An fMRI investigation of procedural learning in unaffected siblings of individuals with schizophrenia

https://doi.org/10.1016/j.schres.2007.04.026Get rights and content

Abstract

Vulnerability for schizophrenia is related, in part, to genetic predisposition. The identification of pathophysiological abnormalities associated with the disorder that are also present in unaffected family members of individuals with schizophrenia may assist in delineating the genetic contributions to vulnerability for schizophrenia. Previous functional Magnetic Resonance Imaging (fMRI) investigations of procedural learning in patients with schizophrenia identified reduced activity in the frontal cortex, basal ganglia, and parietal cortex during performance of the serial reaction time (SRT) task suggesting that abnormal function of these regions may relate to genetic vulnerability for schizophrenia. In order to examine this hypothesis, 12 unaffected siblings of patients and 15 controls underwent fMRI during performance of the SRT task. Unaffected siblings demonstrated normal performance on the SRT task. However, compared to controls unaffected siblings demonstrated less activity in regions of the frontal and parietal lobes and, to a lesser extent, basal ganglia, during procedural learning. Interestingly, unaffected siblings demonstrated greater activity in regions of the frontal cortex during the control condition compared to the procedural learning condition of the SRT task, an idiosyncratic pattern that was also observed in patient groups but not control subjects of two prior imaging studies. The findings support previous investigations suggesting that altered cerebral neurophysiology during performance of cognitive tasks may be related to genetic vulnerability for schizophrenia. Identification of genes related to the function of cerebral regions such as the prefrontal cortex, parietal lobe, and basal ganglia may assist in delineating the genetic contributions to 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.

References (46)

  • J.P. Reiss et al.

    Deficit in schizophrenia to recruit the striatum in implicit learning: A functional magnetic resonance imaging investigation

    Schizophr. Res.

    (2006)
  • M.E. Shenton et al.

    A review of MRI findings in schizophrenia

    Schizophr. Res.

    (2001)
  • M.M. Sitskoorn et al.

    Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis

    Schizophr. Res.

    (2004)
  • H.W. Thermenos et al.

    Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study

    Biol. Psychiatry

    (2004)
  • L. Zedkova et al.

    Procedural learning in schizophrenia investigated with functional magnetic resonance imaging

    Schizophr. Res.

    (2006)
  • G.E. Alexander et al.

    Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions

    Prog. Brain Res.

    (1990)
  • J.H. Callicott et al.

    Brain imaging as an approach to phenotype characterization for genetic studies of schizophrenia

    Methods Mol. Med.

    (2003)
  • J.H. Callicott et al.

    Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited

    Cereb. Cortex

    (2000)
  • J.H. Callicott et al.

    Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia

    Am. J. Psychiatry

    (2003)
  • J.H. Callicott et al.

    Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down

    Am. J. Psychiatry

    (2003)
  • T.D. Cannon et al.

    Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • N.J. Cohen et al.

    Preserved learning and retention of pattern-analyzing skill in amnesia: dissociation of knowing how and knowing that

    Science

    (1980)
  • B.A. Cornblatt et al.

    Impaired attention, genetics, and the pathophysiology of schizophrenia

    Schizophr. Bull.

    (1994)
  • Cited by (24)

    • Possible roles for fronto-striatal circuits in reading disorder

      2017, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Studies were included if they (1) reported standard space coordinates for at least one neurologically normal group; (2) reported results from a task that required participants to respond to a non-linguistic; non-random sequence of stimuli without being explicitly informed of the existence of the sequence; (3) did not exclusively report paradigm manipulation contrasts (e.g., dual vs. single task conditions or explicit vs. implicit instruction) and (4) reported whole-brain results at a single statistical threshold. Three studies (Martis et al., 2004; Woodward et al., 2007; Zedkova et al., 2006) reported activations from regions of interest in addition to reporting whole brain results outside the ROI. Peaks within the ROIs were included if they met the whole brain significance criteria.

    • More than just tapping: Index finger-tapping measures procedural learning in schizophrenia

      2012, Schizophrenia Research
      Citation Excerpt :

      A functional neuroimaging study examined procedural learning in unaffected siblings of schizophrenia participants, and found that they showed reduced activity in prefrontal cortical regions similarly to schizophrenia patients. Notably, both groups performed similarly to healthy controls (Zedkova et al., 2006; Woodward et al., 2007). Another study has demonstrated differences between unmedicated first episode psychosis patients and controls in brain activation to procedural learning in the frontal cortex (Purdon et al., 2011).

    • Altered brain response without behavioral attention deficits in healthy siblings of schizophrenic patients. An event-related fMRI study

      2010, NeuroImage
      Citation Excerpt :

      Schizophrenic patients with a normal attention performance showed a diminished activation in the left insula and an augmented activation in the right insula when rare visual targets were presented (Gur et al., 2007). Our findings could be due to subtle functional differences between siblings and controls, detectable only in high demand conditions, as reported in working memory studies (Callicott et al., 2003), antisaccades (Raemaekers et al., 2006) and procedural learning (Woodward et al., 2007). In this study we observed a reduced activation of the ACC in the sibling group, as previously reported in both patients (Liddle et al., 2006; Neuhaus et al., 2007) and presumed obligate carriers for schizophrenia (Filbey et al., 2008) during different types of attention tasks.

    View all citing articles on Scopus
    View full text