Neural correlates of planning performance in patients with schizophrenia — Relationship with apathy

Abstract

Patients with schizophrenia often suffer from apathy: a quantitative reduction of voluntary, goal-directed behaviors that impairs daily functioning. We hypothesized that schizophrenia patients with high levels of apathy would show decreased activation in brain regions involved in planning and goal-directed behavior.

Patients with schizophrenia or psychotic spectrum disorder (n = 47) and healthy controls (n = 20) performed the Tower of London (ToL) task during fMRI scanning using arterial spin labeling. To investigate the relationship between apathy and planning in patients, a proxy measure of apathy based on the Positive and Negative syndrome Scale was regressed against the task-related brain activation. Brain activation was also compared between patients and healthy controls.

Higher levels of apathy were associated with less task-related activation within the inferior parietal lobule precuneus and thalamus. Compared to controls, patients showed lower activation in lateral prefrontal regions, parietal and motor areas, and a higher activation of medial frontal areas.

Apathy was related to abnormal activation in thalamus and parietal regions during the ToL task. This supports the hypothesis that impaired function of brain regions involved in planning and goal-directed behavior may underlie apathy in schizophrenia. Moreover, impaired lateral prefrontal activation in schizophrenia patients compared to controls is consistent with the hypofrontality model of schizophrenia. In contrast, stronger medial frontal activation in patients may be related to increased effort to perform a task with conflicting task solutions.

Introduction

Patients with schizophrenia frequently experience markedly reduced levels of interest and a lack of initiative in daily activities, which is a hallmark of apathy. Apathy is a core feature of negative symptoms in schizophrenia (Foussias and Remington, 2010). Research has shown that 30% of the patients with a first episode psychosis show enduring levels of apathy (Faerden et al., 2010). Understanding apathy in schizophrenia has important implications, as it has been argued to be the critical component, especially with regard to poor (social) functioning, unemployment, severity of illness and poor functional outcome (Bottlender et al., 2010, Faerden et al., 2010, Foussias and Remington, 2010, Kiang et al., 2003).

Apathy can be described as a quantitative reduction of voluntary, goal-directed behaviors. Levy and Dubois (2006) state that apathy may arise from “planning and working memory impairments, through difficulties in sequencing ideas, maintaining mental representation of goals and sub-goals and manipulating them, may abort the elaboration of goal-directed behaviors, thereby quantitatively (and qualitatively) reducing goal-directed behaviors”. In this view apathy may be rooted, in part, in planning deficits. Planning has been defined as “the goal-directed, trial-and-error exploration of a tree of alternative moves” (Dehaene and Changeux, 1997). Indeed, a direct relation between apathy and executive function or goal-directed behavior has also been observed (Faerden et al., 2010, Foussias and Remington, 2010, Roth et al., 2004), but the neural correlates of this association, to the best of our knowledge, have not been investigated as yet.

Goal-directed behavior and executive functioning are both regulated by a fronto-striatal-parietal brain circuit (Fuster, 2009, Goldberg, 2009) and a similar brain circuit has been implicated in apathy (Levy and Dubois, 2006). Impaired function of a fronto-striatal-parietal network may thus be related to apathy as a consequence of problems in goal-directed behavior (Konstantakopoulos et al., 2011, Roth et al., 2004). Schizophrenia patients with deficit syndrome, showing high levels of negative symptoms, including apathy, have shown abnormal regional cerebral blood flow (Lahti et al., 2001) and white matter deficits (Rowland et al., 2009) in fronto-parietal regions. Moreover, higher levels of apathy in schizophrenia have been related to decreased gray matter volumes in these areas and to neuropsychological deficits (Roth et al., 2004). In the current paper we address the question whether hampered activation of this fronto-striatal-parietal network during planning may be associated with apathy in schizophrenia.

The Tower of London task (ToL) is a suitable task to investigate higher order planning processes in fronto-striatal-parietal brain circuits as it requires subjects to perform a set of subsequent mental operations that involve planning (Shallice, 1982) and thus resembles the definitions of planning and apathy as defined above (Baker et al., 1996, Beauchamp et al., 2003, Unterrainer and Owen, 2006, Wagner et al., 2006). An early PET study using the ToL has shown decreased medial prefrontal activation in schizophrenia, related to the severity of negative symptoms (Andreasen et al., 1992). A more recent fMRI study reported some evidence for prefrontal dysfunction in schizophrenia, but these results were not unequivocal (Rasser et al., 2005).

The ToL has also been used to study frontal lobe lesions, which are characterized by apathy and impaired organizational abilities (Owen et al., 1996). Patients with frontal lobe damage show impaired performance on the ToL task (Dehaene and Changeux, 1997) similar to schizophrenia patients (Morris et al., 1995, Pantelis et al., 1997). Moreover, patients with depression (Elliott et al., 1997) and Parkinson's disease (Dagher et al., 2001, Owen et al., 1996) – both involving apathy and anhedonia – also showed frontal, parietal and striatal dysfunction during the ToL task. Taken together, these findings suggest that apathy in schizophrenia may be related to planning impairments associated with dysfunction of frontal, parietal and striatal connections.

We hypothesized that schizophrenia patients with high levels of apathy would show impaired function of fronto-striatal-parietal brain areas involved in planning. We included a task with different levels of difficulty (1–5 move problems) (Dagher et al., 1999, Schall et al., 2003) to account for differences in task performance between study participants. Furthermore, a healthy control group was included for reference.