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A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 1143 – 1149
A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents Matcheri S. Keshavana,*, Vaibhav A. Diwadkara, Stephen M. Spencera, Keith A. Harenskib, Beatriz Lunaa, John A. Sweeneyc a
Department of Psychiatry, Western Psychiatric Institute and Clinic, Room 984, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USA b Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA c Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL, USA Accepted 1 May 2002
Abstract Studies of high-risk offspring (HR) of schizophrenic patients have found abnormalities in attention, working memory and executive functions, suggesting impaired integrity of the prefrontal cortex and related brain regions. The authors conducted a preliminary high-field (3 T) functional magnetic resonance imaging (fMRI) study to assess performance and activation during a memory-guided saccade (MGS) task, which measures spatial working memory. HR subjects showed significant decreases in fMRI-measured activation in the dorsolateral prefrontal cortex (Brodmann’s areas 8 and 9/46) and the inferior parietal cortex (Brodmann’s area 40) compared to age- and sex-matched healthy controls (HC). Abnormal functional integrity of prefrontal and parietal regions of the heteromodal association cortical (HAC) regions in subjects at genetic risk for schizophrenia is consistent with findings observed in adults with the illness [Callicott et al., Cereb. Cortex 10 (2000) 1078; Manoach et al., Biol. Psychiatry 48 (2000) 99.]. These abnormalities need to be prospectively investigated in nonpsychotic individuals at risk for schizophrenia in order to determine their predictive value for eventual emergence of schizophrenia or related disorders. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Eye movement tasks; fMRI; High risk; Schizophrenia; Spatial working memory
1. Introduction There is mounting evidence for abnormalities in brain structure and function in adults with schizophrenia. Structural abnormalities in the heteromodal association cortex (HAC) have been shown to be linked to adult schizophrenia (Ross and Pearlson, 1996). The areas comprising the HAC are the prefrontal cortex, superior temporal gyrus and Abbreviations: BOLD, blood oxygen level difference; DSM, Diagnostic and Statistical Manual; fMRI, functional magnetic resonance imaging; HAC, heteromodal association cortex; HC, healthy control subjects; HR, high-risk subjects; K-SADS, Schedule for Affective Disorders and Schizophrenia-Child Version; MGS, memory-guided saccades; MRI, magnetic resonance images; SCID, Structured Clinical Interview for DSM diagnosis; SPGR, spoiled gradient recalled; VGS, visually guided saccades. * Corresponding author. Tel.: +1-412-624-0814; fax: +1-412-6241459. E-mail address: [email protected] (M.S. Keshavan).
inferior parietal lobe. These regions receive postprocessed inputs from both sensory and motor systems and are involved in executive functioning, attention and working memory (Goldman-Rakic, 1988; Mesulam, 1998; Ross and Pearlson, 1996). It is widely believed that the pathophysiology of schizophrenia is mediated by abnormal neurodevelopment (Murray and Lewis, 1987; Weinberger, 1987). Neurodevelopmental models propose that brain abnormalities predate the manifestations of the clinical features of the illness by several years and these models have prompted a search for potential precursors. Adolescent offspring at high risk for schizophrenia (HR) are an important group in whom to investigate such potential precursors. These subjects are at elevated risk for schizophrenia, being up to 15 times more likely to develop the illness than the general population (Gottesman and Shields, 1982). The risk of schizophrenia is about 10– 16% in these individuals as compared with 1% among the general population. Child and adolescent studies of relatives who
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have not yet crossed the age of risk for schizophrenia can therefore help elucidate the premorbid pathophysiology of this illness. There is considerable evidence for genetic factors in the etiology of schizophrenia, yet how these factors affect brain development to predispose individuals to schizophrenia remains unclear. Brain structural abnormalities such as enlarged cerebral ventricles tend to aggregate in families of schizophrenic patients (Cannon and Mednick, 1993). Magnetic resonance imaging (MRI) studies have shown regional brain alterations such as hippocampal and thalamic volume reductions (Keshavan et al., 1997; Lawrie et al., 1999). Functional MRI (fMRI) offers a noninvasive approach for investigating brain function. We believe that the use of fMRI to study this population offers a unique methodology for studying potential alterations in the functional architecture of the cortex and will generally provide an impetus for in vivo investigations of neurofunctional vulnerability in at-risk populations (Frangou and Murray, 1996). Abnormalities in executive functions and working memory have been considered to be among the central clinical features of schizophrenia and may underlie predisposition to this disorder (Frith, 1995). Neuroimaging studies of working memory tasks might therefore be valuable in studying brain function in HR subjects. Eye movement tasks offer a simple and elegant paradigm with which to study working memory and to assess the functional integrity of the HAC in normal and abnormal development (Luna and Sweeney, 2001; Luna et al., 2001). The memory-guided saccade (MGS) task (Sweeney et al., 1998) requires subjects to retain information about spatial location over an interval of time after which they are required to make an eye movement to that target location. The task provides a valuable strategy to investigate the integrity of executive regions underlying the ability to sustain spatial information on-line (Funahashi et al., 1989). The task is known to measure the integrity of executive and attentional circuits in the brain and has been used to indicate alterations in spatial working memory in schizophrenia (Park et al., 1995). Electrophysiological studies in primates (Goldman-Rakic, 1988) and neuroimaging studies in humans (Sweeney et al., 1996) have indicated that performing the MGS task activates prefrontal and inferior parietal cortices, which are principal regions of the HAC. The MGS task assumes relevance in investigating functional abnormalities in HR subjects because it activates the same regions that have a known locus of structural abnormalities in schizophrenia (Pearlson, 2000). Furthermore, these regions develop through childhood and adolescence, the latter being a period in which schizophrenia typically begins (Benes et al., 1994; Brody et al., 1987; Fuster, 1989; Ross and Pearlson, 1996) and therefore may be most vulnerable to premorbid abnormalities associated with schizophrenia. In this report, the authors provide preliminary data from an ongoing study of neurofunctional alterations in the offspring of individuals diagnosed with schizophrenia.
fMRI was used to assess cortical activation using the blood oxygen level difference (BOLD) technique while subjects performed blocks of the MGS task and a visually guided saccade (VGS) control task. The VGS task required subjects to perform an eye movement to the location of a visual cue and served as a sensorimotor control to compare memoryrelated activation in the MGS task. A fixation condition was also included to provide a resting baseline.
2. Methods 2.1. Subjects Four HR subjects (age 13.25 ± 2.22, 2 males and 2 females, right handed) of parents with schizophrenia and four age- and sex-matched healthy controls (HC) without psychiatric history in first-degree relatives (age 12.5 ± 3.5, 2 males and 2 females, right handed) were recruited. All subjects were clinically evaluated using the Schedule for Affective Disorders and Schizophrenia-Child Version (KSADS) (Ambrosini et al., 1989). We excluded HR subjects who had any lifetime evidence of psychotic disorders in view of our goal of identifying prepsychotic neurobiological precursors. Two of the HR subjects were diagnosed with Attention-Deficit Hyperactivity Disorder and one was diagnosed with major depression. Healthy controls were identified on the basis of (1) absence of any current or past Axis I disorder as determined by Structured Clinical Interview for Diagnostic and Statistical Manual (DSM) Disorders (SCID) or K-SADS interviews, (2) no prior exposure to psychotropic drugs, (3) no history of neurological or any other chronic medical illnesses with a potential to influence brain function, (4) no current or recent history of substance abuse or dependence, (5) IQ of 75 or greater and (6) no history of psychiatric disorder in any first-degree family member, assessed using the Family History Research Diagnostic Criteria Interviews (FHRDC). Parents of the HR group were diagnosed through SCID interviews (American Psychiatric Association, 1994). The study was approved by the Institutional Review Board of the University of Pittsburgh Medical Center. Informed consent was given by a parent or guardian after full description of the study and the subjects provided assent. 2.2. Scanning and experimental procedures fMRI was performed on a GE Signa 3T whole body scanner (General Electric Medical Systems, Milwaukee, WI) with BOLD echo planar imaging (EPI) capability (Advanced NMR Systems, Wilmington, MA). Gradientecho EPI, sensitive to the BOLD effects (Kwong et al., 1992), was performed using a commercial head RF coil. Acquisition parameters were TE = 25 ms, TR = 1.5 s, singleshot full k-space and 128 64 acquisition matrix with a field of view (FOV) of 40 20 cm, generating an in-plane
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VGS task in one paradigm and between the VGS paradigm and central fixation in a second paradigm. In the VGS paradigm, the target moved with a 50% probability to the left or right every 0.75 s in a 4° step from the previous position, except at the 8° position where the movement was always toward the center. In this way, the targets had a minimum level of spatial predictability. The tasks are depicted in Fig. 1. 2.3. Data analysis
Fig. 1. (a) The VGS task is depicted. Subjects maintained fixation and made an eye movement to the cue location in the periphery. (b) The MGS task is depicted. The arrow of time moves from the foreground pane to the back. Subject maintained fixation even when the peripheral location is cued. Memory for the location is maintained until the subject must make an oculomotor delayed response (ODR) to it after the delay period.
resolution of 3.125 mm2. Seven 5 mm thick axial slices with a 1 mm gap were acquired, spanning from the superior edge of the corpus callosum to the vertex of the brain, allowing excellent coverage of the cortical regions of interest in the study. Anatomical images were collected using a spoiled gradient recalled (SPGR) pulse sequence consisting of 124 slices at 1.5 mm, acquired in the axial plane. To ensure compliance with the instructions, subjects were extensively trained on the MGS and VGS tasks prior to the fMRI experiment. During the experiment, subjects lay supine in the bore of the magnet. Visual stimuli were rear projected through a two-way mirror on a screen 55– 60 cm from the subjects’ eyes (Thulborn et al., 1996). Subjects alternated between 30 s blocks of the MGS task and the
The fMRI data were processed using Functional Imaging Analysis Software-Computational Olio (FIASCO) (Eddy et al., 1996). This involves deghosting, in-plane correction for head motion (in k-space) and image reconstruction (using Fast Fourier Transform). Cubic spline functions were applied to remove slow signal drift. Images with significant head movement (>1 voxel) were discarded from analysis. Functional data were overlaid on coplanar anatomic images using Analysis of Functional NeuroImages (AFNI) (Cox, 1996). Individual data were smoothed with a 5.6 mm fullwidth half-maximum filter and transformed into standardized Talairach space (Talairach and Tournoux, 1988), allowing for the construction of group maps. Significant voxels ( P < .001, one-tailed) were identified in AFNI by comparing the HC group maps and the HR group maps that isolated fMRI activation associated with the MGS component of the task (MGS-VGS).
3. Results The performance of the HR and the HC subjects on the VGS and MGS tasks was comparable. The principal measure of performance on the VGS task, Gain defined as the ratio of the velocity of the eye movement to the velocity of the movement of the target, was assessed for 10°, 20° and 30° movements of the targets. No differences were observed between the groups for any of the distances [10°: t(6) = 1.48, P>.09, 20°: t(6) = 0.13, P>.45, 30°: t(6) = 0.43, P>.34]. Importantly, performance on the MGS task was comparable. The mean magnitude of error for the HR subjects was 4.22° (S.D. = 1.73) while the mean magnitude of error for the HC subjects was 4.58° (S.D. = 1.05). The behavioral performance was not significantly different between the groups [t(6) = 0.42, P=.69].
Table 1 Results of MGS-VGS analysis using AFNI’s cluster detection Volume (mm3) 24 15 11 15
X coordinate of center 37.3 42.0 40.9 33.4
Y coordinate of center 33.8 17.7 4.9 25.1
Z coordinate of center
Brodmann’s area
Cortical area
46.1 39.5 38.1 43.8
40 9 9 8
Right inferior parietal Right DLPFC Left DLPFC Right middle frontal
Coordinates are represented in Talaraich space. DLPFC = dorsolateral prefrontal cortex.
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Fig. 2. Areas (denoted in Table 1) with significant differences between groups (HC vs. HR) are depicted. The images indicate decreased activation in HR subjects compared to HC subjects, associated with the memory component of the task in the parietal and frontal cortices. Images are depicted in radiological convention (left of image = right of brain). Coincident axial (left panels) and coronal views are depicted. (A) Right inferior parietal cortex. (B) Right dorsolateral prefrontal cortex. (C) Left dorsolateral prefrontal cortex. (D) Right middle frontal gyrus.
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Fig. 3. Activation associated with the VGS task (VGS fixation condition) is shown on the same frontal coronal slice in (A) HR subjects and (B) HC subjects. Activation levels associated with the visual task that does not have a memory component are comparable.
In the analysis of fMRI activation, four areas showed sizeable differences in volume of activation (MGS minus VGS) between controls and HR subjects. Table 1 lists the cortical areas that showed significant hypoactivity in the HR subjects compared to the HC subjects in a comparison of the group t-maps. As can be seen, differences were observed in four clusters in two cortical areas: parietal cortex and frontal cortex (Brodmann’s areas 8, 9 and 46). Parietal and frontal cortices are regions that fMRI has shown to be principally associated with spatial working memory (Diwadkar et al., 2000; Jonides et al., 1993). Fig. 2 depicts the location of significant hypoactivation in the HR subjects in the regions listed in Table 1. The differences between HR and HC subjects were unlikely to be due to hypoactivation in HR subjects during the visually guided control condition. Activation maps for the VGS condition appeared comparable between the two groups of subjects (Fig. 3).
4. Discussion Our findings suggest decreases in activation consistent with functional abnormalities of the HAC in schizophrenia. The observed differences were in Brodmann’s area 9 bilaterally. These regions have been known to mediate working memory and executive functions (Levy and GoldmanRakic, 1999) and have been reported to show differences
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between schizophrenia and healthy subjects on histologic examination (Glantz and Lewis, 1997). Observations of decrease in volume of activation in Brodmann’s area 40 are consistent with the possibility that functional abnormalities of the frontal and inferior parietal cortices may be precursors to the onset of schizophrenia (Ross and Pearlson, 1996). This region has been shown to contribute to attentional processes (Colby and Goldberg, 1999) and has been shown to be abnormal in schizophrenia (Cleghorn et al., 1989; Ross and Pearlson, 1996; Tamminga et al., 1992). Our observations are consistent with observations that alterations in working memory and attention impairment are among the behavioral precursors robustly determined in high-risk offspring of schizophrenic parents (Cornblatt et al., 1999). To our knowledge, there are few other reports of the application of fMRI methodology to investigate child and adolescent offspring at risk for schizophrenia. The preliminary evidence of hypofrontality is of significance in light of the attention given to this issue in the literature. PET studies suggested a decrease in metabolic uptake in the frontal lobes in schizophrenia, a result consistent with other MRI-based documentation of decreases in grey matter volume in the frontal lobes. The results from fMRI studies have been mixed and do not readily conform to a simple pattern of hypofrontality, in part because of differences in task performance between patients and controls (Price and Friston, 1999). Thus, hypofrontal fMRI activation could be attributed to fundamental differences in the way in which patients and healthy controls perform cognitive tasks. These concerns have to some extent been met by studies that have matched performance, but even such studies have not conclusively resolved the issue, with studies showing opposing hypoactivation or hyperactivation even in the face of performance matching (Curtis et al., 1998). Recent studies (Callicott et al., 2000) have taken a different approach, employing parametric manipulations of working memory load to examine frontal response. These studies have suggested that patients show greater increases in frontal activation during increases in working memory load compared to healthy controls. This interaction has been interpreted as an aberrant and inefficient frontal response to increases in cognitive work load and has been replicated with different working memory paradigms. The pattern of hypoactivation that we report cannot readily be explained by any extant theories. Although performance could not be measured in the scanner because of technical limitations, performance outside the scanner between the two groups was equivalent, suggesting that hypoactivation was not a result of catastrophic increases in task difficulty or cortical inefficiency. Furthermore, separate neurobehavioral studies on a larger cohort of high-risk subjects revealed that differences between HR and HC subjects were subtle and were primarily developmentally progressive as opposed to groupbased. Clearly, a complete characterization of what is aberrant in HR subjects and indeed schizophrenia patients remains elusive.
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These findings must be viewed with caution given the small sample size: Type I errors cannot therefore be excluded. However, we note that the HR group was ‘‘enriched’’ by the presence of subjects with attentional impairment, a known marker of vulnerability to schizophrenia. Furthermore, studies in a larger sample of subjects indicate only subtle differences in the MGS task between groups (Diwadkar et al., 2001).
5. Conclusion The results in this paper suggest that behavioral and neuroimaging studies on subjects at genetic risk for schizophrenia can be informative about possible deficits in function in this group. Longitudinal fMRI studies of individuals at risk for schizophrenia may therefore be fruitful in research on the pathophysiology, early diagnosis and treatment of this disorder.
Acknowledgements We thank Melissa Ziegler, MS for help with clinical assessments. This study was supported by NIMH grants MH45203 and MH01180 and a NARSAD Established Investigator Award (M.S.K.).
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A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents Matcheri S. Keshavana,*, Vaibhav A. Diwadkara, Stephen M. Spencera, Keith A. Harenskib, Beatriz Lunaa, John A. Sweeneyc a
Department of Psychiatry, Western Psychiatric Institute and Clinic, Room 984, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USA b Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA c Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL, USA Accepted 1 May 2002
Abstract Studies of high-risk offspring (HR) of schizophrenic patients have found abnormalities in attention, working memory and executive functions, suggesting impaired integrity of the prefrontal cortex and related brain regions. The authors conducted a preliminary high-field (3 T) functional magnetic resonance imaging (fMRI) study to assess performance and activation during a memory-guided saccade (MGS) task, which measures spatial working memory. HR subjects showed significant decreases in fMRI-measured activation in the dorsolateral prefrontal cortex (Brodmann’s areas 8 and 9/46) and the inferior parietal cortex (Brodmann’s area 40) compared to age- and sex-matched healthy controls (HC). Abnormal functional integrity of prefrontal and parietal regions of the heteromodal association cortical (HAC) regions in subjects at genetic risk for schizophrenia is consistent with findings observed in adults with the illness [Callicott et al., Cereb. Cortex 10 (2000) 1078; Manoach et al., Biol. Psychiatry 48 (2000) 99.]. These abnormalities need to be prospectively investigated in nonpsychotic individuals at risk for schizophrenia in order to determine their predictive value for eventual emergence of schizophrenia or related disorders. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Eye movement tasks; fMRI; High risk; Schizophrenia; Spatial working memory
1. Introduction There is mounting evidence for abnormalities in brain structure and function in adults with schizophrenia. Structural abnormalities in the heteromodal association cortex (HAC) have been shown to be linked to adult schizophrenia (Ross and Pearlson, 1996). The areas comprising the HAC are the prefrontal cortex, superior temporal gyrus and Abbreviations: BOLD, blood oxygen level difference; DSM, Diagnostic and Statistical Manual; fMRI, functional magnetic resonance imaging; HAC, heteromodal association cortex; HC, healthy control subjects; HR, high-risk subjects; K-SADS, Schedule for Affective Disorders and Schizophrenia-Child Version; MGS, memory-guided saccades; MRI, magnetic resonance images; SCID, Structured Clinical Interview for DSM diagnosis; SPGR, spoiled gradient recalled; VGS, visually guided saccades. * Corresponding author. Tel.: +1-412-624-0814; fax: +1-412-6241459. E-mail address: [email protected] (M.S. Keshavan).
inferior parietal lobe. These regions receive postprocessed inputs from both sensory and motor systems and are involved in executive functioning, attention and working memory (Goldman-Rakic, 1988; Mesulam, 1998; Ross and Pearlson, 1996). It is widely believed that the pathophysiology of schizophrenia is mediated by abnormal neurodevelopment (Murray and Lewis, 1987; Weinberger, 1987). Neurodevelopmental models propose that brain abnormalities predate the manifestations of the clinical features of the illness by several years and these models have prompted a search for potential precursors. Adolescent offspring at high risk for schizophrenia (HR) are an important group in whom to investigate such potential precursors. These subjects are at elevated risk for schizophrenia, being up to 15 times more likely to develop the illness than the general population (Gottesman and Shields, 1982). The risk of schizophrenia is about 10– 16% in these individuals as compared with 1% among the general population. Child and adolescent studies of relatives who
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have not yet crossed the age of risk for schizophrenia can therefore help elucidate the premorbid pathophysiology of this illness. There is considerable evidence for genetic factors in the etiology of schizophrenia, yet how these factors affect brain development to predispose individuals to schizophrenia remains unclear. Brain structural abnormalities such as enlarged cerebral ventricles tend to aggregate in families of schizophrenic patients (Cannon and Mednick, 1993). Magnetic resonance imaging (MRI) studies have shown regional brain alterations such as hippocampal and thalamic volume reductions (Keshavan et al., 1997; Lawrie et al., 1999). Functional MRI (fMRI) offers a noninvasive approach for investigating brain function. We believe that the use of fMRI to study this population offers a unique methodology for studying potential alterations in the functional architecture of the cortex and will generally provide an impetus for in vivo investigations of neurofunctional vulnerability in at-risk populations (Frangou and Murray, 1996). Abnormalities in executive functions and working memory have been considered to be among the central clinical features of schizophrenia and may underlie predisposition to this disorder (Frith, 1995). Neuroimaging studies of working memory tasks might therefore be valuable in studying brain function in HR subjects. Eye movement tasks offer a simple and elegant paradigm with which to study working memory and to assess the functional integrity of the HAC in normal and abnormal development (Luna and Sweeney, 2001; Luna et al., 2001). The memory-guided saccade (MGS) task (Sweeney et al., 1998) requires subjects to retain information about spatial location over an interval of time after which they are required to make an eye movement to that target location. The task provides a valuable strategy to investigate the integrity of executive regions underlying the ability to sustain spatial information on-line (Funahashi et al., 1989). The task is known to measure the integrity of executive and attentional circuits in the brain and has been used to indicate alterations in spatial working memory in schizophrenia (Park et al., 1995). Electrophysiological studies in primates (Goldman-Rakic, 1988) and neuroimaging studies in humans (Sweeney et al., 1996) have indicated that performing the MGS task activates prefrontal and inferior parietal cortices, which are principal regions of the HAC. The MGS task assumes relevance in investigating functional abnormalities in HR subjects because it activates the same regions that have a known locus of structural abnormalities in schizophrenia (Pearlson, 2000). Furthermore, these regions develop through childhood and adolescence, the latter being a period in which schizophrenia typically begins (Benes et al., 1994; Brody et al., 1987; Fuster, 1989; Ross and Pearlson, 1996) and therefore may be most vulnerable to premorbid abnormalities associated with schizophrenia. In this report, the authors provide preliminary data from an ongoing study of neurofunctional alterations in the offspring of individuals diagnosed with schizophrenia.
fMRI was used to assess cortical activation using the blood oxygen level difference (BOLD) technique while subjects performed blocks of the MGS task and a visually guided saccade (VGS) control task. The VGS task required subjects to perform an eye movement to the location of a visual cue and served as a sensorimotor control to compare memoryrelated activation in the MGS task. A fixation condition was also included to provide a resting baseline.
2. Methods 2.1. Subjects Four HR subjects (age 13.25 ± 2.22, 2 males and 2 females, right handed) of parents with schizophrenia and four age- and sex-matched healthy controls (HC) without psychiatric history in first-degree relatives (age 12.5 ± 3.5, 2 males and 2 females, right handed) were recruited. All subjects were clinically evaluated using the Schedule for Affective Disorders and Schizophrenia-Child Version (KSADS) (Ambrosini et al., 1989). We excluded HR subjects who had any lifetime evidence of psychotic disorders in view of our goal of identifying prepsychotic neurobiological precursors. Two of the HR subjects were diagnosed with Attention-Deficit Hyperactivity Disorder and one was diagnosed with major depression. Healthy controls were identified on the basis of (1) absence of any current or past Axis I disorder as determined by Structured Clinical Interview for Diagnostic and Statistical Manual (DSM) Disorders (SCID) or K-SADS interviews, (2) no prior exposure to psychotropic drugs, (3) no history of neurological or any other chronic medical illnesses with a potential to influence brain function, (4) no current or recent history of substance abuse or dependence, (5) IQ of 75 or greater and (6) no history of psychiatric disorder in any first-degree family member, assessed using the Family History Research Diagnostic Criteria Interviews (FHRDC). Parents of the HR group were diagnosed through SCID interviews (American Psychiatric Association, 1994). The study was approved by the Institutional Review Board of the University of Pittsburgh Medical Center. Informed consent was given by a parent or guardian after full description of the study and the subjects provided assent. 2.2. Scanning and experimental procedures fMRI was performed on a GE Signa 3T whole body scanner (General Electric Medical Systems, Milwaukee, WI) with BOLD echo planar imaging (EPI) capability (Advanced NMR Systems, Wilmington, MA). Gradientecho EPI, sensitive to the BOLD effects (Kwong et al., 1992), was performed using a commercial head RF coil. Acquisition parameters were TE = 25 ms, TR = 1.5 s, singleshot full k-space and 128 64 acquisition matrix with a field of view (FOV) of 40 20 cm, generating an in-plane
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VGS task in one paradigm and between the VGS paradigm and central fixation in a second paradigm. In the VGS paradigm, the target moved with a 50% probability to the left or right every 0.75 s in a 4° step from the previous position, except at the 8° position where the movement was always toward the center. In this way, the targets had a minimum level of spatial predictability. The tasks are depicted in Fig. 1. 2.3. Data analysis
Fig. 1. (a) The VGS task is depicted. Subjects maintained fixation and made an eye movement to the cue location in the periphery. (b) The MGS task is depicted. The arrow of time moves from the foreground pane to the back. Subject maintained fixation even when the peripheral location is cued. Memory for the location is maintained until the subject must make an oculomotor delayed response (ODR) to it after the delay period.
resolution of 3.125 mm2. Seven 5 mm thick axial slices with a 1 mm gap were acquired, spanning from the superior edge of the corpus callosum to the vertex of the brain, allowing excellent coverage of the cortical regions of interest in the study. Anatomical images were collected using a spoiled gradient recalled (SPGR) pulse sequence consisting of 124 slices at 1.5 mm, acquired in the axial plane. To ensure compliance with the instructions, subjects were extensively trained on the MGS and VGS tasks prior to the fMRI experiment. During the experiment, subjects lay supine in the bore of the magnet. Visual stimuli were rear projected through a two-way mirror on a screen 55– 60 cm from the subjects’ eyes (Thulborn et al., 1996). Subjects alternated between 30 s blocks of the MGS task and the
The fMRI data were processed using Functional Imaging Analysis Software-Computational Olio (FIASCO) (Eddy et al., 1996). This involves deghosting, in-plane correction for head motion (in k-space) and image reconstruction (using Fast Fourier Transform). Cubic spline functions were applied to remove slow signal drift. Images with significant head movement (>1 voxel) were discarded from analysis. Functional data were overlaid on coplanar anatomic images using Analysis of Functional NeuroImages (AFNI) (Cox, 1996). Individual data were smoothed with a 5.6 mm fullwidth half-maximum filter and transformed into standardized Talairach space (Talairach and Tournoux, 1988), allowing for the construction of group maps. Significant voxels ( P < .001, one-tailed) were identified in AFNI by comparing the HC group maps and the HR group maps that isolated fMRI activation associated with the MGS component of the task (MGS-VGS).
3. Results The performance of the HR and the HC subjects on the VGS and MGS tasks was comparable. The principal measure of performance on the VGS task, Gain defined as the ratio of the velocity of the eye movement to the velocity of the movement of the target, was assessed for 10°, 20° and 30° movements of the targets. No differences were observed between the groups for any of the distances [10°: t(6) = 1.48, P>.09, 20°: t(6) = 0.13, P>.45, 30°: t(6) = 0.43, P>.34]. Importantly, performance on the MGS task was comparable. The mean magnitude of error for the HR subjects was 4.22° (S.D. = 1.73) while the mean magnitude of error for the HC subjects was 4.58° (S.D. = 1.05). The behavioral performance was not significantly different between the groups [t(6) = 0.42, P=.69].
Table 1 Results of MGS-VGS analysis using AFNI’s cluster detection Volume (mm3) 24 15 11 15
X coordinate of center 37.3 42.0 40.9 33.4
Y coordinate of center 33.8 17.7 4.9 25.1
Z coordinate of center
Brodmann’s area
Cortical area
46.1 39.5 38.1 43.8
40 9 9 8
Right inferior parietal Right DLPFC Left DLPFC Right middle frontal
Coordinates are represented in Talaraich space. DLPFC = dorsolateral prefrontal cortex.
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Fig. 2. Areas (denoted in Table 1) with significant differences between groups (HC vs. HR) are depicted. The images indicate decreased activation in HR subjects compared to HC subjects, associated with the memory component of the task in the parietal and frontal cortices. Images are depicted in radiological convention (left of image = right of brain). Coincident axial (left panels) and coronal views are depicted. (A) Right inferior parietal cortex. (B) Right dorsolateral prefrontal cortex. (C) Left dorsolateral prefrontal cortex. (D) Right middle frontal gyrus.
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Fig. 3. Activation associated with the VGS task (VGS fixation condition) is shown on the same frontal coronal slice in (A) HR subjects and (B) HC subjects. Activation levels associated with the visual task that does not have a memory component are comparable.
In the analysis of fMRI activation, four areas showed sizeable differences in volume of activation (MGS minus VGS) between controls and HR subjects. Table 1 lists the cortical areas that showed significant hypoactivity in the HR subjects compared to the HC subjects in a comparison of the group t-maps. As can be seen, differences were observed in four clusters in two cortical areas: parietal cortex and frontal cortex (Brodmann’s areas 8, 9 and 46). Parietal and frontal cortices are regions that fMRI has shown to be principally associated with spatial working memory (Diwadkar et al., 2000; Jonides et al., 1993). Fig. 2 depicts the location of significant hypoactivation in the HR subjects in the regions listed in Table 1. The differences between HR and HC subjects were unlikely to be due to hypoactivation in HR subjects during the visually guided control condition. Activation maps for the VGS condition appeared comparable between the two groups of subjects (Fig. 3).
4. Discussion Our findings suggest decreases in activation consistent with functional abnormalities of the HAC in schizophrenia. The observed differences were in Brodmann’s area 9 bilaterally. These regions have been known to mediate working memory and executive functions (Levy and GoldmanRakic, 1999) and have been reported to show differences
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between schizophrenia and healthy subjects on histologic examination (Glantz and Lewis, 1997). Observations of decrease in volume of activation in Brodmann’s area 40 are consistent with the possibility that functional abnormalities of the frontal and inferior parietal cortices may be precursors to the onset of schizophrenia (Ross and Pearlson, 1996). This region has been shown to contribute to attentional processes (Colby and Goldberg, 1999) and has been shown to be abnormal in schizophrenia (Cleghorn et al., 1989; Ross and Pearlson, 1996; Tamminga et al., 1992). Our observations are consistent with observations that alterations in working memory and attention impairment are among the behavioral precursors robustly determined in high-risk offspring of schizophrenic parents (Cornblatt et al., 1999). To our knowledge, there are few other reports of the application of fMRI methodology to investigate child and adolescent offspring at risk for schizophrenia. The preliminary evidence of hypofrontality is of significance in light of the attention given to this issue in the literature. PET studies suggested a decrease in metabolic uptake in the frontal lobes in schizophrenia, a result consistent with other MRI-based documentation of decreases in grey matter volume in the frontal lobes. The results from fMRI studies have been mixed and do not readily conform to a simple pattern of hypofrontality, in part because of differences in task performance between patients and controls (Price and Friston, 1999). Thus, hypofrontal fMRI activation could be attributed to fundamental differences in the way in which patients and healthy controls perform cognitive tasks. These concerns have to some extent been met by studies that have matched performance, but even such studies have not conclusively resolved the issue, with studies showing opposing hypoactivation or hyperactivation even in the face of performance matching (Curtis et al., 1998). Recent studies (Callicott et al., 2000) have taken a different approach, employing parametric manipulations of working memory load to examine frontal response. These studies have suggested that patients show greater increases in frontal activation during increases in working memory load compared to healthy controls. This interaction has been interpreted as an aberrant and inefficient frontal response to increases in cognitive work load and has been replicated with different working memory paradigms. The pattern of hypoactivation that we report cannot readily be explained by any extant theories. Although performance could not be measured in the scanner because of technical limitations, performance outside the scanner between the two groups was equivalent, suggesting that hypoactivation was not a result of catastrophic increases in task difficulty or cortical inefficiency. Furthermore, separate neurobehavioral studies on a larger cohort of high-risk subjects revealed that differences between HR and HC subjects were subtle and were primarily developmentally progressive as opposed to groupbased. Clearly, a complete characterization of what is aberrant in HR subjects and indeed schizophrenia patients remains elusive.
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These findings must be viewed with caution given the small sample size: Type I errors cannot therefore be excluded. However, we note that the HR group was ‘‘enriched’’ by the presence of subjects with attentional impairment, a known marker of vulnerability to schizophrenia. Furthermore, studies in a larger sample of subjects indicate only subtle differences in the MGS task between groups (Diwadkar et al., 2001).
5. Conclusion The results in this paper suggest that behavioral and neuroimaging studies on subjects at genetic risk for schizophrenia can be informative about possible deficits in function in this group. Longitudinal fMRI studies of individuals at risk for schizophrenia may therefore be fruitful in research on the pathophysiology, early diagnosis and treatment of this disorder.
Acknowledgements We thank Melissa Ziegler, MS for help with clinical assessments. This study was supported by NIMH grants MH45203 and MH01180 and a NARSAD Established Investigator Award (M.S.K.).
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