An fMRI investigation of procedural learning in unaffected siblings of individuals with schizophrenia
Introduction
A genetic basis for schizophrenia is strongly suggested by the increased familial risk for the disorder (Gottesman, 1991). However, the lack of 100% concordance in monozygotic twins and aggregation of illness risk in affected families implies that schizophrenia is a polygenetic disorder with a complicated etiology involving a dynamic interplay between multiple susceptibility genes and environmental factors (Gottesman and Shields, 1967, Shields and Gottesman, 1972, Caspi et al., 2005). Schizophrenia is characterized by abnormalities in neuropsychological function, cerebral morphology, and neurophysiology (Heinrichs and Zakzanis, 1998, Shenton et al., 2001, Kircher and Thienel, 2005) and searching for similar deficits in unaffected family members may provide insight into underlying pathological mechanisms that are related to genetic liability. This approach has identified abnormalities in neuropsychological function, cerebral morphology, and neurophysiology, in unaffected family members, including siblings of patients, that are similar to those observed in affected family members (Cornblatt and Keilp, 1994, Myles-Worsley and Park, 2002, Sitskoorn et al., 2004, Cannon et al., 2002, Narr et al., 2002, Steel et al., 2002).
Abnormalities in cerebral activity detected in patients during performance of a variety of cognitive tasks are also observed in their unaffected relatives; although only a handful of studies have been carried out. Callicott and colleagues identified abnormalities in cerebral activity related to a verbal working memory task in two independent groups of unaffected siblings that were remarkably similar to the alterations observed in patients (Callicott et al., 2003a, Callicott et al., 2000, Callicott et al., 2003b). Consistent with their findings in patients using the same working memory paradigm, unaffected siblings evinced greater activity in the dorsolateral and inferior prefrontal cortex (PFC) and parietal lobe during performance of a verbal N-back task, despite performing relatively normal compared to controls. Alterations in working memory related cerebral activity in prefrontal cortex and parietal lobe has also been reported by others (Thermenos et al., 2004, Brahmbhatt et al., 2006). Abnormal cerebral neurophysiology in unaffected first degree relatives of patients is not limited to working memory tasks. Abnormal activity in the frontal lobes and basal ganglia during performance of eye tracking and antisaccade tasks, respectively, has been documented (O'Driscoll et al., 1999, Raemaekers et al., in press) as have differences in the neural timing of activations in the PFC during performance of a stimulus-response incompatibility task (MacDonald et al., 2006). Combined, these studies suggest that unaffected relatives demonstrate abnormal activation of cortical-sub-cortical circuits during performance of a variety of tasks and that, in some cases, the alteration in brain activity is not accompanied by impaired behavioral performance.
The goal of the current experiment was to identify the neural correlates of performance on the Serial Reaction Time (SRT) task (Nissen and Bullemer, 1987), a commonly used test of procedural learning, in a sample of unaffected siblings of patients with schizophrenia and an aged matched group of controls in order to determine if the functional alterations observed in patients in prior studies is related to genetic liability for schizophrenia. Procedural learning refers to the ability to acquire a motor skill or cognitive routine in the absence of declarative knowledge (Cohen and Squire, 1980), and the SRT task is frequently used to examine procedural learning in healthy, psychiatric, and neurological populations. Three previous imaging studies of SRT performance in schizophrenia produced several important findings. The first study, by Kumari et al. (2002), revealed a performance deficit in patients that was accompanied by an absence of activity in the frontal cortex, striatum, thalamus, and cerebellum relative to an age-matched control sample. Unfortunately, the results of this study are difficult to interpret because patients were receiving typical antipsychotic drugs (APDs) at the time of scanning, drugs that interfere with procedural learning (Purdon et al., 2003, Stevens et al., 2002, Kumari et al., 1997), and there were marked performance differences between patients and controls. Two subsequent studies by Zedkova et al. (2006) and Reiss et al. (2006) avoided the treatment confound by scanning subjects being treated predominantly or exclusively with atypical APDs, drugs that have a more benign D2 binding profile (Kapur and Seeman, 2001, Seeman, 2002) and do not impair procedural learning (Purdon et al., 2002, Purdon et al., 2003, Stevens et al., 2002). Both studies confirmed that patients fail to activate the striatum, caudate in particular, during performance of the SRT. Additional abnormalities were identified in left premotor cortex in both studies and, in the case of one study, reduced activity in the left parietal cortex and increased activity in the anterior cingulate and temporal lobe, relative to controls, was also observed (Zedkova et al., 2006). Interestingly, reduced volume of the pre-supplementary area is inversely correlated with procedural learning on the SRT task in schizophrenia (Exner et al., 2006). The abnormalities identified in the two subsequent studies could not be explained by differential performance between controls and patients as the patient groups in both studies demonstrated the same degree of procedural learning as controls. Interestingly, in both the Zedkova et al. (2006) and Reiss et al. (2006) studies, patients demonstrated greater activation in the PFC during the control condition relative to the procedural learning condition, an idiosyncratic pattern that was not observed in the control groups of either study.
The initial findings reported by Kumari et al. (2002) suggested that SRT performance deficits in schizophrenia result from a failure to activate structures central to PL circuitry and that this may reflect a core deficit in schizophrenia, but may also be a deleterious side effect of treatment with typical APDs. On the other hand, the findings reported by Zedkova et al. (2006) and Reiss et al. (2006) suggest that patients do not demonstrate the same degree of activity in the prefrontal cortex, striatum, and perhaps parietal cortex, despite performing the SRT task relatively normally, at least when receiving predominantly atypical APDs. Moreover, preliminary evidence suggests that patients may compensate for a failure to activate regions normally implicated in the SRT task by recruiting alternate regions. If siblings also fail to activate similar regions or recruit alternate ones compared to controls during performance of the SRT task then the alterations observed in patients may relate to genetic liability for schizophrenia. Conversely, if siblings demonstrate normal cerebral activity then the abnormalities observed in patients likely reflects disease specific alterations unrelated to genetic liability for schizophrenia or a medication induced alteration in neural activity.
Section snippets
Subjects
Twelve, right handed, unaffected siblings of individuals with schizophrenia and fifteen, right handed, age-matched controls were recruited for this study. Controls were recruited largely from employees and students of the University of Alberta. Siblings were recruited from first episode and chronic patients with schizophrenia seen at the Edmonton Early Psychosis Intervention Clinic (EEPIC) or the Schizophrenia Clinic at the University of Alberta Hospital. All subjects were provided a verbal and
Behavioral data
Behavioral data from one control subject was lost due to experimenter error leaving complete behavioral data for 14 controls and 12 siblings. Mean median reaction times during the pre-scanning and scanning sessions are presented in Fig. 1. Analysis of the SRT RTs for the pre-scanning session revealed a main effect of block (F(4,21) = 4.83, p < .007), but no main effect of group (F(1,24) = 1.94, p < .177) or block by group interaction (F(4,21) = 0.25, p < .908). Subjects got progressively faster over blocks
Discussion
The present study examined behavioral performance and cerebral activity related to procedural learning, as quantified using the SRT task, in a sample of unaffected siblings of individuals with schizophrenia and an aged matched control sample with no family history of schizophrenia. Both siblings and controls demonstrated a significant reaction time advantage to blocks where the location of the target followed a repeating pattern relative to blocks in which the location of the target appeared
Role of funding source
This work was supported in part by a grant from the Alberta Heritage Foundation awarded to Phil Tibbo.
Contributors
Each of the authors listed contributed equally to this study.
Conflict of Interests
The authors have no conflicts of interest to report.
Acknowledgements
The authors would like to thank Lenka Zedkova and Ian Harding for their assistance in recruiting and screening subjects for enrollment in this study.
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