Bilateral decrease in ventrolateral prefrontal cortex activation during motor response inhibition in mania

Available online at www.sciencedirect.com

JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 43 (2009) 432–441

www.elsevier.com/locate/jpsychires

Bilateral decrease in ventrolateral prefrontal cortex activation during motor response inhibition in mania q Pascale Mazzola-Pomietto a,*, Arthur Kaladjian a,b, Jean-Michel Azorin a,b, Jean-Luc Anton c, Re´gine Jeanningros a a

Institut de Neurosciences Cognitives de la Me´diterrane´e (INCM), UMR 6193, CNRS-Universite´ de la Me´diterrane´e, 31 chemin Joseph Aiguier, 13402 Marseille Cedex 20, France b Poˆle Universitaire de Psychiatrie Adultes, Hoˆpital Sainte Marguerite, Marseille, France c IFR 131, Centre d’Imagerie par Re´sonance Magne´tique fonctionnelle, Marseille, France Received 22 December 2007; received in revised form 25 April 2008; accepted 8 May 2008

Abstract Mania has been frequently associated with impaired inhibitory control. The present study aimed to identify brain functional abnormalities specifically related to motor response inhibition in mania by using event-related fMRI in combination with a Go/NoGo task designed to control for extraneous cognitive processes involved in task performance. Sixteen manic patients and 16 healthy subjects, group-matched for age and sex, were imaged while performing a warned equiprobable Go/NoGo task during event-related fMRI. Between-group differences in brain activation associated with motor response inhibition were assessed using analyses of covariance. Although no significant between-group differences in task performance accuracy were observed, patients showed significantly longer response times on Go trials. After controlling for covariates, the only brain region that differentiated the two groups during motor response inhibition was the ventrolateral prefrontal cortex (VLPFC), where activation was significantly decreased in both the right and left hemispheres in manic patients. Our data suggest that response inhibition in mania is associated with a lack of engagement of the bilateral VLPFC, which is known to play a primary role in the suppression of irrelevant responses. This result might give clues to understanding the pathophysiology of dishinhibition and impulsivity that characterize mania. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Mania; fMRI; Response inhibition; Ventrolateral prefrontal cortex; Bipolar disorder

1. Introduction Individuals with mania exhibit a cluster of symptoms involving impulsivity and increased motor activity (Swann et al., 2001; Akiskal et al., 2003), which suggests a breakdown in the processes underlying inhibitory control. Consistent with this view, neuropsychological studies have shown that manic patients are impaired on various executive function tasks, which have in common to require inhibq

Mazzola-Pomietto and Kaladjian equally contributed to this work. Corresponding author. Tel.: +33 491 164 318; fax: +33 491 164 498. E-mail address: [email protected] (P. MazzolaPomietto). *

0022-3956/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2008.05.004

itory control (McGrath et al., 1997; Swann et al., 2003; Dixon et al., 2004; Larson et al., 2005; Bora et al., 2006). Thus, an important direction of research in mania involves investigating the neural correlates of inhibitory control. A number of authors have suggested that the neural correlates of inhibitory control are best explored when studied in relative isolation within the motor domain (Mostofsky et al., 2003; Aron et al., 2004; Friedman and Miyake, 2004). The Go/NoGo task has been widely used to study brain function associated with motor response inhibition. In this task, subjects are required to perform speeded responses, generally with a button-press, on the presentation of Go stimuli and to inhibit responding upon the appearance of NoGo stimuli.

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

So far, only one functional neuroimaging study of motor response inhibition has been performed in individuals with mania (Altshuler et al., 2005), most likely because of the challenge of imaging this clinically unstable group of patients. This study used a Go/NoGo task in combination with functional magnetic resonance imaging (fMRI). It was found that manic patients relative to healthy subjects exhibited reduced activation in several brain regions, including the right ventrolateral prefrontal cortex (VLPFC) and left anterior cingulate cortex (ACC) during the inhibition condition of the task. However, it remains unclear whether these abnormalities are specific to motor response inhibition. The study employed a blocked design in which the brain areas supporting this inhibitory function were inferred from the brain activity elicited by blocks containing both Go and NoGo stimuli relative to Go-only blocks. The problem with this contrast is that it also shows activation related to a host of other cognitive processes including change in set, overcoming conflict in action selection, error monitoring, and oddball effects associated with the presentation of relatively rare NoGo stimuli (for criticism of block Go/NoGo design see Liddle et al., 2001; Menon et al., 2001; Rubia et al., 2001). In the present study, we aimed to examine functional abnormalities in the neural system specifically subserving motor response inhibition in manic patients. For this purpose, we used a warned equiprobable Go/NoGo task in conjunction with an event-related fMRI design. This design allows detection of activations specifically associated with motor response inhibition by excluding activations related to errors and by controlling for those related to extraneous cognitive processes (Liddle et al., 2001). The study was performed in relatively large groups of manic patients and healthy subjects to increase the power with respect to identifying between-group differences in brain activation. We hypothesized that manic patients,

433

when compared to healthy subjects, would show a decrease in activation restricted to the VLPFC region, which has been shown to be a key node in the brain network subserving motor response inhibition and thought to be dysfunctional in mania. 2. Methods and materials 2.1. Subjects Thirty seven inpatients with bipolar I disorder and 25 healthy comparison subjects participated in the study. All participants met the following inclusion criteria: (1) no history of substance or alcohol abuse or other medical or neurological disorder that might affect brain function; (2) right-handedness as assessed using the Edinburgh Handedness Inventory (Oldfield, 1971); (3) no contraindication for fMRI. Participants were interviewed using the French version of the Structured Clinical Interview for the DSM-IV Axis I Disorders, Patient Version (SCID-I/P) or Nonpatient Version (SCID-I/NP) (First et al., 1994), as appropriate. These interviews confirmed that patients met DSM-IV criteria for bipolar I disorder with current manic episode and without any active comorbid Axis I conditions, and that comparison subjects were free of current or past psychiatric diagnoses. Each participant completed the French version of the National Adult Reading Test (fNART) to estimate the premorbid intelligence quotient (IQ) (Mackinnon et al., 1999). The severity of mood symptoms in patients were rated using the Young Mania Rating Scale (YMRS; Young et al., 1978; Favre et al., 2003) and the 21-item Hamilton Depression Rating Scale (HDRS; Hamilton, 1960) within 24 h of scanning. We excluded 21 patients because they presented excessive movements or were unable to complete the procedure (demographic and clinical characteristics of these patients are shown online

Table 1 Demographic and clinical characteristics of the samples included in the study Characteristic

Manic subjects (N = 16) N

Gender (female/male) Age (years) Right handedness score (%)a Premorbid IQb Age at onset (years) Duration of illness (years) Number of mood episodes Manic Depressive Number of hospitalization YMRS score HDRS score

10/6 Mean 35.8 84.0 108.4 25.1 10.8 4.9 4.1 0.8 4.2 22.4 4.5

Healthy subjects (N = 16)

Statistic

%

N

%

v2 value

p value

62.5/37.5 SD

10/6 Mean

62.5/37.5 SD

0 t value

1.0 p value

12.1 19.3 5.9 7.7 12.9 5.1 4.8 1.2 5.0 5.4 2.6

34.6 89.9 112.3 – – – – – – – –

12.6 8.9 3.09 – – – – – – – –

0.94 1.10 2.15 – – – – – – – –

0.777 0.279 0.039 – – – – – – – –

Abbreviations: IQ, Intelligence Quotient; HDRS, Hamilton Depression Rating Scale; YMRS, Young Mania Rating Scale; –, not applicable. a Measured by using the Edinburgh Handedness Inventory. b Estimated WAIS-R Full Scale IQ score, derived from the score to the French National Adult Reading Test.

434

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

as a supplementary material). The 16 patients whose data were included in the study were compared with 16 healthy subjects group-matched for sex and age. All patients were taking psychotropic medications at the time of scanning. Eleven patients were receiving either mood stabilizers (N = 6) or atypical antipsychotics (N = 5) and five a combined pharmacological treatment of these medications. The procedures were approved by the ethical committee from Marseille II. After complete description of the study, all participants provided written informed consent. 2.2. Go/NoGo task The Go-NoGo task is typically designed with many more Go than NoGo stimuli to establish a prepotent tendency to respond. However, under conditions in which NoGo stimuli are rare, brain activation associated with inhibition of the prepotent response is entailed by that related to processing of novelty and conflict (Braver et al., 2001; Nieuwenhuis et al., 2003). An alternative approach to establish a prepotent tendency to respond consists in introducing a warning phase to signal the impending presentation of a stimulus, no matter its type (Go or NoGo) (Konishi et al., 1999; Liddle et al., 2001; Watanabe et al., 2002; Kaladjian et al., 2007: Karch et al., 2008). The warning phase facilitates speeded responding to Go stimuli and increases the difficulty of withholding responses to NoGo stimuli. This approach allows to match the Go and NoGo trials for frequency and thus to perform unbiased comparison of brain activation during these two types of trials. The present study used the same version of the warned equiprobable Go/NoGo task to that described by Kaladjian et al. (2007). Briefly, the task consisted of two runs. Each run contained 25 NoGo and 25 Go trials, presented in a pseudo-random order. Each trial began with a 5 s warning phase consisting of a countdown (i.e., a series of circles with decreasing diameters). Subjects were instructed to press a right-handed button box as quickly as possible upon the presentation of the letter ‘X’ (i.e., the Go stimuli) and to withhold response on the appearance of the letter ‘A’ (i.e., the NoGo stimuli). Errors of omission (EO), errors of commission (EC) and response times to Go trials (RT) were recorded. Perceptual sensitivity (d0 ) and response bias (b) were calculated for each individual. Participants completed a brief practice run of the task before scanning to familiarize them with the task instructions. 2.3. Image acquisition Images were obtained using a 3T whole body MRI scanner (Medspec 30/80 AVANCE, BRUKER, Ettlingen, Germany) with a circular polarized head coil. A vacuum-bag was used to limit head movements within the coil. An axial anatomical volume was acquired using a 3D T1-weighted MPRAGE sequence (TI 800 ms, TR 25 ms, TE 5 ms, Trecov 2300 ms, flip angle of 15°, field of view 256  230  180 mm, voxel size, 1.0  1.2  1.73 mm). Blood-oxygen-

level-dependent (BOLD) images were acquired using a T2*-weighted FID echoplanar sequence (36 contiguous interleaved axial slices, TR 3 s, TE 35 ms, flip angle of 83°, field of view 192  192 mm, voxel size 3  3  3 mm). Anatomical and BOLD images were collected during a single acquisition period. 2.4. Data analysis The sociodemographic characteristics, clinical ratings and behavioral data of the manic patient and healthy subject groups were compared using chi-square and two-sample Student’s t tests, as appropriate. Image data were processed using standard procedures, as implemented in SPM99 (Wellcome Department of Cognitive Neurology, University College, London). Data from each subject were corrected for slice timing and movement parameters were estimated. Subjects whose movements exceeded one voxel size were excluded from further analyses. Data from subjects included in the study were spatially realigned to remove any minor (subvoxel) motion-related signal change. Whatever the direction considered in translation or rotation, there were no significant differences for means of estimated inter-scan movement parameters between the manic patient and healthy subject groups (all jt30j < 1.4, all p > 0.17). Anatomical images were transformed into standardized SPM/MNI stereotaxic space and transformation parameters were applied to the functional images. Functional images were smoothed with a Gaussian filter (9-mm kernel). The resulting time series across each voxel were high-pass-filtered with a cut-off period of 120 s. A statistical analytical design which took into account the trial outcome and the preparation phase was constructed in each individual subject within the framework of the General Linear Model as implemented in SPM99 (Friston et al., 1995). Four types of trial outcomes were distinguished: correct Go trial, incorrect Go trial, correct NoGo trial, incorrect NoGo trial. Each of them was modeled with a canonical hemodynamic response function. The preparation phase was modeled with a delayed box-car function convolved with a hemodynamic response function. In the first level of analysis, regional brain activations associated with successful response inhibition were assessed by creating one contrast image for each subject: correct NoGo trials minus correct Go trials. These contrast images were used for the second-level group statistics. Error trials were not entered into any contrast because there were not enough incorrect NoGo or incorrect Go trials, providing little power to estimate the hemodynamic response to these trials. An initial examination of within-group activation was made up for each group separately by computing a onesample Student’s t test. Between-group differences in activation were assessed by using analyses of covariance (ANCOVAs) with IQ and RT as covariates of non-interest. Furthermore, to avoid confounding effects of relative deactivation in one group, the ANCOVAs were constrained with an inclusive mask in which only voxels surviving a

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

height threshold of p < 0.05 for within-group analyses were retained. Activations were reported if they exceeded p < 0.001 uncorrected for multiple comparisons at the voxel level and p < 0.05 corrected at the cluster level. MNI coordinates were transformed to Talairach coordinates using a nonlinear transformation (Brett, 2000). To further interpret our data, we performed post hoc analyses on the clusters showing between-group differences. The relationship between the level of activation in these clusters (effect size extracted in each subject with MarsBaR, http://marsbar.sourceforge.net/) and the YMRS score was examined in patients by using Pearson’s correlation tests. The differential effect of two classes of medications was investigated by distinguishing a normothymic-treated subgroup (N = 6) and a antipsychotic-treated subgroup (N = 5). Differences in the level of activation between these subgroups and between each of these subgroups and the healthy subject group were assessed using Mann–Whitney tests. 3. Results

uli with a similar ease and developed a similar tendency toward responding. 3.2. fMRI data Within-group analysis in healthy subjects revealed significant activation during motor response inhibition in a distributed network of brain areas (Table 3 and Fig. 1A). Within prefrontal cortex, activations were localized in the right VLPFC (Broadmann’s area [BA] 47), left VLPFC extending to dorsolateral prefrontal cortex (BA 47/45/9/ 8) and left anteromedial prefrontal cortex (BA 10/9/8). Within posterior brain areas, activations were observed in the bilateral inferior parietal lobule and adjacent areas (BA 7/39/40), right superior and middle temporal gyri (BA 22/21) and bilateral posterior cingulate and precuneus (BA 31/7). Table 3 Significant within-group activation during response inhibitiona in manic patients and healthy comparison subjects and between-group differences in activation

3.1. Demographic, psychometric and behavioral data

Group and region

Manic patients and healthy subjects were closely matched in terms of sex, age and handedness (Table 1). Patients had significantly lower premorbid IQs than healthy subjects. There were no significant between-group differences regarding task performance accuracy (i.e., percentage of EO and EC) (Table 2). A significant between-group difference for RT was found, with patients being slower than healthy subjects. There were no significant between-group differences for perceptual sensitivity and response bias. According to Cohen’s benchmarks (Cohen, 1988), the effect size of the between-group difference for perceptual sensitivity was small (d = 0.35) and that for response bias was negligible (d = 0.05). These data indicate that patients and healthy subjects distinguished the Go and NoGo stim-

Healthy subjects Right inferior frontal gyrus Left inferior frontal gyrus extending to middle frontal gyrus Left superior frontal gyrus extending to medial frontal gyrus Right superior temporal gyrus extending to middle temporal gryus Right inferior parietal lobule extending to supramarginal gyrus Left superior parietal lobule extending to inferior parietal lobule Bilateral posterior cingulate extending to precuneus

Table 2 Performance, perceptual sensitivity and response bias on the Go/NoGo task for manic patients and healthy comparison subjects Manic patients (N = 16) Mean Accuracy Errors of omission (%) Errors of commission (%) Response time in Go trials (ms) Perceptual sensitivity Response bias

Healthy subjects (N = 16) SD

Mean

Statistic

SD

t value

p value

1.2

2.0

0.4

0.8

1.59

0.12

9.4

6.5

8.4

8.1

0.41

0.69

407.5

70.0

360.8

42.4

2.28

0.03

1.30 0.11

0.21 0.91

3.6 0.32

0.6 0.22

3.8 0.33

0.6 0.23

435

Manic patients Right middle and superior frontal gyri Left supramarginal gyrus extending to left superior temporal gyrus Right posterior cingulate gyrus extending to precuneus

BA

Z scoreb

X

Y

Z

Cluster size

47 47/ 45/ 9/8 10/ 9/8

5.30 5.28

42 36

29 31

9 11

73 445

4.55

21

59

5

265

22/ 21

4.11

59

17

1

68

39/ 40

5.30

48

57

25

118

7/ 39/ 40 31/ 7

4.40

36

63

51

400

3.48

3

42

41

72

8/6

4.22

24

20

49

34

39

4.42

39

57

30

64

31/ 7

4.69

6

45

41

26

5.04 4.48

42 39

26 23

6 9

31 62

Healthy subjects > manic patientsc Right inferior frontal gyrus 47 Left inferior frontal gyrus 47

BA = Brodmann’s area; X, Y, Z = Talairach coordinates. a Assessed by the contrast ‘‘correct NoGo trials versus correct Go trials”, p < 0.001 uncorrected at the voxel level and p< 0.05 corrected at the cluster level. b For peak area of activation. c Assessed by an analysis of covariance with intelligence quotient and response time to Go trials as covariates of non-interest.

436

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

Fig. 1. Brain regions exhibiting significant activations during response inhibition in healthy subjects (A) and manic patients (B). Response inhibition was assessed by the contrast ‘‘correct NoGo trials versus correct Go trials”. Regional activations were surface-rendered onto transaxial slices of a standard reference brain. Activation maps were thresholded at p < 0.001 uncorrected at the voxel level and p < 0.05 corrected at the cluster level. The color scale represents voxel t values. L = left; R = right.

Within-group analysis in manic patients revealed significant activation during response inhibition in a less widespread network of brain areas than that observed in healthy subjects (Table 3 and Fig. 1B). Within prefrontal areas, activation was localized in the right dorsal prefrontal cortex (BA 8/6). Within posterior brain areas, activations were detected in the left temporoparietal cortex (BA 39) and bilateral posterior cingulate and precuneus (BA 31/7). Between-group comparisons revealed that the manic patient group, as compared with the healthy subject group, showed a significant decrease in activation during motor response inhibition in bilateral VLPFC (BA 47) only (Table 3 and Fig. 2). No brain area was significantly more activated in the manic patient group relative to the healthy subject group. Post hoc analyses did not show significant correlations between the YMRS score and the level of activation in either the right (r16 = 0.027, p > 0.9) or left VLPFC (r16 = 0.251, p > 0.3) in patients. Regarding the impact of the different classes of medications on the level of activation, there were no significant differences between the normothymic- and antipsychotic-treated patient subgroups (Zright VLPFC = 1.38, p = 0.17; Zleft VLPFC = 1.00, p = 0.32). Further, each of these subgroups exhibited significantly reduced level of activation in both the right and left VLPFC as compared to healthy subjects (all Z < 2.43; all p < 0.01). 4. Discussion The present study compared the neural correlates of motor response inhibition in manic patients and healthy

subjects by using a warned equiprobable Go/NoGo task during event-related fMRI. The principal finding is that the only region that differentiated the two groups during response inhibition was the VLPFC, where activation was significantly decreased in both the right and left hemispheres for manic patients. We observed that manic patients relative to healthy subjects had the greatest decrease in activation within a cluster located in the right VLPFC, more precisely in the pars orbitalis (X = 42, Y = 26, Z = 6). This is consistent with the data of the only prior fMRI study of the Go/NoGo task in mania (Altshuler et al., 2005), which also evidenced reduced activation in the same region (X = 34, Y = 30, Z = 4) when manic patients were compared to healthy subjects. In addition, we demonstrated significantly reduced activation in the homologous region of the left hemisphere (X = 39, Y = 23, Z = 9). This finding contrasts with that of Altshuler et al. (2005) who did not report between-group difference in activation within the left VLPFC. The divergence of results is not surprising given that the prior study failed to identify left-sided VLPFC activation in healthy subjects, rendering the test of the functionality of this region in patients impossible. The great majority of fMRI studies of motor response inhibition performed in healthy subjects have reported bilateral VLPFC activation (Liddle et al., 2001; Menon et al., 2001; Rubia et al., 2001; Durston et al., 2002; Horn et al., 2003; Matthews et al., 2005; Rubia et al., 2005a; Evers et al., 2006; Kaladjian et al., 2007; Leung and Cai, 2007; Rubia et al., 2007). In the studies using a parametric design, it has been described that increasing the motor

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

437

Fig. 2. Significant blunted activation during response inhibition in bilateral ventrolateral prefrontal cortex in manic patients versus healthy subjects. Response inhibition was assessed by the contrast ‘‘correct NoGo trials versus correct Go trials”. The between-group comparison was performed by using an analysis of covariance with intelligence quotient and response time on Go trials as covariates of non-interest. The statistical parametric map was thresholded at p < 0.001 uncorrected at the voxel level and p < 0.05 corrected at the cluster level and surface-rendered onto a canonical image of a standard reference brain. The color scale represents voxel t values.

response inhibition load yields increased activity in both the right and left VLPFC (Durston et al., 2002; Matthews et al., 2005). It is also interesting to point out that in an electrophysiological study of the Go/NoGo task, it was found that the sources of the brain potentials associated with response inhibition were localized in the bilateral VLPFC (Bokura et al., 2001). Altogether, these data converge to indicate that both the right and left VLPFC are key regions of the neural circuitry mediating motor response inhibition in healthy subjects. Our data are consistent with this view. The bilateral VLPFC dysfunction seen in manic patients in the current study is in line with the findings of a prior cross-sectional fMRI study of bipolar disorder which have explored inhibition of cognitive interference by using a Stroop task in manic, depressed and euthymic patients (Blumberg et al., 2003). In this study, a deficit of activation was evidenced in the right ventral prefrontal cortex when manic patients were compared to euthymic patients. In addition, a blunted activation in the left ventral prefrontal cortex was observed when all patients, regardless of their mood state, were compared to healthy subjects. The authors proposed that the decrease in activation of the right ventral prefrontal cortex was specific to the manic phase whereas that of the left ventral prefrontal cortex was a trait-related feature of bipolar disorder. So far, this hypothesis has been neither confirmed nor infirmed. Among the two recent investigations of the Stroop task performed in euthymic bipolar patients, none reported a deficit of activation within the right ventral prefrontal cortex (Strakowski et al., 2005; Kronhaus et al., 2006), and one evidenced a deficit of activation within the left VLPFC (Kronhaus et al., 2006). In another study of the Go/NoGo task conducted by our group in euthymic bipolar patients, no VLPFC dysfunction was observed (Kaladjian et al., submitted for publication). Thus, it remains unclear as to whether a left VLPFC dysfunction within the context of

inhibitory control tasks is a trait-related feature of bipolar disorder. In the other hand, it remains also uncertain if VLPFC dysfunction is related to the state of mania. In the current study, there were no significant correlations between the severity of manic symptoms and VLPFC activation in either the left or right hemisphere. These results are in line with those of the prior study of the Go/NoGo task in mania (Altshuler et al., 2005). However, in our study like in the prior one, the manic patient group was quite homogeneous regarding mood severity. Thus, if there were a relationship between the level of activation and the severity of mood symptoms, it might not have been detected because of the restricted range of YMRS scores. It will be interesting in future longitudinal studies to compare brain activation in bipolar patients scanned during both manic and euthymic phases to better delineate whether or not VLPFC activity is sensitive to mood states. Functional abnormalities within the VLPFC have also been frequently reported in neuroimaging studies of emotion processing in bipolar disorder (Kruger et al., 2003; Elliott et al., 2004; Lawrence et al., 2004; Chen et al., 2006; Malhi et al., 2005, 2007; Wessa et al., 2007; Foland et al., 2008). Of particular interest, we feel, are the results of a fMRI study of an emotional Go/NoGo task in mania (Elliott et al., 2004). This study showed that manic patients, relative to healthy subjects, had enhanced VLPFC activation when response inhibition was guided by emotional information. Such findings contrast with the reduced VLPFC activation that was observed during response inhibition in a non-emotional context in the current study and that of Altshuler et al. (2005). VLPFC is a brain region where inputs coming from executive and emotional systems are integrated (Sakagami and Pan, 2007; Pessoa, 2008). It is possible that, during mania, functional changes within the neural circuitry underlying emotional processing induces an increase of VLPFC responsiveness to irrelevant emotional information, which is accompanied by a

438

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

decrease of the ability of this region to be engaged in ‘‘nonemotional” cognitive processes, and more especially in response inhibition. The neural bases of motor response inhibition have been studied in other disorders that, like mania, manifest disinhibited behavior. Defective VLPFC activation has been reported in fMRI studies of attention-deficit/hyperactivity disorder (Rubia et al., 2005b; Dickstein et al., 2006; Durston et al., 2006), fragile X syndrome (Hoeft et al., 2007), schizophrenia (Kaladjian et al., 2007) and borderline and antisocial personality disorders (Vollm et al., 2004). A decrease in brain perfusion within the VLPFC of patients with borderline and antisocial personality disorders has also been found in an investigation using single photon emission computed tomography (Goethals et al., 2005). Thus, the current results add to the growing literature suggesting that a VLPFC dysfunction is a common characteristic of clinical populations demonstrating symptoms of disinhibition. Another important finding of our study is that functional abnormalities in manic patients were restricted to the sole VLPFC. This finding differs from those of Altshuler et al. (2005) who evidenced that functional abnormalities also affected the ACC and hippocampus. These authors designed their Go/NoGo task with a block-design approach where brain activations related to response inhibition were determined by subtracting blocks containing mixed Go and NoGo stimuli with blocks consisting solely of Go stimuli. This subtraction does not allow to disentangle brain activations associated with response inhibition from those associated with incidental cognitive processes, which also occur in the mixed Go/NoGo blocks, such as overcoming conflict in action selection, error monitoring and novelty processing (Liddle et al., 2001; Menon et al., 2001; Rubia et al., 2001). This may be especially relevant for the dorsal ACC, which is sensitive to the extraneous cognitive processes mentioned above (Braver et al., 2001; Kerns et al., 2004; van Veen et al., 2004). Consistent with our findings, prior event-related fMRI studies of the Go/ NoGo task, which have also matched the frequency of NoGo and Go stimuli, did not report that ACC activation was associated with motor response inhibition in healthy subjects (Braver et al., 2001; Liddle et al., 2001; Watanabe et al., 2002). Otherwise, it has been reported that euthymic bipolar patients had decreased ACC activation during response conflict (Gruber et al., 2004). Thus, it is likely that the ACC activation deficit observed in manic patients by Altshuler et al. (2005) was not related to response inhibition per se but related to incidental cognitive processes involved in task performance. In the present study, manic patients relative to healthy subjects showed reduced VLPFC activation in the absence of between-group difference in task performance accuracy. It is likely that, to compensate for localized functional deficits and maintain task accuracy, manic patients recruited alternative brain regions whose activations were too heterogeneous to be detected by using a random-effect model for

fMRI data analysis. Otherwise, it is of note that manic patients had longer RT on Go trials than healthy subjects. Longer RT in patients is likely to result from several factors, such as the effects of medications and mood state. Whatever the origin of the difference in RT, one could argue that it has biased the between-group comparison of the fMRI data. However, the VLPFC dysfunction was evidenced while the RT was factored in this comparison. Further, it has been recently reported that the level of VLPFC activation during NoGo trials was not sensitive to the average speed of responding on Go trials (Garavan et al., 2006). Therefore, it is unlikely that the between-group difference in RT may have accounted for our findings. The main limitation of the present study is that all manic patients were on psychotropic medications. Thus, we were unable to determine the extent to which the between-group differences in VLPFC activation were confounded by medication effects. However, our data showed that the magnitude of the decrease in neural response in both the right and left VLPFC was not influenced by the class of mediations the patients were receiving (normothymics versus antipsychotics). It is interesting to note that in the prior fMRI study of the Go/NoGo task in mania, it was reported that a small subgroup of unmedicated patients (N = 4) still demonstrated blunted VLPFC activation as compared to healthy subjects (Altshuler et al., 2005). Otherwise, a few fMRI studies of euthymic bipolar patients have compared changes in regional brain activation between medicated or unmedicated patients and healthy volunteers during performance of other cognitive paradigms (Caligiuri et al., 2003; Blumberg et al., 2005; Leibenluft et al., 2007). All of these studies have reported that changes in frontal or subcortical activities differed more markedly between unmedicated patients and healthy subjects than between medicated patients and healthy subjects. Thus, it is unlikely that the between-group differences in activation observed in the current study result from an effect of medication. Another limitation was that the task was designed to investigate only the neural correlates of successful response inhibition. Given that inhibitory control is intimately related to error processing, it would be interesting in future studies of manic patients to use a paradigm that allows the simultaneous examination of brain regions involved in successful and unsuccessful response inhibition. Offsetting these potential limitations, a major strength of the study is the size of the manic patient group (N = 16), which is larger, to our knowledge, than those of the previous functional neuroimaging studies conducted in mania. This increases the validity of our findings. In sum, our data indicate that, relative to healthy subjects, patients with bipolar I disorder in a manic state may have deficits in their ability to engage the right and left VLPFC during motor response inhibition. This is a region whose literature has emphasized the importance for the inhibition of irrelevant motor responses. These results may give clues to understanding the pathophysiology of disinhibition and impulsivity that characterize mania.

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

Conflicts of interest All authors declare that they have no conflicts of interest. Contributors The contributions of each author to this work are the following: – Mazzola-Pomietto P. and Kaladjian A. equally contributed to it by designing the study and carrying out the fRMI acquisitions. They also undertook the statistical analyses and the writing of the first draft of the manuscript. – Anton J.L. provided MRI acquisition sequences and the program for the behavioral task. He also contributed to fMRI data acquisition and analyses. – Azorin J.M. contributed to the design of the clinical aspects of the study as well as to patients recruitment. – Jeanningros R. had the idea of this study. She was involved in its design, in the interpretation of the results, as well as in the writing of the manuscript. All authors reviewed the manuscript critically and approved the version that has been submitted. Role of the funding source Funding for this study was provided by the Centre National de la Recherche Scientifique (CNRS). The CNRS had no further role in the design of the study; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Acknowledgement This work was supported by funds from the ‘‘Centre National de la Recherche Scientifique” (CNRS). The authors thank Bruno Nazarian and Muriel Roth, who assisted in the fMRI task design and data acquisition, and He´le`ne Rescigno who helped with the behavioral data analysis and literature search. References Akiskal HS, Azorin JM, Hantouche EG. Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy. Journal of Affective Disorders 2003;73:7–18. Altshuler LL, Bookheimer SY, Townsend J, Proenza MA, Eisenberger N, Sabb F, et al. Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study. Biological Psychiatry 2005;58:763–9. Aron AR, Robbins TW, Poldrack RA. Inhibition and the right inferior frontal cortex. Trends in Cognitive Sciences 2004;8:170–7. Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, et al. A functional magnetic resonance imaging study of

439

bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Archives of General Psychiatry 2003;60:601–9. Blumberg HP, Donegan NH, Sanislow CA, Collins S, Lacadie C, Skudlarski P, et al. Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorder. Psychopharmacology (Berl) 2005;183:308–13. Bokura H, Yamaguchi S, Kobayashi S. Electrophysiological correlates for response inhibition in a Go/NoGo task. Clinical Neurophysiology 2001;112:2224–32. Bora E, Vahip S, Akdeniz F. Sustained attention deficits in manic and euthymic patients with bipolar disorder. Progress in Neuro-psychopharmacology and Biological Psychiatry 2006;30:1097–102. Braver TS, Barch DM, Gray JR, Molfese DL, Snyder A. Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors. Cerebral Cortex 2001;11:825–36. Brett M. http://imaging.mrc-cbu.cam.ac.uk/imaging/mnitalairach; 2000. Caligiuri MP, Brown GG, Meloy MJ, Eberson SC, Kindermann SS, Frank LR, et al. An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder. Psychiatry Research 2003;123:171–82. Chen CH, Lennox B, Jacob R, Calder A, Lupson V, BisbrownChippendale R, et al. Explicit and implicit facial affect recognition in manic and depressed states of bipolar disorder: a functional magnetic resonance imaging study. Biological Psychiatry 2006;59:31–9. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, New Jersey: Lawrence Erlbaum Press; 1988. Dickstein SG, Bannon K, Castellanos FX, Milham MP. The neural correlates of attention deficit hyperactivity disorder: an ALE metaanalysis. Journal of Child Psychology and Psychiatry 2006;47:1051–62. Dixon T, Kravariti E, Frith C, Murray RM, McGuire PK. Effect of symptoms on executive function in bipolar illness. Psychological Medicine 2004;34:811–21. Durston S, Thomas KM, Worden MS, Yang Y, Casey BJ. The effect of preceding context on inhibition: an event-related fMRI study. Neuroimage 2002;16:449–53. Durston S, Mulder M, Casey BJ, Ziermans T, van Engeland H. Activation in ventral prefrontal cortex is sensitive to genetic vulnerability for attention-deficit hyperactivity disorder. Biological Psychiatry 2006;60:1062–70. Elliott R, Ogilvie A, Rubinsztein JS, Calderon G, Dolan RJ, Sahakian BJ. Abnormal ventral frontal response during performance of an affective go/nogo task in patients with mania. Biological Psychiatry 2004;55:1163–70. Evers EA, van der Veen FM, van Deursen JA, Schmitt JA, Deutz NE, Jolles J. The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers. Psychopharmacology (Berl) 2006;187:200–8. Favre S, Aubry JM, Gex-Fabry M, Ragama-Pardos E, McQuillan A, Bertschy G. Translation and validation of a French version of the Young Mania Rating Scale (YMRS). Encephale 2003;29:499–505. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV-Axis I disorders, research version, patient edition (SCID-I/P) and non patient edition. New York: Biometrics Research, New York State Psychiatric Institute; 1994. Foland LC, Altshuler LL, Bookheimer SY, Eisenberger N, Townsend J, Thompson PM. Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania. Psychiatry Research: Neuroimaging 2008;162:27–37. Friedman NP, Miyake A. The relations among inhibition and interference control functions: a latent-variable analysis. Journal of Experimental Psychology General 2004;133:101–35. Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frakowiack RSJ. Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping 1995;2:189–210. Garavan H, Hester R, Murphy K, Fassbender C, Kelly C. Individual differences in the functional neuroanatomy of inhibitory control. Brain Research 2006;1105:130–42.

440

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441

Goethals I, Audenaert K, Jacobs F, Van den Eynde F, Bernagie K, Kolindou A, et al. Brain perfusion SPECT in impulsivity-related personality disorders. Behavioural Brain Research 2005;157:187–92. Gruber SA, Rogowska J, Yurgelun-Todd DA. Decreased activation of the anterior cingulate in bipolar patients: an fMRI study. Journal of Affective Disorders 2004;82:191–201. Hamilton M. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 1960;23:56–62. Hoeft F, Hernandez A, Parthasarathy S, Watson CL, Hall SS, Reiss AL. Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome. Human Brain Mapping 2007;28:543–54. Horn NR, Dolan M, Elliott R, Deakin JF, Woodruff PW. Response inhibition and impulsivity: an fMRI study. Neuropsychologia 2003;41:1959–66. Kaladjian A, Jeanningros R, Azorin JM, Grimault S, Anton JL, MazzolaPomietto P. Blunted activation in right ventrolateral prefrontal cortex during motor response inhibition in schizophrenia. Schizophrenia Research 2007;97:184–93. Kaladjian A, Jeanningros R, Azorin JM, Nazarian B, Roth M, MazzolaPomietto P. Reduced brain activation in euthymic bipolar patients during response inhibition: an event-related fMRI study. Psychiatry Research: Neuroimaging, submitted for publication. Karch S, Jager L, Karamatskos E, Graz C, Stammel A, Flatz W, et al. Influence of trait anxiety on inhibitory control in alcohol-dependent patients: simultaneous acquisition of ERPs and BOLD responses. Journal of Psychiatric Research 2008;42:734–45. Kerns JG, Cohen JD, MacDonald AW, Cho RY, Stenger VA, Carter CS. Anterior cingulate conflict monitoring and adjustments in control. Science 2004;303:1023–6. Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y. Common inhibitory mechanism in human inferior prefrontal cortex revealed by event-related functional MRI. Brain 1999;122:981–91. Kronhaus DM, Lawrence NS, Williams AM, Frangou S, Brammer MJ, Williams SC, et al. Stroop performance in bipolar disorder: further evidence for abnormalities in the ventral prefrontal cortex. Bipolar Disorders 2006;8:28–39. Kruger S, Seminowicz D, Goldapple K, Kennedy SH, Mayberg HS. State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge. Biological Psychiatry 2003;54:1274–83. Larson ER, Shear PK, Krikorian R, Welge J, Strakowski SM. Working memory and inhibitory control among manic and euthymic patients with bipolar disorder. Journal of International Neuropsychological Society 2005;11:163–72. Lawrence NS, Williams AM, Surguladze S, Giampietro V, Brammer MJ, Andrew C, et al. Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biological Psychiatry 2004;55:578–87. Leibenluft E, Rich BA, Vinton DT, Nelson EE, Fromm SJ, Berghorst LH, et al. Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. American Journal of Psychiatry 2007;164:52–60. Leung HC, Cai W. Common and differential ventrolateral prefrontal activity during inhibition of hand and eye movements. Journal of Neurosciences 2007;27:9893–900. Liddle PF, Kiehl KA, Smith AM. Event-related fMRI study of response inhibition. Human Brain Mapping 2001;12:100–9. Mackinnon A, Ritchie K, Mulligan R. The measurement properties of a French language adaptation of the national adult reading test. International Journal of Methods in Psychiatric Research 1999;8:27–38. Malhi GS, Lagopoulos J, Owen AM, Ivanovski B, Shnier R, Sachdev P. Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study. Journal of Affective Disorders 2007;97:109–22.

Malhi GS, Lagopoulos J, Sachdev PS, Ivanovski B, Shnier R. An emotional Stroop functional MRI study of euthymic bipolar disorder. Bipolar Disorders 2005;7(Suppl 5):58–69. Matthews SC, Simmons AN, Arce E, Paulus MP. Dissociation of inhibition from error processing using a parametric inhibitory task during functional magnetic resonance imaging. Neuroreport 2005;16:755–60. McGrath J, Scheldt S, Welham J, Clair A. Performance on tests sensitive to impaired executive ability in schizophrenia, mania and well controls: acute and subacute phases. Schizophrenia Research 1997;26:127–37. Menon V, Adleman NE, White CD, Glover GH, Reiss AL. Error-related brain activation during a Go/NoGo response inhibition task. Human Brain Mapping 2001;12:131–43. Mostofsky SH, Schafer JG, Abrams MT, Goldberg MC, Flower AA, Boyce A, et al. fMRI evidence that the neural basis of response inhibition is task-dependent. Cognitive Brain Research 2003;17:419–30. Nieuwenhuis S, Yeung N, van den Wildenberg W, Ridderinkhof KR. Electrophysiological correlates of anterior cingulate function in a go/ no-go task: effects of response conflict and trial type frequency. Cognitive, Affective and Behavioral Neuroscience 2003;3:17–26. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113. Pessoa L. On the relationship between emotion and cognition. Nature Reviews Neuroscience 2008;9:148–58. Rubia K, Russell T, Bullmore ET, Soni W, Brammer MJ, Simmons A, et al. An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function. Schizophrenia Research 2001;52:47–55. Rubia K, Lee F, Cleare AJ, Tunstall N, Fu CH, Brammer M, et al. Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI. Psychopharmacology (Berl) 2005a;179:791–803. Rubia K, Smith AB, Brammer MJ, Toone B, Taylor E. Abnormal brain activation during inhibition and error detection in medication-naive adolescents with ADHD. American Journal of Psychiatry 2005b;162:1067–75. Rubia K, Smith AB, Taylor E, Brammer M. Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes. Human Brain Mapping 2007;28:1163–77. Sakagami M, Pan X. Functional role of the ventrolateral prefrontal cortex in decision making. Current Opinion in Neurobiology 2007;17:228–33. Strakowski SM, Adler CM, Holland SK, Mills NP, DelBello MP, Eliassen JC. Abnormal FMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task. American Journal of Psychiatry 2005;162:1697–705. Swann AC, Janicak PL, Calabrese JR, Bowden CL, Dilsaver SC, Morris DD, et al. Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants. Journal of Affective Disorders 2001;67:123–32. Swann AC, Pazzaglia P, Nicholls A, Dougherty DM, Moeller FG. Impulsivity and phase of illness in bipolar disorder. Journal of Affective Disorders 2003;73:105–11. van Veen V, Holroyd CB, Cohen JD, Stenger VA, Carter CS. Errors without conflict: implications for performance monitoring theories of anterior cingulate cortex. Brain and Cognition 2004;56:267–76. Vollm B, Richardson P, Stirling J, Elliott R, Dolan M, Chaudhry I, et al. Neurobiological substrates of antisocial and borderline personality disorder: preliminary results of a functional fMRI study. Criminal Behaviour and Mental Health 2004;14:39–54. Watanabe J, Sugiura M, Sato K, Sato Y, Maeda Y, Matsue Y, et al. The human prefrontal and parietal association cortices are involved in NOGO performances: an event-related fMRI study. Neuroimage 2002;17:1207–16.

P. Mazzola-Pomietto et al. / Journal of Psychiatric Research 43 (2009) 432–441 Wessa M, Houenou J, Paillere-Martinot ML, Berthoz S, Artiges E, Leboyer M, et al. Fronto-striatal overactivation in euthymic bipolar patients during an emotional go/nogo task. American Journal of Psychiatry 2007;164:638–46.

441

Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 1978;133:429–35.