1 Department of Neurology, Johns Hopkins University School of Medicine, Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA, 2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA, 3 Neuroimaging Research Branch, DHHS, NIH/NIDA Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA, 4 Molecular Neuropsychiatry Branch, DHHS, NIH/NIDA Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA
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Abstract |
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Key Words: decision-making, neuroimaging, orbitofrontal, prefrontal cortex, sex-related differences
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Introduction |
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Using similar neuroimaging technology, we investigated sex-related differences in brain activity in the orbitofrontal cortex (OFC) during performance of a decision-making task. This interest stemmed from several sources. First, in non-human primates, the OFC develops more rapidly in male infants and males perform better than female infant monkeys on an object reversal task that utilizes the OFC (Goldman et al., 1974; Clark and Goldman-Rakic, 1989
). Second, the OFC together with the dorsolateral prefrontal cortex (DLPFC) comprise part of a neural network that mediates performance on the Iowa Gambling Task (Bechara et al., 1994
, 2000a,b; Ernst et al., 2002
; Manes et al., 2002
; Bolla et al., 2003
). The Iowa Gambling Task is frequently used to assess decision-making and OFC functioning in patients with lesions to the ventromedial prefrontal cortex (VMPFC) (Bechara et al., 1994
) and substance abusers (Bolla et al., 2003
). Third, men out-performed women on the Iowa Gambling task (Reavis and Overman, 2001).
This study was designed to investigate sex-related differences in performance and brain activity in the OFC during performance of a decision making task. On the basis of previous studies (Reavis and Overman, 2001) we predicted (i) that men would perform better than women on the computerized version of the Iowa Gambling Task; and (ii) that, based on our previous work (Ernst et al., 2002; Bolla et al., 2003
), men would show patterns of activation different from those of women in the OFC and DLPFC during performance of this task.
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Materials and Methods |
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Twenty healthy subjects participated in this study (10 women and 10 men). All participants received a full medical and psychiatric screening with the Psychiatric Diagnostic Interview Schedule (DIS) (Robins et al., 1981). Inclusion criteria were age between 21 and 45, IQ > 80 (assessed by the Shipley Institute of Living Scale) (Zachary, 1991
), right handedness, English as a first language, no past history or current use of illicit drugs (screened by urine toxicology), as assessed by the Drug Use Survey Questionnaire (Smith, 1991
) and the Addiction Severity Index (McLellan et al., 1980
), and consumed <10 alcoholic drinks/week. Participants were excluded if they reported past or current Axis I disorder other than nicotine dependence by DSM-IV criteria according to the DIS (e.g. anxiety disorder or major depressive disorder), evidence of acute or chronic medical problems, or positive pregnancy test for women. This study was approved by the institutional review boards at the Johns Hopkins Medical Institutions Joint Committee on Clinical Investigation and the Johns Hopkins Bayview Medical Center. The study was also approved by National Institute on Drug Abuse Intramural Research Program (NIDA-IRP). All volunteers gave written informed consent and were compensated for their time. Volunteers were recruited through newspaper advertisements.
Data Collection
After successfully completing the consent process, participants were admitted to our General Clinical Research Center (GCRC) for a 3 day inpatient stay. Over this period they also participated in other aspects of a larger study that will be reported elsewhere. This inpatient stay ensured that participants received adequate nutrition and rest.
Design
For the positron emission tomography (PET) session (on day 3 of the residential stay) participants received six injections of H215O water (10 mCi each). A 1 min acquisition scan was collected after the injection. Three cognitive conditions were studied: rest (R; eyes fixated on a target); active task (A; Iowa Gambling Task); and control task (C; sensorimotor control task). Two scans were acquired for each of the three conditions. Task order was counterbalanced within and between participants. The tasks began 1 min before injection of the tracer to ensure that the participant was cognitively engaged in the task at the time of image acquisition. The task ended when the participant had selected 100 cards (6 min). Before the actual scanning, participants performed a practice task to acclimate them to responding with the mouse while in the scanner. A molded facemask was created to minimize head movement during scan acquisition, limiting the participants ability to speak without hindering vision or manual responding. Stimuli were presented at the center of an LCD monitor, controlled by a Toshiba laptop computer. The monitor was mounted
1 m above and in front of the participant, tilted
40° from the bed so that the participant could view the screen from inside the scanner when wearing the facemask. Participants were instructed to abstain from smoking cigarettes and caffeinated beverages for 3 h before the study.
Iowa Gambling Task (Active Task)
Since decision-making and OFC function are frequently studied in neuropsychiatric disorders such as substance abuse (Bolla et al., 2003), the Iowa Gambling Task was used as our activation task. Lesion and neuroimaging studies indicate that the right OFC is a primary component in performing well on this task (Bechara et al., 2000a
,b; Ernst et al., 2002
; Bolla et al., 2003
). The task evaluates decision-making by measuring the participants ability to choose between high gains with a risk of extremely high losses (negative net score), and low gains with a risk of smaller losses (positive net score). Participants were instructed to win as much money as possible by picking one card at a time from each of four decks (A, B, C and D) in any order until the computer instructed them to stop (after the selection of the 100th card). They were also told that some decks are worse than others and that they would win if they stayed away from the worse decks. While performing the task participants were informed of the amount of money they had remaining after each card was selected. Participants selected on average
17 cards/min. A net global outcome score (net score) was calculated by subtracting the total number of cards selected from the disadvantage decks (A + B) from the total number of cards selected from the advantage decks (C + D) in trials 1 and 2, and then deriving a mean for both trials. To motivate participants to perform well on this task they were informed that for each game dollar they won, we would pay them one cent real money equaling a possible $20.00 per trial and maximum total of $40.00 for both trials.
Control Task
The control task was designed to be analogous to the Iowa Gambling Task with respect to sensorimotor demands and exposure to gains and losses. Unlike the active task, the gains and losses associated with the control task were equal between decks and participants were instructed to select cards sequentially in the fixed order of A-B-C-D-A-B-C-D, etc. Consequently, card selection did not require decision-making. Although the sensory and motor aspects of the control task were identical to those in the active task, rewards and penalties were contingent upon behavior in the active task but non-contingent in the control task.
PET Scan Acquisition
Scans were acquired with a Siemens ECAT EXACT HR +, in 63 planes with a 15.5 cm field of view in 3-D mode. Images were reconstructed using a Hann filter with 0.5 cut off frequency. The average transverse resolutions (full width half maximum (FWHM)) of the scanner at 1 and 10 cm from the center of the field of view, measured in 3-D mode and determined using a fluorine-18 line source and a ramp filter (with a 0.5 cutoff frequency), were 4.66 and 5.45 mm, respectively. Axial resolutions of the scanner (FWHM), measured using a point source of 18F and the same reconstruction algorithm were 4.21 and 5.0 mm at 0 and 10 cm from the center, respectively. In case of application of a Hann filter with a 0.5 cutoff frequency, used for reconstruction of brain images, the average transverse resolutions were 6.52 and 7.16 mm, respectively. For the same reconstruction algorithm, the average axial resolution at 0 cm from the center was 3.72 mm and at 10 cm, 5.64 mm.
Image Processing and Statistical Analyses
PET images were realigned, spatially normalized into the Montreal Neurological Institute coordinate system, and smoothed with a 12 x 12 x 12 mm Gaussian kernel by using Statistical Parametric Mapping Software (SPM 99; Welcome Department of Cognitive Neurology). A two-stage procedure was implemented for statistical analyses for within-group effects (n = 10) and between-group effects (n = 20). In the first stage, PET images from each participant were used to create an individual adjusted mean image, representing the relative change in brain activity (normalized rCBF) between the active and control tasks (all scans from the active task minus the control task). Thus, the adjusted mean image represents the change in brain activation between the active task and the control task. This change in brain activity was taken to reflect the process of decision-making by subtracting the motor, auditory and visual components involved in the task (control task) from the higher cognitive functions of decision-making (active task). Proportional scaling was used to correct for within-session variations in global signal for each adjusted mean image. Importantly, no significant differences were found in the correlation between global signal and the conditions of interest (Worsley et al., 1996; Andersson, 1997
; Desjardins et al., 2001
). To examine within-subject effects, we then entered the adjusted image from each participant into a random effects one-sample t-test (n = 10) with 9 degrees of freedom (df). Stage two of the procedure to examine between-group differences involved entering the adjusted mean image for each participant into a random effects two-sample t-test (n = 20) with 18 df.
To examine our specific regions of interest (OFC and DLPFC) and correct for multiple comparisons, we employed the small volume correction method featured in SPM99 using our own voxel volume of interest (VVOI) image templates (Matochik et al., 2003). This method did not restrict the search volume for statistical analyses to a single stereotaxic xyz coordinate point taken from previous findings in the literature, but rather used the actual spatially normalized volume of the region of interest to limit the search. For example, the entire lateral OFC region volume is searched rather than an area within a sphere or box centered around single coordinate that may be on or near the region of interest. This procedure ensured that our experiment-wise false positive rate (Type I error) for a particular region of interest was maintained at the
< 0.05 level. Bilateral small volume templates were constructed for the following brain regions: orbitofrontal cortex [medial region (Brodmann area BA 11), including the gyrus rectus and medial orbital gyrus; and the lateral orbital region (BA 11, 47), including lateral orbital gyrus and a portion of the inferior frontal gyrus], and the lateral prefrontal cortex [middle and inferior frontal gyrus (BA 9, 10, 44, 45, 46)].
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Results |
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The group of men (n = 10) was matched to the group of women (n = 10) on the Shipley IQ score. There were no significant group differences in age, years of education, maternal education, Shipley IQ, Hollingshead Index of Socioeconomic Status, race, alcohol use or proportion of smokers (Table 1).
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Figure 1 shows the results of the MannWhitney U-test that was used to test for group differences between men and women in net outcome score (cards from advantage decks minus cards from disadvantage decks; the higher the score the better the performance; mean ± SD net score: men, 25.2 ± 14.8; women, 12.2 ± 25.3). Men performed significantly better than women on the task (Z = 2.86; P < 0.01). We also examined sex-related differences in performance between the first and second trials (learning) of the task using a Wilcoxon Signed Rank test. Men significantly increased performance from trial 1 to trial 2 (trial 1: mean = 8.2 ± 17.7, trial 2: mean = 42.2 ± 22.0, Z = 2.55, P < 0.01; women did not show this significant increase (trial 1: mean = 15.0 ± 22.1, trial 2: mean = 9.4 ± 33.0, Z = 0.71, P = 0.47).
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Patterns of activation during task performance were examined for men and women in a random effects one-sample t-test. When voxel volume of interest (VVOI) templates were applied to correct for multiple comparisons, men showed significant activation in two large clusters, one in the right lateral OFC (845 contiguous voxels) and one in the left lateral OFC (217 contiguous voxels) whereas women showed a single smaller significant cluster in the left medial OFC (173 voxels activated) (Table 2, Fig. 3). However, when the entire brain was searched for areas of activation, men showed large areas of activation in an additional region of the right lateral OFC, two regions in the right DLPFC, and the right parietal lobe (Table 2).
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Differences between Men and Women in Brain Activity during Performance on the Iowa Gambling Task
When VVOI templates were applied to correct for multiple comparisons, men showed significantly greater activation than women in the right lateral OFC. Women showed greater activation than men in the left DLPFC (Table 3, Fig. 4). Post hoc between-group exploratory analyses of the entire brain determined that women had greater activation than men in the left medial frontal gyrus and left temporal lobe [t(18) 3.61, height threshold P < 0.001, extent 50 contiguous voxels, uncorrected; Table 3].
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Discussion |
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In addition to better mean performance, men also showed a significant learning effect from trial 1 to trial 2, whereas women failed to show similar improvements (Fig. 1). These results suggest that women may be using less effective strategies, given their initial poor performance and their failure to improve during a second trial. Thus, brain mechanisms engaged by men and women when solving the same decision-making task are different, which appears to put women at a relative disadvantage. This view is supported by epidemiological data that show pathological gambling to be less prevalent in women. Because only 30% of pathological gamblers are women (Coventry and Constable, 1999), it is not far-fetched to suggest women gamblers might perform similarly to men on this task. This remains to be tested.
Since the pattern of performance and brain activity was so different between men and women we were concerned that our group of women was in some way unusual. To examine this we compared the performance and brain activity of the exact same women and men used in the present study on another task, the Stroop. We found no sex-related differences in either performance or brain activity (also assessed by PET), suggesting these results are specific to the Iowa Gambling Task and not an artifact of participant selection. Also, in a study using the same version of the task that we used, mean group scores of patients with different brain lesions ranged from 23.6 ± 25 to 9.5 ± 18 (Clark et al., 2003). Our mean values are comparable to their values (mean net scores: men = 25.2 ± 14.8, women = 12.2 ± 25.3). Although age was not significantly different between men and women there was however a five year age difference between the groups. Nevertheless, we do not believe that this difference in age contributed to the large performance difference between groups since age was not correlated with task performance (r = 0.17). Nevertheless, these results should be replicated in a larger sample.
Brain activity in men was lateralized almost exclusively to the RH and men showed significantly more activation in the right lateral OFC than women. Based on a variety of sources, we believe that these findings are biologically plausible since they replicate and extend the work of others. First, findings from ventral medial prefrontal cortex lesion studies reveal that impairment on this task and with decision-making in real-life primarily occurs after right OFC unilateral lesions, while left unilateral lesions appear to have little effect on decision-making (Bechara et al., 2000a,b; Manes et al., 2002
; Tranel et al., 2002
). The lateral OFC is sensitive to punishment and overrides behavior based on the previous rewarding values of stimuli and responses, whereas the medial OFC is involved in reward and guessing situations when the outcomes are undetermined (O'Doherty et al., 2001
). It is probable that better task performance in men may be directly related to more substantial activation in the right lateral OFC, a sub-region that appears to be the crucial in punishment and the higher cognitive demands of decision-making. Therefore, increased lateral OFC activation in men could be a representation of the punishing consequences of selecting cards from the bad deck, and thus a substrate of good decision-making, or alternatively could simply be a response to more positive feedback. We speculate that the first interpretation is more accurate since other studies showed increased activation in the lateral OFC (bilaterally) in response to a punishing outcome (O'Doherty et al., 2001
). In addition, the OFC has been shown to mediate the valence of olfactory stimuli. For example, the right OFC was shown to be associated with pleasant olfactory stimulation while activation in the left OFC was associated with unpleasant olfactory stimulation (Anderson et al., 2003
). It is therefore likely that men and women perceive the valence of the Iowa Gambling Task differently, which would result in different patterns of brain activity. In order to identify the aspect(s) of decision-making that is associated with greater OFC activation, experimental conditions within a decision-making task will need to be manipulated in future studies. Second, other investigators have reported that men have higher activity in the RH, activity that is associated with better performance on RH cognitive tasks (Azari et al., 1995
). In contrast, women show higher brain activity in a specific hemisphere that is associated with better cognitive performance on tests reflecting functioning of the contralateral hemisphere (Azari et al., 1995
). In our study, women showed greater activation in the LH (OFC and DLPFC) while performing a task that is predominantly an RH task (Ernst et al., 2002
). Therefore, as suggested by others (Azari et al., 1995
), men may have greater hemisphere functional specialization and women may have greater inter-hemispheric transfer. Third, men show greater right than left frontal asymmetry that is not found in women (Rodriguez et al., 1988
). Finally, men have more lateralized brain activation than women, and women have more diffuse brain activation than men (Kawachi et al., 2002
; Rodriguez et al., 1988
; Rossell et al., 2002
). All of these observations were confirmed in our current study.
These results have important clinical implications and provide evidence to support sexual dimorphism of the brain. Our results show that women are not as adept as men in decision-making when performing the Iowa Gambling Task. In addition, these sex-related differences in performance are related to differential brain functioning. These observations indicate that women utilize different cognitive strategies and alternative neural networks when performing this specific task. These findings illustrate the usefulness of combining neurocognitive measures with functional neuroimaging techniques to investigate sex differences in cognitive processing and to understand the mechanisms behind them.
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Notes |
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Address correspondence to Karen I. Bolla, Ph.D., Johns Hopkins Bayview Medical Center, Department of Neurology, 4940 Eastern Avenue, Baltimore, MD 21224, USA. Email: kbolla{at}jhmi.edu.
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