Functional magnetic resonance imaging of executive control in bipolar disorder

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1 BRAIN IMAGING Functional magnetic resonance imaging of executive control in bipolar disorder Robert M. Roth, Nancy S. Koven, John J. Randolph, Laura A. Flashman, Heather S. Pixley, SarahM.Ricketts,HeatherA.WishartandAndrewJ.Saykin Brain Imaging Laboratory, Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire, USA Correspondence and requests for reprints to Robert M. Roth, PhD, Brain Imaging Laboratory, Department of Psychiatry, Dartmouth Medical School/DHMC, One Medical Center Drive, Lebanon, NH , USA Tel: ; fax: ; Robert.M.Roth@Dartmouth.Edu Sponsorship: Supported by grants from NARSAD, the Hitchcock Foundation, the National Multiple Sclerosis Society, and the National Alliance for Medical Image Computing (NA-MIC) funded by Grant U54 EB from the National Institutes of Health through the NIH Roadmap for Medical Research. Received 20 April 2006; accepted10 May 2006 Bipolar disorder has been associated with dysfunction of executive control processes. Using functional magnetic resonance imaging, we examined brain activation during a counting Stroop task in 11 healthy adults and 11 patients with bipolar I disorder. Results revealed greater activation for the healthy than bipolar disorder group in distributed brain regions that included the right inferior and medial frontal gyri. With the exception of one area within the left posterior cingulate gyrus that was correlated with mania severity, regional activations where group di erences were observed were not associated with mood symptoms in the patient group. These ndings add to the growing body of evidence implicating neural circuitry subserving executive control in bipolar disorder. NeuroReport17:1085^1089 c 2006 Lippincott Williams & Wilkins. Keywords: bipolar disorder, executive function, frontal lobe, imaging Introduction Bipolar disorder is characterized in part by problems with impulsivity and impaired regulation of mood. These difficulties appear to be consistent with dysfunction of executive control processes observed in neuropsychological studies of manic [1] and euthymic [2] patients with the disorder, as well as unaffected relatives [3]. These findings suggest that executive dysfunction may reflect a trait rather than the state characteristic of the disorder. The Stroop task [4] has been used in functional neuroimaging investigations of the neural substrates of executive control in healthy adults. These studies have observed activation in several brain regions during the interference condition of the task, including frontal regions such as the dorsal anterior cingulate gyrus, as well as the cerebellum and other cortical areas [5,6]. Patients with bipolar disorder have been reported to show abnormal activation in a number of brain regions during performance of the Stroop task, including several frontal subregions implicated in executive control such as the anterior cingulate [7] and dorsolateral [7] and ventrolateral [8] frontal cortices. In a recent study [9], euthymic patients with bipolar disorder completed a counting Stroop task [10], which uses a manual rather than a verbal response, thereby minimizing extraneous movement that can interfere with functional magnetic resonance imaging (fmri). Results showed hypoactivation in several regions including the middle frontal gyrus. In the present study, we employed a counting Stroop task in order to investigate further the neural substrates of executive control in patients with bipolar disorder. In addition, we included patients varying in mood state in order to provide an initial evaluation of whether brain activation, in regions where the patient group showed abnormality, was independent of mood state. We predicted that the patients with bipolar disorder would show reduced frontal lobe activation in comparison to a healthy control group, and that this would be independent of current mood state. Materials and methods Study participants Participants included 11 adults with bipolar I disorder (seven women) and 11 healthy comparison subjects (eight women). Participants were between 18 and 55 years of age, had a minimum 10 years of education or a high school equivalency degree, and were right-handed (with the exception of one patient) as determined by the Edinburgh Handedness Inventory [11]. Diagnosis was established using the Structured Clinical Interview for DSM-IV [12]. Among the patients, cooccurring diagnoses included polysubstance abuse (n¼1), alcohol use disorder (n¼2), and post-traumatic stress disorder (n¼1). Patients were excluded if they met criteria for a substance use disorder within the 6 months preceding participation. Patients had an average age of onset of 22.7 years (SD¼9.0). Patients were administered the Young Mania Rating Scale (mean score¼8.6, SD¼9.1, range¼0 24) c Lippincott Williams & Wilkins Vol 17 No 11 31July

2 ROTH ETAL. [13] and the Hamilton Depression Rating Scale (mean score¼4.6, SD¼6.0, range¼0 20) [14] to assess mood. Four patients were in a mixed state, one was manic, one was depressed, and five were euthymic. Psychosis in the form of delusions was present in five of the patients based on the Structured Clinical Interview for DSM-IV. One patient was receiving lithium and one doxepin monotherapy. The other patients were receiving various combinations of lithium (n¼5), divalproex (n¼1), valproic acid (n¼1), lamotrigine (n¼2), quetiapine (n¼2), mirtazapine (n¼1), ziprasidone (n¼1), aripiprazole (n¼1), and venlafaxine (n¼1). Healthy comparison subjects were excluded if they met current or lifetime criteria for any psychiatric illness based on the SCID-Non Patient version, reported having a firstdegree relative with either a schizophrenia-spectrum or a mood disorder, or had ever been prescribed a psychotropic medication. Potential participants were excluded if they had any history of head trauma with loss of consciousness greater than 5 min, neurological illness, any medical condition that could impact cognitive functioning, or factors contraindicating MRI. Participants provided written informed consent for the procedures approved by the Dartmouth Committee for the Protection of Human Subjects. Behavioral procedures The counting Stroop task was composed of three conditions during which participants were shown one to four lines of text in black font against a white background and were asked to report via button-press the number of lines presented. In the neutral condition, each line of text consisted of a series of four Xs. In the congruent condition, the number of words presented was always consistent with the number of lines of text (e.g. the word two written twice). In the incongruent condition, the number of words presented was always different from the number of lines of text (e.g. the word two written four times). Participants were instructed to ignore the words and Xs and respond to each trial by pressing the button corresponding to the number of lines of text. Responses were made with the index and middle fingers of the left and right hand using an MRI-compatible response device, with each finger mapped to a specific number from one to four. Participants received extensive practice with a mock button response device before scanning. Each of the task conditions was presented three times. The first three epochs of the task were presented in the order neutral congruent incongruent [15], followed by counterbalanced presentation of the remaining epochs of each condition. The three conditions each contained 14 stimuli per epoch for a total of 42 trials per condition. All stimuli were presented for 1500 ms. Interstimulus interval was pseudorandomized with intervals of 2000, 2200, or 2400 ms. Twelve-second rest periods were provided between each set of three epochs. During the rest periods, participants were instructed to look at a centrally presented black fixation dot. Stimuli were presented via an MRI-compatible goggle system (Resonance Technology, Northridge, California, USA). Functional magnetic resonance imaging data acquisition procedures All scans were obtained on a GE Signa 1.5 T Horizon LX scanner (GE Healthcare, Waukesha, Wisconsin, USA) using a gradient-echo echo planar imaging sequence for blood oxygenation level-dependent fmri [repetition time (TR)¼2500 ms, echo time (TE)¼40 ms, field of view (FOV)¼24 cm, number of excitations (NEX)¼1, flip angle¼91] with 29 contiguous 5 mm sagittal slices in a matrix with in-plane resolution of 3.75 mm 2 to provide whole-brain coverage. Structural scanning included a T1-weighted sagittal scan used for anatomical reference (TR¼525 ms, TE¼9 ms, axial 5 mm slices), and a T2-weighted fast spin echo scan [TR¼3000 ms, TE¼100 ms, echo train length (ETL)¼13, axial 3 mm slices] reviewed by a neuroradiologist to rule out incidental pathology. Foam padding was employed in order to reduce motion artifact by limiting head movement within the scanner coil. Data analysis fmri data were preprocessed using standard procedures, as implemented in the Statistical Parametric Mapping package (SPM2; Wellcome Department of Cognitive Neurology, University College, London, UK) after ruling out artifacts and excessive motion. fmri data were spatially realigned to remove any minor (subvoxel) motion-related signal change, normalized to the Montreal Neurological Institute standard atlas space using a 12-parameter affine approach followed by default nonlinear warping with spatial basis functions, and re-sampled to 2 mm 3 isotropic voxels. Spatial smoothing was performed with a Gaussian filter (full-width halfmaximum of 10 mm). This was followed by statistical parametric mapping on a voxel-by-voxel basis using the general linear model [16] and random effects procedures [17] as implemented in SPM2. The random effects analyses involved deriving one contrast image (incongruous condition4congruous condition) per individual for the task. The threshold for significance was set at Po0.005 (uncorrected) with a minimum cluster extent of 50 contiguous voxels (i.e. 400 mm 3 ) to reduce the probability of Type I errors for main and interaction effects, and at Po0.001 with 50 contiguous voxels for correlation analyses. Coordinates were converted to Talairach and Tournoux space [18] using the Talairach Daemon (version 2.0) [19]. Results Participant characteristic data The groups did not differ significantly with respect to age (bipolar disorder: mean¼37.7 years, SD¼14.4; control: mean¼35.2 years, SD¼14.5) [t(20)¼0.46, P¼0.65], years of education (bipolar disorder: mean¼15.1, SD¼2.5; control: mean¼15.0, SD¼2.5) [t(20)¼0.21, P¼0.65], sex composition [w 2 (1)¼0.46, P¼0.65], or handedness [w 2 (20)¼1.05, P¼0.31]. Behavioral data Table 1 presents behavioral data. Data for one healthy subject were missing owing to a technical error. Groups did not differ in the percentage of incorrect responses or reaction time for any of the task conditions, nor for the interference effect reaction time (interference condition congruent condition). Functional magnetic resonance imaging data Table 2 presents the significant main and interaction effects for the counting Stroop Vol 17 No July 2006

3 FMRI OF EXECUTIVE CONTROL IN BIPOLAR DISORDER Table 1 Behavioral data Healthy adult (n¼11) Bipolar disorder (n¼11) t P Neutral condition Reaction time, mean (ms) 816 (83.6) 884 (94.6) 1.74 NS Responses, % errors 1.0 (1.3) 3.0 (3.1) 2.02 NS Congruent condition Reaction time, mean (ms) 829 (121.2) 880 (98.4) 1.05 NS Responses, % errors 0.5 (1.0) 3.2 (4.7) 1.83 NS Interference condition Reaction time, mean (ms) 876 (106.3) 937 (115.2) 1.23 NS Responses, % errors 1.2 (1.7) 4.6 (6.1) 1.69 NS Interference e ect Reaction time, mean (ms) 46.7 (84.0) 57.7 (45.7) 0.36 NS All values are given as mean (SD) unless otherwise indicated. Degrees of freedom are19 for all comparisons. Table 2 Brain activation during the counting Stroop (incongruent 4 congruent contrast) Brain area BA x y z Z Cluster size (voxels) Healthy comparison Right inferior frontal gyrus Right posterior cerebellum Left precentral gyrus Left fusiform gyrus Bipolar disorder Right posterior cerebellum Activations greater for healthy comparison than bipolar disorder Right inferior frontal gyrus Right medial frontal gyrus Right pons Left posterior cingulate gyrus Left parahippocampal gyrus Left fusiform gyrus Left middle occipital gyrus Activations greater for bipolar disorder than healthy comparison None BA refers to Brodmann area. Z-value refers to Z-transformed t-statistic for the maximally signi cant voxel within a cluster. Coordinates of voxels are presented intalairach and Tournoux space. The healthy group showed activation of the right inferior frontal gyrus and cerebellum, and the left precentral and fusiform gyri (Fig. 1a). In contrast, the patient group only showed activation of the right cerebellum (Fig. 1b). Comparison of the groups revealed significantly greater activation for the healthy relative to the patient group in the right inferior gyrus and right pons, as well as the left posterior cingulate, fusiform, parahippocampal, and middle occipital gyri (Fig. 1c). The healthy group also had greater activation in the right posterior medial frontal gyrus (Fig. 1d). No regions of greater activation were noted for the patient relative to healthy group. Table 3 presents regional brain activations that were significantly correlated with mood. Activation in regions where group differences were observed was not associated with mood symptoms in the patient group, with the exception of an inverse correlation between mania severity and activation in the left posterior cingulate gyrus. Discussion We observed hypoactivation of the right inferior and medial frontal gyri, as well as a number of posterior brain regions, in adults with bipolar disorder when performing an executive control task. The right frontal lobe hypoactivation during a counting Stroop was also reported in a group of euthymic adults with bipolar disorder, albeit in the right medial frontal gyrus [9]. Together, these findings implicate dysfunction of a distributed circuitry including the right frontal lobe in adults with bipolar disorder. Right inferior frontal gyrus abnormality has been previously observed in bipolar disorder, including reduced gray matter density [20] and hypoactivation during decision making in manic patients [21]. The activation of this region has been associated with response inhibition during go/nogo tasks in healthy adults [22]. Although Stroop and go/nogo tasks differ with respect to the nature of the response required, both involve inhibition of cognitivemotor processes. Hypoactivation of the right inferior frontal gyrus in bipolar disorder may thus reflect dysfunction of neural circuitry subserving cognitive-motor response inhibition. Consistent with this interpretation, manic patients have been reported to demonstrate hypoactivation in the right orbitofrontal cortex during a go/nogo task, this region being also commonly implicated in inhibitory control [23]. Our patient group also showed hypoactivation in the right medial frontal gyrus, in an area considered variably to be part of the supplementary motor area [24] or part of the dorsal anterior cingulate gyrus [5]. Reduced activation in the dorsal anterior cingulate gyrus in bipolar disorder has Vol 17 No July

4 ROTH ETAL. Table 3 Correlations between brain activation and severity of mood symptoms in the bipolar disorder group Brain area BA x y z Z Cluster size (voxels) Positive correlations with mania None Negative correlations with mania Left posterior cingulate gyrus Positive correlations with depression Right cerebellum F Right cerebellum F Left insula Left middle frontal gyrus Right precentral gyrus Negative correlations with depression Left fusiform gyrus BA refers to Brodmann area. Z-value refers to Z-transformed t-statistic for the maximally signi cant voxel within a cluster. Coordinates of that voxel are presented intalairach and Tournoux space. Fig. 1 Surface renderings showing main e ect for the healthy comparison (a) and bipolar disorder (b) groups, as well as renderings showing areas of greater activation for the healthy relative to bipolar disorder group on the cortical surface (c) and right medial frontal gyrus (d) during the counting Stroop. been reported in prior work [7]. Dorsal medial areas of the frontal cortex such as the dorsal anterior cingulate gyrus are richly interconnected with limbic, striatal, and other frontal regions, and have been implicated in the selection of behavioral responses and more generally in attention and executive control processes [24]. That both the right medial and the inferior frontal regions were hypoactive in the patient group may itself have functional significance. It has been proposed that dorsal areas of the medial frontal cortex monitor ongoing behaviors and the outcomes of responses, and generate signals that engage cognitive control processes in the lateral frontal cortex in order to adjust behavior [25]. The reduced activations observed in the right dorsal medial and inferior frontal cortices in our patient group raise the possibility that bipolar disorder may involve difficulty monitoring ongoing behaviors, resulting in insufficient or ineffective engagement of cognitive control processes such as response inhibition under high conflict situations such as those found in the counting Stroop. Brain regions showing hypoactivation in the bipolar disorder group were relatively independent of current mood state. These results, in the context of a recent counting Stroop study in euthymic patients showing right frontal hypoactivation [9], raise the possibility that abnormality of right frontal circuitry represents a trait rather than state characteristic of the disorder. No firm conclusions with respect to the association between mood state and brain activation can be drawn, however, given our sample size. Further studies employing larger samples of patients in discrete mood states will be helpful in examining this hypothesis. Our findings should be interpreted in the context of the limitations of the study, including modest sample size and a history of substance use disorder in a subset of patients. In addition, several patients were delusional based on the SCID, but we did not include a measure that would permit quantification of the severity of delusions. Future studies would benefit from the assessment of psychosis severity in order to evaluate its impact on brain activation in bipolar disorder. We cannot exclude the possibility that our findings may have been influenced by medication effects. In a recent study greater activation in anterior cingulate and dorsolateral frontal cortex was noted in medicated relative to unmedicated patients with bipolar disorder during a Stroop task, although comparison of these patient sub-groups to a healthy comparison group was not reported [9]. In the present investigation, all patients were medicated; nevertheless, decreased activation was observed in right frontal regions relative to a healthy group. These findings suggest that medication effects are unlikely to fully account for the present findings. Additional research will be necessary to clarify the impact of medications on brain activation related to executive control in bipolar disorder. Finally, while our finding of functional abnormalities in the frontal and other brain regions is generally consistent with prior Stroop studies of bipolar disorder, differences between investigations are noted in the specific pattern and direction of regional abnormalities observed. The reasons for these discrepancies remain to be elucidated, but likely include 1088 Vol 17 No July 2006

5 FMRI OF EXECUTIVE CONTROL IN BIPOLAR DISORDER differences in patient sample characteristics such as medication status, symptom severity (mood state, presence of psychosis), and differences in the nature and parameters of the Stroop tasks employed. Conclusion The present findings provide further evidence of dysfunction in a distributed neural circuitry, including the right dorsal medial and inferior frontal cortices, during executive control in adults with bipolar disorder. Furthermore, results of the present investigation and a previous counting Stroop study of euthymic patients suggest that frontal hypoactivation may be relatively independent of current mood state, thus potentially representing a trait rather than state characteristic of the disorder. Acknowledgements We thank Robert Ferranti, Alice Davison, and colleagues for help with MRI scanning, and Alexander Mamourian for reviewing structural MR scans for incidental pathology. References 1. Clark L, Iversen SD, Goodwin GM. A neuropsychological investigation of prefrontal cortex involvement in acute mania. Am J Psychiatry 2001; 158: Altshuler LL, Ventura J, van Gorp WG, Green MF, Theberge DC, Mintz J. Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects. Biol Psychiatry 2004; 56: Zalla T, Joyce C, Szoke A, Schurhoff F, Pillon B, Komano O, et al. Executive dysfunctions as potential markers of familial vulnerability to bipolar disorder and schizophrenia. Psychiatry Res 2004; 121: Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935; 18: Carter CS, Mintun M, Cohen JD. Interference and facilitation effects during selective attention: an H 2 15O PET study of Stroop task performance. Neuroimage 1995; 2: Peterson BS, Kane MJ, Alexander GM, Lacadie C, Skudlarski P, Leung HC, et al. An event-related functional MRI study comparing interference effects in the Simon and Stroop tasks. Cogn Brain Res 2002; 13: Gruber SA, Rogowska J, Yurgelun-Todd DA. Decreased activation of the anterior cingulate in bipolar patients: an fmri study. J Affect Disord 2004; 82: Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, et al. A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 2003; 60: 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. Am J Psychiatry 2005; 162: Bush G, Whalen PJ, Rosen BR, Jenike MA, McInerney SC, Rauch SL. The counting Stroop: an interference task specialized for functional neuroimaging validation study with functional MRI. Hum Brain Mapp 1998; 6: Oldfield R. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders (SCID-I), patient edition. Washington, DC: American Psychiatric Publishing, Inc.; Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 1988; 45: Gruber SA, Rogowska J, Holcomb P, Soraci S, Yurgelun-Todd D. Stroop performance in normal control subjects: an fmri study. Neuroimage 2002; 16: Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: A general linear approach. Hum Brain Mapp 1995; 2: Holmes A, Friston K. Generalizability, random effects, and population inferences. Neuroimage 1998; 7:S Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. Stuttgart: Thieme; Kochunov P, Uecker A. Talairach daemon client. San Antonio, TX: The Research Imaging Center-UTHSCSA; Lyoo IK, Kim MJ, Stoll AL, Demopulos CM, Parow AM, Dager SR, et al. Frontal lobe gray matter density decreases in bipolar I disorder. Biol Psychiatry 2004; 55: Rubinsztein JS, Fletcher PC, Rogers RD, Ho LW, Aigbirhio FI, Paykel ES, et al. Decision-making in mania: a PET study. Brain 2001; 124: Garavan H, Ross TJ, Stein EA. Right hemispheric dominance of inhibitory control: an event-related functional MRI study. Proc Natl Acad Sci USA 1999; 96: Altshuler LL, Bookheimer SY, Townsend J, Proenza MA, Eisenberger N, Sabb FW, et al. Blunted activation in orbitofrontal cortex during mania: a functional magnetic resonance imaging study. Biol Psychiatry 58: Braver TS, Barch DM, Gray JR, Molfese DL, Snyder A. Anterior cingulate cortex and response conflict: effects of frequency, inhibition and errors. Cereb Cortex 2001; 11: Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S. The role of the medial frontal cortex in cognitive control. Science 2004; 306: Vol 17 No July