to the inability of the current task to activate these regions (see eTable 1 and eTable 2 in the Supplement). Although both the dACC and rACC participate in error-related processing, the dACC is involved in error detection and is closely interconnected with higher-order frontal brain regions involved in adaptive behavior (eg, lateral PFC), whereas the rACC is involved in generating the (presumably negative) affective response that occurs shortly after error commission and is interconnected with several limbic brain regions (eg, amygdala, hypothalamus, and insula).36 The insula is involved in forming an interoceptive representation of one’s subjective feeling state,20 participating in drug craving in addiction2224 and error awareness in health.25,26 Null effects in the dACC and the insula could collectively indicate that although iCUD cases can recognize (both cognitively and interoceptively) that an error has occurred, this error might fail to elicit the appropriate emotional significance. This interpretation is bolstered by previous findings indicating that error-induced rACC activity tracks autonomic arousal,35 increases when error salience is amplified (eg, when attached to monetary loss),37 and participates in learning optimal task strategies.84 Given that iCUD cases also had reduced LEAS scores, our results could indicate that this compromised salience tagging of negative emotional events may generalize to other emotional contexts (ie, extending beyond task-related errors into more complex socioemotional scenarios of potential relevance to drug-taking behavior). For example, one could speculate that for iCUD cases attempting to remain abstinent, a lapse (error) may not elicit the requisite salience or aversive valence, increasing the probability of subsequent full relapse into frequent drug use—well anticipated from our negative correlation between rACC activity and current cocaine use.

A limitation of this study is the relatively small sample size for VBM, possibly explaining the lack of whole-brain results. Although in subsequent ROI analyses we accordingly restricted gray matter group comparisons to the region that first showed (corrected) functional effects (rACC), future studies with larger samples should replicate these results. Another limitation is that we cannot determine the precise neurobiological mechanisms underlying the decreased rACC error response; structure, although a plausible mediator,71 did not directly correlate with function. An alternative possibility could involve abnormalities in anterior frontal cortex cerebral blood flow in CUD cases, as suggested by previous perfusion fMRI studies85; because such frontal blood flow abnormalities are seemingly more pronounced in men than women,86 future studies should also replicate these effects in samples that include more women. Future studies could also use novel tasks that target functioning of other insight- and self-awareness–related regions not observed in this study (eg, anterior insula20 but also somatosensory cortex87).

In conclusion, because the rACC has been implicated in appraising the affective and motivational significance of errors and self-referential processing and given the association of impaired insight with diminished emotional self-awareness (LEAS), functional and structural abnormalities in this region could be expressed behaviorally as lessened concern regarding behavioral outcomes, potentially resulting in increased drug use. The current research therefore challenges the long-held clinical assumption that impaired insight in addiction is simply a manifestation of minimization and denial; instead, such impaired insight may stem from functional and structural abnormalities of the rACC. Our results extend prior research on compromised error awareness and processing6,18,88 and gray matter abnormalities42,43,69 in drug addiction, offering the intriguing suggestion that impaired insight may drive such effects. Our results also raise the possibility that a specific CUD subgroup (iCUD) might benefit from therapeutic interventions directed at enhancing the neuropsychological mechanisms underlying insight and self-awareness1 (eg, self-relevant [tailored] motivational interventions89,90). More broadly, our results can inform other neuropsychiatric disorders (eg, anosognosia, alexithymia, schizophrenia, and mania),91 similarly characterized by impaired insight and disadvantageous, unwanted, or inappropriate behaviors (eg, leading to violence or self-harm).

Corresponding Author: Rita Z. Goldstein, PhD, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, PO Box 1230, New York, NY 10029-6574 (rita.goldstein@mssm.edu).

Submitted for Publication: November 9, 2012; final revision received April 22, 2013; accepted June 4, 2013.

Published Online: November 20, 2013. doi:10.1001/jamapsychiatry.2013.2833.

Author Contributions: Drs Moeller and Goldstein had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Moeller, Konova, Parvaz, Goldstein.

Acquisition of data: Parvaz, Tomasi, Goldstein.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Moeller.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Moeller, Konova, Parvaz.

Obtained funding: Moeller, Goldstein.

Administrative, technical, and material support: Parvaz, Tomasi, Lane, Fort, Goldstein.

Study supervision: Moeller, Tomasi, Goldstein.

Conflict of Interest Disclosures: None report.

Funding/Support: This research was supported by grants 1R01DA023579 (Dr Goldstein), 1F32DA030017-01 (Dr Moeller), and 1F32DA033088 (Dr Parvaz) from the National Institute on Drug Abuse.

Role of the Sponsor: The National Institute on Drug Abuse had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Michail Misyrlis, MS, Thomas Maloney, PhD, and Patricia A. Woicik, PhD, provided additional administrative, technical, or material support. Nelly Alia-Klein, PhD, performed psychiatric interviews as needed. Gene-Jack Wang, MD, performed medical screens as needed.

Goldstein  RZ, Craig  AD, Bechara  A,  et al.  The neurocircuitry of impaired insight in drug addiction. Trends Cogn Sci. 2009;13(9):372-380.
PubMed   |  Link to Article
Klein  TA, Ullsperger  M, Danielmeier  C.  Error awareness and the insula: links to neurological and psychiatric diseases. Front Hum Neurosci. 2013;7(14):14.
PubMed
Goldstein  RZ, Alia-Klein  N, Tomasi  D,  et al.  Is decreased prefrontal cortical sensitivity to monetary reward associated with impaired motivation and self-control in cocaine addiction? Am J Psychiatry. 2007;164(1):43-51.
PubMed   |  Link to Article
Goldstein  RZ, Parvaz  MA, Maloney  T,  et al.  Compromised sensitivity to monetary reward in current cocaine users: an ERP study. Psychophysiology. 2008;45(5):705-713.
PubMed   |  Link to Article
Moeller  SJ, Maloney  T, Parvaz  MA,  et al.  Enhanced choice for viewing cocaine pictures in cocaine addiction. Biol Psychiatry. 2009;66(2):169-176.
PubMed   |  Link to Article
Hester  R, Simões-Franklin  C, Garavan  H.  Post-error behavior in active cocaine users: poor awareness of errors in the presence of intact performance adjustments. Neuropsychopharmacology. 2007;32(9):1974-1984.
PubMed   |  Link to Article
Moeller  SJ, Maloney  T, Parvaz  MA,  et al.  Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour. Brain. 2010;133(pt 5):1484-1493.
PubMed   |  Link to Article
Gehring  WJ, Goss  B, Coles  MG, Meyer  DE.  A neural system for error detection and compensation. Psychol Sci. 1993;4(6):385-390.
Link to Article
Ridderinkhof  KR, Ullsperger  M, Crone  EA, Nieuwenhuis  S.  The role of the medial frontal cortex in cognitive control. Science. 2004;306(5695):443-447.
PubMed   |  Link to Article
van Veen  V, Carter  CS.  The anterior cingulate as a conflict monitor: fMRI and ERP studies. Physiol Behav. 2002;77(4-5):477-482.
PubMed   |  Link to Article
Egner  T, Etkin  A, Gale  S, Hirsch  J.  Dissociable neural systems resolve conflict from emotional versus nonemotional distracters. Cereb Cortex. 2008;18(6):1475-1484.
PubMed   |  Link to Article
Swick  D, Turken  AU.  Dissociation between conflict detection and error monitoring in the human anterior cingulate cortex. Proc Natl Acad Sci U S A. 2002;99(25):16354-16359.
PubMed   |  Link to Article
Danielmeier  C, Eichele  T, Forstmann  BU, Tittgemeyer  M, Ullsperger  M.  Posterior medial frontal cortex activity predicts post-error adaptations in task-related visual and motor areas. J Neurosci. 2011;31(5):1780-1789.
PubMed   |  Link to Article
Garavan  H, Stout  JC.  Neurocognitive insights into substance abuse. Trends Cogn Sci. 2005;9(4):195-201.
PubMed   |  Link to Article
Goldstein  RZ, Alia-Klein  N, Tomasi  D,  et al.  Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc Natl Acad Sci U S A. 2009;106(23):9453-9458.
PubMed   |  Link to Article
Laureys  S.  The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci. 2005;9(12):556-559.
PubMed   |  Link to Article
Bechara  A.  Disturbances of emotion regulation after focal brain lesions. Int Rev Neurobiol. 2004;62:159-193.
PubMed
Hester  R, Nestor  L, Garavan  H.  Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users. Neuropsychopharmacology. 2009;34(11):2450-2458.
PubMed   |  Link to Article
Amanzio  M, Torta  DM, Sacco  K,  et al.  Unawareness of deficits in Alzheimer’s disease: role of the cingulate cortex. Brain. 2011;134(pt 4):1061-1076.
PubMed   |  Link to Article
Craig  AD.  How do you feel—now? the anterior insula and human awareness. Nat Rev Neurosci. 2009;10(1):59-70.
PubMed   |  Link to Article
Critchley  HD, Wiens  S, Rotshtein  P, Ohman  A, Dolan  RJ.  Neural systems supporting interoceptive awareness. Nat Neurosci. 2004;7(2):189-195.
PubMed   |  Link to Article
Naqvi  NH, Bechara  A.  The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Struct Funct. 2010;214(5-6):435-450.
PubMed   |  Link to Article
Naqvi  NH, Bechara  A.  The hidden island of addiction: the insula. Trends Neurosci. 2009;32(1):56-67.
PubMed   |  Link to Article
Naqvi  NH, Rudrauf  D, Damasio  H, Bechara  A.  Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315(5811):531-534.
PubMed   |  Link to Article
Hester  R, Foxe  JJ, Molholm  S, Shpaner  M, Garavan  H.  Neural mechanisms involved in error processing: a comparison of errors made with and without awareness. Neuroimage. 2005;27(3):602-608.
PubMed   |  Link to Article
Klein  TA, Endrass  T, Kathmann  N, Neumann  J, von Cramon  DY, Ullsperger  M.  Neural correlates of error awareness. Neuroimage. 2007;34(4):1774-1781.
PubMed   |  Link to Article
Hester  R, Fassbender  C, Garavan  H.  Individual differences in error processing: a review and reanalysis of three event-related fMRI studies using the GO/NOGO task. Cereb Cortex. 2004;14(9):986-994.
PubMed   |  Link to Article
Moeller  SJ, Hajcak  G, Parvaz  MA, Dunning  JP, Volkow  ND, Goldstein  RZ.  Psychophysiological prediction of choice: relevance to insight and drug addiction. Brain. 2012;135(pt 11):3481-3494.
PubMed   |  Link to Article
Stroop  JR.  Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643-662.
Link to Article
Moeller  SJ, Tomasi  D, Honorio  J, Volkow  ND, Goldstein  RZ.  Dopaminergic involvement during mental fatigue in health and cocaine addiction. Transl Psychiatry. 2012;2:e176.
PubMed   |  Link to Article
Mayer  AR, Teshiba  TM, Franco  AR,  et al.  Modeling conflict and error in the medial frontal cortex. Hum Brain Mapp. 2012;33(12):2843-2855.
PubMed   |  Link to Article
Sozda  CN, Larson  MJ, Kaufman  DA, Schmalfuss  IM, Perlstein  WM.  Error-related processing following severe traumatic brain injury: an event-related functional magnetic resonance imaging (fMRI) study. Int J Psychophysiol. 2011;82(1):97-106.
PubMed   |  Link to Article
Holmes  AJ, Pizzagalli  DA.  Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder. Arch Gen Psychiatry. 2008;65(2):179-188.
PubMed   |  Link to Article
Kerns  JG, Cohen  JD, MacDonald  AW  III,  et al.  Decreased conflict- and error-related activity in the anterior cingulate cortex in subjects with schizophrenia. Am J Psychiatry. 2005;162(10):1833-1839.
PubMed   |  Link to Article
Critchley  HD, Tang  J, Glaser  D, Butterworth  B, Dolan  RJ.  Anterior cingulate activity during error and autonomic response. Neuroimage. 2005;27(4):885-895.
PubMed   |  Link to Article
Edwards  BG, Calhoun  VD, Kiehl  KA.  Joint ICA of ERP and fMRI during error-monitoring. Neuroimage. 2012;59(2):1896-1903.
PubMed   |  Link to Article
Taylor  SF, Martis  B, Fitzgerald  KD,  et al.  Medial frontal cortex activity and loss-related responses to errors. J Neurosci. 2006;26(15):4063-4070.
PubMed   |  Link to Article
Ramautar  JR, Slagter  HA, Kok  A, Ridderinkhof  KR.  Probability effects in the stop-signal paradigm: the insula and the significance of failed inhibition. Brain Res. 2006;1105(1):143-154.
PubMed   |  Link to Article
Debener  S, Ullsperger  M, Siegel  M, Fiehler  K, von Cramon  DY, Engel  AK.  Trial-by-trial coupling of concurrent electroencephalogram and functional magnetic resonance imaging identifies the dynamics of performance monitoring. J Neurosci. 2005;25(50):11730-11737.
PubMed   |  Link to Article
Garavan  H, Ross  TJ, Kaufman  J, Stein  EA.  A midline dissociation between error-processing and response-conflict monitoring. Neuroimage. 2003;20(2):1132-1139.
PubMed   |  Link to Article
Ullsperger  M, von Cramon  DY.  Subprocesses of performance monitoring: a dissociation of error processing and response competition revealed by event-related fMRI and ERPs. Neuroimage. 2001;14(6):1387-1401.
PubMed   |  Link to Article
Franklin  TR, Acton  PD, Maldjian  JA,  et al.  Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol Psychiatry. 2002;51(2):134-142.
PubMed   |  Link to Article
Matochik  JA, London  ED, Eldreth  DA, Cadet  JL, Bolla  KI.  Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study. Neuroimage. 2003;19(3):1095-1102.
PubMed   |  Link to Article
Ersche  KD, Barnes  A, Jones  PS, Morein-Zamir  S, Robbins  TW, Bullmore  ET.  Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain. 2011;134(pt 7):2013-2024.
PubMed   |  Link to Article
Gardini  S, Venneri  A.  Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction. Brain Res Bull. 2012;87(2-3):205-211.
PubMed   |  Link to Article
Lane  RD, Quinlan  DM, Schwartz  GE, Walker  PA, Zeitlin  SB.  The Levels of Emotional Awareness Scale: a cognitive-developmental measure of emotion. J Pers Assess. 1990;55(1-2):124-134.
PubMed   |  Link to Article
Wilkinson  G. WRAT-3: Wide-Range Achievement Test 3 Administration Manual. Wilmington, DE: Wide Range Inc; 1993.
Wechsler  D. Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: Psychological Corporation; 1999.
Beck  AT, Steer  RA, Brown  GK. Beck Depression Inventory Manual.2nd ed. San Antonio, TX: The Psychological Corporation; 1996.
Lang PJ, Bradley MM, Cuthbert BN. International affective picture system (IAPS): affective ratings of pictures and instruction manual. Technical Report A-8. Gainesville: University of Florida; 2008.
Hogarth  L, Chase  HW, Baess  K.  Impaired goal-directed behavioural control in human impulsivity .Q J Exp Psychol.2012;65(2):305-316.
Klossek  UM, Russell  J, Dickinson  A.  The control of instrumental action following outcome devaluation in young children aged between 1 and 4 years. J Exp Psychol Gen. 2008;137(1):39-51.
PubMed   |  Link to Article
Tanaka  SC, Balleine  BW, O’Doherty  JP.  Calculating consequences: brain systems that encode the causal effects of actions. J Neurosci. 2008;28(26):6750-6755.
PubMed   |  Link to Article
Leung  HC, Skudlarski  P, Gatenby  JC, Peterson  BS, Gore  JC.  An event-related functional MRI study of the Stroop color word interference task. Cereb Cortex. 2000;10(6):552-560.
PubMed   |  Link to Article
Moeller  SJ, Honorio  J, Tomasi  D,  et al.  Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction [published online November 16, 2012]. Cereb Cortex. doi:10.1093/cercor/bhs345.
PubMed
Logan  GD, Crump  MJ.  Cognitive illusions of authorship reveal hierarchical error detection in skilled typists. Science. 2010;330(6004):683-686.
PubMed   |  Link to Article
Lee  JH, Garwood  M, Menon  R,  et al.  High contrast and fast three-dimensional magnetic resonance imaging at high fields. Magn Reson Med. 1995;34(3):308-312.
PubMed   |  Link to Article
Hennig  J, Scheffler  K.  Hyperechoes. Magn Reson Med. 2001;46(1):6-12.
PubMed   |  Link to Article
Caparelli  EC, Tomasi  D.  K-space spatial low-pass filters can increase signal loss artifacts in echo-planar imaging. Biomed Signal Process Control. 2008;3(1):107-114.
PubMed   |  Link to Article
Ashburner  J, Neelin  P, Collins  DL, Evans  A, Friston  K.  Incorporating prior knowledge into image registration. Neuroimage. 1997;6(4):344-352.
PubMed   |  Link to Article
Friston  KJ, Holmes  AP, Worsley  KJ, Poline  JB, Frith  CD, Frackowiak  RS.  Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2:189-210.
Link to Article
Friston  KJ, Worsley  KJ, Frackowiak  RSJ, Mazziotta  JC, Evans  AC.  Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994;1:210-220.
Link to Article
Slotnick  SD, Moo  LR, Segal  JB, Hart  J  Jr.  Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Res Cogn Brain Res. 2003;17(1):75-82.
PubMed   |  Link to Article
Tardif  CL, Collins  DL, Pike  GB.  Sensitivity of voxel-based morphometry analysis to choice of imaging protocol at 3 T. Neuroimage. 2009;44(3):827-838.
PubMed   |  Link to Article
Ashburner  J, Friston  KJ.  Voxel-based morphometry: the methods. Neuroimage. 2000;11(6, pt 1):805-821.
PubMed   |  Link to Article
Ashburner  J, Friston  KJ.  Unified segmentation. Neuroimage. 2005;26(3):839-851.
PubMed   |  Link to Article
Cuadra  MB, Cammoun  L, Butz  T, Cuisenaire  O, Thiran  JP.  Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images. IEEE Trans Med Imaging. 2005;24(12):1548-1565.
PubMed   |  Link to Article
Alia-Klein  N, Parvaz  MA, Woicik  PA,  et al.  Gene x disease interaction on orbitofrontal gray matter in cocaine addiction. Arch Gen Psychiatry. 2011;68(3):283-294.
PubMed   |  Link to Article
Tanabe  J, Tregellas  JR, Dalwani  M,  et al.  Medial orbitofrontal cortex gray matter is reduced in abstinent substance-dependent individuals. Biol Psychiatry. 2009;65(2):160-164.
PubMed   |  Link to Article
Makris  N, Oscar-Berman  M, Jaffin  SK,  et al.  Decreased volume of the brain reward system in alcoholism. Biol Psychiatry. 2008;64(3):192-202.
PubMed   |  Link to Article
Konova  AB, Moeller  SJ, Tomasi  D,  et al.  Structural and behavioral correlates of abnormal encoding of money value in the sensorimotor striatum in cocaine addiction. Eur J Neurosci. 2012;36(7):2979-2988.
PubMed   |  Link to Article
Frewen  P, Lane  RD, Neufeld  RW, Densmore  M, Stevens  T, Lanius  R.  Neural correlates of levels of emotional awareness during trauma script-imagery in posttraumatic stress disorder. Psychosom Med. 2008;70(1):27-31.
PubMed   |  Link to Article
Lane  RD, Sechrest  L, Riedel  R.  Sociodemographic correlates of alexithymia. Compr Psychiatry. 1998;39(6):377-385.
PubMed   |  Link to Article
Subramaniam  K, Luks  TL, Fisher  M, Simpson  GV, Nagarajan  S, Vinogradov  S.  Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia. Neuron. 2012;73(4):842-853.
PubMed   |  Link to Article
Takahashi  H, Yahata  N, Koeda  M, Matsuda  T, Asai  K, Okubo  Y.  Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study. Neuroimage. 2004;23(3):967-974.
PubMed   |  Link to Article
Sturm  VE, Sollberger  M, Seeley  WW,  et al.  Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity. Soc Cogn Affect Neurosci. 2012;8(4):468-474.
PubMed   |  Link to Article
Shin  LM, Dougherty  DD, Orr  SP,  et al.  Activation of anterior paralimbic structures during guilt-related script-driven imagery. Biol Psychiatry. 2000;48(1):43-50.
PubMed   |  Link to Article
Amodio  DM, Frith  CD.  Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006;7(4):268-277.
PubMed   |  Link to Article
Gilbert  SJ, Spengler  S, Simons  JS,  et al.  Functional specialization within rostral prefrontal cortex (area 10): a meta-analysis. J Cogn Neurosci. 2006;18(6):932-948.
PubMed   |  Link to Article
Bolla  K, Ernst  M, Kiehl  K,  et al.  Prefrontal cortical dysfunction in abstinent cocaine abusers. J Neuropsychiatry Clin Neurosci. 2004;16(4):456-464.
PubMed   |  Link to Article
Franklin  T, Wang  Z, Suh  JJ,  et al.  Effects of varenicline on smoking cue–triggered neural and craving responses. Arch Gen Psychiatry. 2011;68(5):516-526.
PubMed   |  Link to Article
Culbertson  CS, Bramen  J, Cohen  MS,  et al.  Effect of bupropion treatment on brain activation induced by cigarette-related cues in smokers. Arch Gen Psychiatry. 2011;68(5):505-515.
PubMed   |  Link to Article
Pizzagalli  DA.  Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36(1):183-206.
PubMed   |  Link to Article
Amiez  C, Sallet  J, Procyk  E, Petrides  M.  Modulation of feedback related activity in the rostral anterior cingulate cortex during trial and error exploration. Neuroimage. 2012;63(3):1078-1090.
PubMed   |  Link to Article
Holman  BL, Carvalho  PA, Mendelson  J,  et al Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99m-HMPAO and ASPECT .J Nucl Med.1991;32(6):1206-1210.
Levin  JM, Holman  BL, Mendelson  JH,  et al Gender differences in cerebral perfusion in cocaine abuse: technetium-99m-HMPAO SPECT study of drug-abusing women .J Nucl Med.1994;35(12):1902-1909.
Khalsa  SS, Rudrauf  D, Feinstein  JS, Tranel  D.  The pathways of interoceptive awareness. Nat Neurosci. 2009;12(12):1494-1496.
PubMed   |  Link to Article
Li  CS, Huang  C, Yan  P, Bhagwagar  Z, Milivojevic  V, Sinha  R.  Neural correlates of impulse control during stop signal inhibition in cocaine-dependent men. Neuropsychopharmacology. 2008;33(8):1798-1806.
PubMed   |  Link to Article
Chua  HF, Liberzon  I, Welsh  RC, Strecher  VJ.  Neural correlates of message tailoring and self-relatedness in smoking cessation programming. Biol Psychiatry. 2009;65(2):165-168.
PubMed   |  Link to Article
Chua  HF, Ho  SS, Jasinska  AJ,  et al.  Self-related neural response to tailored smoking-cessation messages predicts quitting. Nat Neurosci. 2011;14(4):426-427.
PubMed   |  Link to Article
Orfei  MD, Robinson  RG, Bria  P, Caltagirone  C, Spalletta  G.  Unawareness of illness in neuropsychiatric disorders: phenomenological certainty versus etiopathogenic vagueness. Neuroscientist. 2008;14(2):203-222.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Brain and Levels of Emotional Awareness Scales Analyses

A, Reduced error greater than correct rostral anterior cingulate cortex (rACC) mean blood oxygenation level–dependent (BOLD) signal change in the 15 impaired insight cocaine use disorder (iCUD) cases compared with the other 2 study groups (18 unimpaired insight cocaine use disorder cases and 20 healthy controls) during the color-word Stroop task (with corresponding image, which for display purposes only was thresholded at 2.4 ≤ T ≤ 7.0 and masked by an anatomical ACC region of interest) (Pcorrected < .05 for impaired less than others). B, This reduced error-related rACC activity correlated with more frequent drug use in the last 30 days in all CUD participants (r = −0.50, P = .007). In parallel and compared with the other study groups, impaired iCUD cases had lower (C) voxel-based morphometry (VBM) gray matter volume in the same rACC region and (D) emotional awareness (Levels of Emotional Awareness Scale [LEAS] scores) (P < .05 for impaired less than others) for both (C) and (D). Error bars indicate SEs. Note that BOLD signal values below 0 do not necessarily reflect deactivations (because the contrast with error is not with a fixation baseline but rather with an implicit, active baseline of correct trials; see Methods).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Rostral Anterior Cingulate Cortex Involvement in Neuropsychiatric Illnesses Characterized by Impaired Insight

A, Current results. B, Activations during reality monitoring (the ability to distinguish internally generated information from externally generated information) in health (that do not emerge under the same task conditions in schizophrenia)74 (adapted with permission from Elsevier). C, Activity during a go/no-go task in patients with Alzheimer disease with unimpaired insight relative to those with impaired insight19 (adapted with permission from Oxford University Press). D, Activity during error on an error awareness task, which was lower during unaware errors in cannabis abusers18 (note that although peak anterior cingulate cortex activity in this cannabis study is more caudal and dorsal, the cluster indeed extends to the rostral anterior cingulate cortex) (adapted with permission from Nature Publishing Group).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Demographic Characteristics and Drug Use of All Study Participantsa
Table Graphic Jump LocationTable 2.  Performance on the Color-Word Stroop fMRI Task Across All Study Participantsa
Table Graphic Jump LocationTable 3.  Color-Word Stroop Task Between-Group Differences During Errora

References

Goldstein  RZ, Craig  AD, Bechara  A,  et al.  The neurocircuitry of impaired insight in drug addiction. Trends Cogn Sci. 2009;13(9):372-380.
PubMed   |  Link to Article
Klein  TA, Ullsperger  M, Danielmeier  C.  Error awareness and the insula: links to neurological and psychiatric diseases. Front Hum Neurosci. 2013;7(14):14.
PubMed
Goldstein  RZ, Alia-Klein  N, Tomasi  D,  et al.  Is decreased prefrontal cortical sensitivity to monetary reward associated with impaired motivation and self-control in cocaine addiction? Am J Psychiatry. 2007;164(1):43-51.
PubMed   |  Link to Article
Goldstein  RZ, Parvaz  MA, Maloney  T,  et al.  Compromised sensitivity to monetary reward in current cocaine users: an ERP study. Psychophysiology. 2008;45(5):705-713.
PubMed   |  Link to Article
Moeller  SJ, Maloney  T, Parvaz  MA,  et al.  Enhanced choice for viewing cocaine pictures in cocaine addiction. Biol Psychiatry. 2009;66(2):169-176.
PubMed   |  Link to Article
Hester  R, Simões-Franklin  C, Garavan  H.  Post-error behavior in active cocaine users: poor awareness of errors in the presence of intact performance adjustments. Neuropsychopharmacology. 2007;32(9):1974-1984.
PubMed   |  Link to Article
Moeller  SJ, Maloney  T, Parvaz  MA,  et al.  Impaired insight in cocaine addiction: laboratory evidence and effects on cocaine-seeking behaviour. Brain. 2010;133(pt 5):1484-1493.
PubMed   |  Link to Article
Gehring  WJ, Goss  B, Coles  MG, Meyer  DE.  A neural system for error detection and compensation. Psychol Sci. 1993;4(6):385-390.
Link to Article
Ridderinkhof  KR, Ullsperger  M, Crone  EA, Nieuwenhuis  S.  The role of the medial frontal cortex in cognitive control. Science. 2004;306(5695):443-447.
PubMed   |  Link to Article
van Veen  V, Carter  CS.  The anterior cingulate as a conflict monitor: fMRI and ERP studies. Physiol Behav. 2002;77(4-5):477-482.
PubMed   |  Link to Article
Egner  T, Etkin  A, Gale  S, Hirsch  J.  Dissociable neural systems resolve conflict from emotional versus nonemotional distracters. Cereb Cortex. 2008;18(6):1475-1484.
PubMed   |  Link to Article
Swick  D, Turken  AU.  Dissociation between conflict detection and error monitoring in the human anterior cingulate cortex. Proc Natl Acad Sci U S A. 2002;99(25):16354-16359.
PubMed   |  Link to Article
Danielmeier  C, Eichele  T, Forstmann  BU, Tittgemeyer  M, Ullsperger  M.  Posterior medial frontal cortex activity predicts post-error adaptations in task-related visual and motor areas. J Neurosci. 2011;31(5):1780-1789.
PubMed   |  Link to Article
Garavan  H, Stout  JC.  Neurocognitive insights into substance abuse. Trends Cogn Sci. 2005;9(4):195-201.
PubMed   |  Link to Article
Goldstein  RZ, Alia-Klein  N, Tomasi  D,  et al.  Anterior cingulate cortex hypoactivations to an emotionally salient task in cocaine addiction. Proc Natl Acad Sci U S A. 2009;106(23):9453-9458.
PubMed   |  Link to Article
Laureys  S.  The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci. 2005;9(12):556-559.
PubMed   |  Link to Article
Bechara  A.  Disturbances of emotion regulation after focal brain lesions. Int Rev Neurobiol. 2004;62:159-193.
PubMed
Hester  R, Nestor  L, Garavan  H.  Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users. Neuropsychopharmacology. 2009;34(11):2450-2458.
PubMed   |  Link to Article
Amanzio  M, Torta  DM, Sacco  K,  et al.  Unawareness of deficits in Alzheimer’s disease: role of the cingulate cortex. Brain. 2011;134(pt 4):1061-1076.
PubMed   |  Link to Article
Craig  AD.  How do you feel—now? the anterior insula and human awareness. Nat Rev Neurosci. 2009;10(1):59-70.
PubMed   |  Link to Article
Critchley  HD, Wiens  S, Rotshtein  P, Ohman  A, Dolan  RJ.  Neural systems supporting interoceptive awareness. Nat Neurosci. 2004;7(2):189-195.
PubMed   |  Link to Article
Naqvi  NH, Bechara  A.  The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making. Brain Struct Funct. 2010;214(5-6):435-450.
PubMed   |  Link to Article
Naqvi  NH, Bechara  A.  The hidden island of addiction: the insula. Trends Neurosci. 2009;32(1):56-67.
PubMed   |  Link to Article
Naqvi  NH, Rudrauf  D, Damasio  H, Bechara  A.  Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315(5811):531-534.
PubMed   |  Link to Article
Hester  R, Foxe  JJ, Molholm  S, Shpaner  M, Garavan  H.  Neural mechanisms involved in error processing: a comparison of errors made with and without awareness. Neuroimage. 2005;27(3):602-608.
PubMed   |  Link to Article
Klein  TA, Endrass  T, Kathmann  N, Neumann  J, von Cramon  DY, Ullsperger  M.  Neural correlates of error awareness. Neuroimage. 2007;34(4):1774-1781.
PubMed   |  Link to Article
Hester  R, Fassbender  C, Garavan  H.  Individual differences in error processing: a review and reanalysis of three event-related fMRI studies using the GO/NOGO task. Cereb Cortex. 2004;14(9):986-994.
PubMed   |  Link to Article
Moeller  SJ, Hajcak  G, Parvaz  MA, Dunning  JP, Volkow  ND, Goldstein  RZ.  Psychophysiological prediction of choice: relevance to insight and drug addiction. Brain. 2012;135(pt 11):3481-3494.
PubMed   |  Link to Article
Stroop  JR.  Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643-662.
Link to Article
Moeller  SJ, Tomasi  D, Honorio  J, Volkow  ND, Goldstein  RZ.  Dopaminergic involvement during mental fatigue in health and cocaine addiction. Transl Psychiatry. 2012;2:e176.
PubMed   |  Link to Article
Mayer  AR, Teshiba  TM, Franco  AR,  et al.  Modeling conflict and error in the medial frontal cortex. Hum Brain Mapp. 2012;33(12):2843-2855.
PubMed   |  Link to Article
Sozda  CN, Larson  MJ, Kaufman  DA, Schmalfuss  IM, Perlstein  WM.  Error-related processing following severe traumatic brain injury: an event-related functional magnetic resonance imaging (fMRI) study. Int J Psychophysiol. 2011;82(1):97-106.
PubMed   |  Link to Article
Holmes  AJ, Pizzagalli  DA.  Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder. Arch Gen Psychiatry. 2008;65(2):179-188.
PubMed   |  Link to Article
Kerns  JG, Cohen  JD, MacDonald  AW  III,  et al.  Decreased conflict- and error-related activity in the anterior cingulate cortex in subjects with schizophrenia. Am J Psychiatry. 2005;162(10):1833-1839.
PubMed   |  Link to Article
Critchley  HD, Tang  J, Glaser  D, Butterworth  B, Dolan  RJ.  Anterior cingulate activity during error and autonomic response. Neuroimage. 2005;27(4):885-895.
PubMed   |  Link to Article
Edwards  BG, Calhoun  VD, Kiehl  KA.  Joint ICA of ERP and fMRI during error-monitoring. Neuroimage. 2012;59(2):1896-1903.
PubMed   |  Link to Article
Taylor  SF, Martis  B, Fitzgerald  KD,  et al.  Medial frontal cortex activity and loss-related responses to errors. J Neurosci. 2006;26(15):4063-4070.
PubMed   |  Link to Article
Ramautar  JR, Slagter  HA, Kok  A, Ridderinkhof  KR.  Probability effects in the stop-signal paradigm: the insula and the significance of failed inhibition. Brain Res. 2006;1105(1):143-154.
PubMed   |  Link to Article
Debener  S, Ullsperger  M, Siegel  M, Fiehler  K, von Cramon  DY, Engel  AK.  Trial-by-trial coupling of concurrent electroencephalogram and functional magnetic resonance imaging identifies the dynamics of performance monitoring. J Neurosci. 2005;25(50):11730-11737.
PubMed   |  Link to Article
Garavan  H, Ross  TJ, Kaufman  J, Stein  EA.  A midline dissociation between error-processing and response-conflict monitoring. Neuroimage. 2003;20(2):1132-1139.
PubMed   |  Link to Article
Ullsperger  M, von Cramon  DY.  Subprocesses of performance monitoring: a dissociation of error processing and response competition revealed by event-related fMRI and ERPs. Neuroimage. 2001;14(6):1387-1401.
PubMed   |  Link to Article
Franklin  TR, Acton  PD, Maldjian  JA,  et al.  Decreased gray matter concentration in the insular, orbitofrontal, cingulate, and temporal cortices of cocaine patients. Biol Psychiatry. 2002;51(2):134-142.
PubMed   |  Link to Article
Matochik  JA, London  ED, Eldreth  DA, Cadet  JL, Bolla  KI.  Frontal cortical tissue composition in abstinent cocaine abusers: a magnetic resonance imaging study. Neuroimage. 2003;19(3):1095-1102.
PubMed   |  Link to Article
Ersche  KD, Barnes  A, Jones  PS, Morein-Zamir  S, Robbins  TW, Bullmore  ET.  Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain. 2011;134(pt 7):2013-2024.
PubMed   |  Link to Article
Gardini  S, Venneri  A.  Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction. Brain Res Bull. 2012;87(2-3):205-211.
PubMed   |  Link to Article
Lane  RD, Quinlan  DM, Schwartz  GE, Walker  PA, Zeitlin  SB.  The Levels of Emotional Awareness Scale: a cognitive-developmental measure of emotion. J Pers Assess. 1990;55(1-2):124-134.
PubMed   |  Link to Article
Wilkinson  G. WRAT-3: Wide-Range Achievement Test 3 Administration Manual. Wilmington, DE: Wide Range Inc; 1993.
Wechsler  D. Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: Psychological Corporation; 1999.
Beck  AT, Steer  RA, Brown  GK. Beck Depression Inventory Manual.2nd ed. San Antonio, TX: The Psychological Corporation; 1996.
Lang PJ, Bradley MM, Cuthbert BN. International affective picture system (IAPS): affective ratings of pictures and instruction manual. Technical Report A-8. Gainesville: University of Florida; 2008.
Hogarth  L, Chase  HW, Baess  K.  Impaired goal-directed behavioural control in human impulsivity .Q J Exp Psychol.2012;65(2):305-316.
Klossek  UM, Russell  J, Dickinson  A.  The control of instrumental action following outcome devaluation in young children aged between 1 and 4 years. J Exp Psychol Gen. 2008;137(1):39-51.
PubMed   |  Link to Article
Tanaka  SC, Balleine  BW, O’Doherty  JP.  Calculating consequences: brain systems that encode the causal effects of actions. J Neurosci. 2008;28(26):6750-6755.
PubMed   |  Link to Article
Leung  HC, Skudlarski  P, Gatenby  JC, Peterson  BS, Gore  JC.  An event-related functional MRI study of the Stroop color word interference task. Cereb Cortex. 2000;10(6):552-560.
PubMed   |  Link to Article
Moeller  SJ, Honorio  J, Tomasi  D,  et al.  Methylphenidate enhances executive function and optimizes prefrontal function in both health and cocaine addiction [published online November 16, 2012]. Cereb Cortex. doi:10.1093/cercor/bhs345.
PubMed
Logan  GD, Crump  MJ.  Cognitive illusions of authorship reveal hierarchical error detection in skilled typists. Science. 2010;330(6004):683-686.
PubMed   |  Link to Article
Lee  JH, Garwood  M, Menon  R,  et al.  High contrast and fast three-dimensional magnetic resonance imaging at high fields. Magn Reson Med. 1995;34(3):308-312.
PubMed   |  Link to Article
Hennig  J, Scheffler  K.  Hyperechoes. Magn Reson Med. 2001;46(1):6-12.
PubMed   |  Link to Article
Caparelli  EC, Tomasi  D.  K-space spatial low-pass filters can increase signal loss artifacts in echo-planar imaging. Biomed Signal Process Control. 2008;3(1):107-114.
PubMed   |  Link to Article
Ashburner  J, Neelin  P, Collins  DL, Evans  A, Friston  K.  Incorporating prior knowledge into image registration. Neuroimage. 1997;6(4):344-352.
PubMed   |  Link to Article
Friston  KJ, Holmes  AP, Worsley  KJ, Poline  JB, Frith  CD, Frackowiak  RS.  Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp. 1995;2:189-210.
Link to Article
Friston  KJ, Worsley  KJ, Frackowiak  RSJ, Mazziotta  JC, Evans  AC.  Assessing the significance of focal activations using their spatial extent. Hum Brain Mapp. 1994;1:210-220.
Link to Article
Slotnick  SD, Moo  LR, Segal  JB, Hart  J  Jr.  Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Res Cogn Brain Res. 2003;17(1):75-82.
PubMed   |  Link to Article
Tardif  CL, Collins  DL, Pike  GB.  Sensitivity of voxel-based morphometry analysis to choice of imaging protocol at 3 T. Neuroimage. 2009;44(3):827-838.
PubMed   |  Link to Article
Ashburner  J, Friston  KJ.  Voxel-based morphometry: the methods. Neuroimage. 2000;11(6, pt 1):805-821.
PubMed   |  Link to Article
Ashburner  J, Friston  KJ.  Unified segmentation. Neuroimage. 2005;26(3):839-851.
PubMed   |  Link to Article
Cuadra  MB, Cammoun  L, Butz  T, Cuisenaire  O, Thiran  JP.  Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images. IEEE Trans Med Imaging. 2005;24(12):1548-1565.
PubMed   |  Link to Article
Alia-Klein  N, Parvaz  MA, Woicik  PA,  et al.  Gene x disease interaction on orbitofrontal gray matter in cocaine addiction. Arch Gen Psychiatry. 2011;68(3):283-294.
PubMed   |  Link to Article
Tanabe  J, Tregellas  JR, Dalwani  M,  et al.  Medial orbitofrontal cortex gray matter is reduced in abstinent substance-dependent individuals. Biol Psychiatry. 2009;65(2):160-164.
PubMed   |  Link to Article
Makris  N, Oscar-Berman  M, Jaffin  SK,  et al.  Decreased volume of the brain reward system in alcoholism. Biol Psychiatry. 2008;64(3):192-202.
PubMed   |  Link to Article
Konova  AB, Moeller  SJ, Tomasi  D,  et al.  Structural and behavioral correlates of abnormal encoding of money value in the sensorimotor striatum in cocaine addiction. Eur J Neurosci. 2012;36(7):2979-2988.
PubMed   |  Link to Article
Frewen  P, Lane  RD, Neufeld  RW, Densmore  M, Stevens  T, Lanius  R.  Neural correlates of levels of emotional awareness during trauma script-imagery in posttraumatic stress disorder. Psychosom Med. 2008;70(1):27-31.
PubMed   |  Link to Article
Lane  RD, Sechrest  L, Riedel  R.  Sociodemographic correlates of alexithymia. Compr Psychiatry. 1998;39(6):377-385.
PubMed   |  Link to Article
Subramaniam  K, Luks  TL, Fisher  M, Simpson  GV, Nagarajan  S, Vinogradov  S.  Computerized cognitive training restores neural activity within the reality monitoring network in schizophrenia. Neuron. 2012;73(4):842-853.
PubMed   |  Link to Article
Takahashi  H, Yahata  N, Koeda  M, Matsuda  T, Asai  K, Okubo  Y.  Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study. Neuroimage. 2004;23(3):967-974.
PubMed   |  Link to Article
Sturm  VE, Sollberger  M, Seeley  WW,  et al.  Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity. Soc Cogn Affect Neurosci. 2012;8(4):468-474.
PubMed   |  Link to Article
Shin  LM, Dougherty  DD, Orr  SP,  et al.  Activation of anterior paralimbic structures during guilt-related script-driven imagery. Biol Psychiatry. 2000;48(1):43-50.
PubMed   |  Link to Article
Amodio  DM, Frith  CD.  Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006;7(4):268-277.
PubMed   |  Link to Article
Gilbert  SJ, Spengler  S, Simons  JS,  et al.  Functional specialization within rostral prefrontal cortex (area 10): a meta-analysis. J Cogn Neurosci. 2006;18(6):932-948.
PubMed   |  Link to Article
Bolla  K, Ernst  M, Kiehl  K,  et al.  Prefrontal cortical dysfunction in abstinent cocaine abusers. J Neuropsychiatry Clin Neurosci. 2004;16(4):456-464.
PubMed   |  Link to Article
Franklin  T, Wang  Z, Suh  JJ,  et al.  Effects of varenicline on smoking cue–triggered neural and craving responses. Arch Gen Psychiatry. 2011;68(5):516-526.
PubMed   |  Link to Article
Culbertson  CS, Bramen  J, Cohen  MS,  et al.  Effect of bupropion treatment on brain activation induced by cigarette-related cues in smokers. Arch Gen Psychiatry. 2011;68(5):505-515.
PubMed   |  Link to Article
Pizzagalli  DA.  Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology. 2011;36(1):183-206.
PubMed   |  Link to Article
Amiez  C, Sallet  J, Procyk  E, Petrides  M.  Modulation of feedback related activity in the rostral anterior cingulate cortex during trial and error exploration. Neuroimage. 2012;63(3):1078-1090.
PubMed   |  Link to Article
Holman  BL, Carvalho  PA, Mendelson  J,  et al Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99m-HMPAO and ASPECT .J Nucl Med.1991;32(6):1206-1210.
Levin  JM, Holman  BL, Mendelson  JH,  et al Gender differences in cerebral perfusion in cocaine abuse: technetium-99m-HMPAO SPECT study of drug-abusing women .J Nucl Med.1994;35(12):1902-1909.
Khalsa  SS, Rudrauf  D, Feinstein  JS, Tranel  D.  The pathways of interoceptive awareness. Nat Neurosci. 2009;12(12):1494-1496.
PubMed   |  Link to Article
Li  CS, Huang  C, Yan  P, Bhagwagar  Z, Milivojevic  V, Sinha  R.  Neural correlates of impulse control during stop signal inhibition in cocaine-dependent men. Neuropsychopharmacology. 2008;33(8):1798-1806.
PubMed   |  Link to Article
Chua  HF, Liberzon  I, Welsh  RC, Strecher  VJ.  Neural correlates of message tailoring and self-relatedness in smoking cessation programming. Biol Psychiatry. 2009;65(2):165-168.
PubMed   |  Link to Article
Chua  HF, Ho  SS, Jasinska  AJ,  et al.  Self-related neural response to tailored smoking-cessation messages predicts quitting. Nat Neurosci. 2011;14(4):426-427.
PubMed   |  Link to Article
Orfei  MD, Robinson  RG, Bria  P, Caltagirone  C, Spalletta  G.  Unawareness of illness in neuropsychiatric disorders: phenomenological certainty versus etiopathogenic vagueness. Neuroscientist. 2008;14(2):203-222.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Supplement.

eAppendix.

eTable 1. Color-Word Stroop Activations and Deactivations to Error Across All Participants

eTable 2. Color-Word Stroop Activations and Deactivations to Conflict Across All Participants

eTable 3. Color-Word Stroop Between-Group Differences During Conflict

eFigure 1. Temporal patterns for regions of interest in the rostral anterior cingulate cortex (rACC) for error events (top panel) and correct events (bottom panel). To visualize the differences among the 3 study groups, we plotted the signal change from the time of the event (eg, error) (TR=1) to 12.8 seconds after the event (TR=9). At TR=1, the functional magnetic resonance imaging signal is normalized to zero; therefore, each subsequent TR reflects the signal minus zero. To show the breadth of activity within the rACC cluster, we show the signal averaged across our 4 peak rACC coordinates from Table 1 (main text). These time-series plots indicate that the reduced error greater than correct signal in impaired insight cocaine use disorder stems from a deactivation in this region to error, not an enhancement in this region to correct.

eFigure 2. Comparison of error greater than correct (error) and incongruent greater than congruent (conflict) mean percentage BOLD signal change in ACC (with corresponding ROI mask), as a function of study group (impaired insight cocaine participants, unimpaired insight cocaine participants, and healthy controls). The impaired group showed reduced ACC activity to error compared with the other study groups (as indicated by the asterisks, P < .05); in contrast, no group differences emerged for conflict.

eFigure 3. Correlation between craving and cocaine greater than pleasant probabilistic choice as a function of insight. Scatterplot shows the significant correlation in the unimpaired cocaine participants, but nonsignificant correlation in the impaired cocaine participants (note that controls were excluded from this analysis).

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

1,797 Views
6 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
×