Alterations of theory of mind network activation in chronic cannabis users

Abstract

Chronic cannabis use is associated with cognitive impairment and has been identified as a risk factor for schizophrenia. Patients with schizophrenia show profound deficits in social cognition such as the ability to attribute mental states to others, referred to as “theory of mind” (ToM). Aberrant activation of the ToM network has been demonstrated across different phases of schizophrenia, including at-risk stages. Accordingly, we aimed to investigate the ToM network in chronic cannabis users. Fifteen cannabis users received functional brain imaging during performance of a ToM cartoon story task. Findings were compared with 14 control subjects. Cannabis users showed less activation in the left parahippocampal gyrus, the right precuneus and cuneus, but greater activation in the left cuneus and the right anterior cingulate gyrus compared to healthy controls. These activation patterns resemble those found in at-risk populations, suggesting that cannabis use can affect the processing of social information similar to other risk factor constellations for psychosis.

Introduction

Cannabis is one of the most commonly used illicit drug worldwide (Perkonigg et al., 2008). Its well documented psychotropic effects are primarily produced by the plant cannabinoid ∆⁹-tetrahydrocannabinol (∆⁹-THC) via the central cannabinoid receptor CB₁ (Pertwee, 2008). Cannabis-induced cognitive impairments particularly include deficits in attention, learning, memory, and executive functioning (Pope et al., 2001, Solowij et al., 2002, Lundqvist, 2005), and may be present even after 28 days of abstinence (Bolla et al., 2002, Medina et al., 2007). Consistent with these neuropsychological findings, brain imaging studies in cannabis users have revealed altered morphology, function, blood flow, and metabolism in prefrontal, hippocampal, and cerebellar regions (Lundqvist et al., 2001, Quickfall and Crockford, 2006, Yücel et al., 2008). These brain regions are critically involved in cognition and characterized by high densities of CB₁ receptors (Herkenham et al., 1990). Interestingly, cognitive impairments appear to increase with duration and frequency of cannabis use, suggesting persistent deficits as a result of long-term changes due to a neurotoxic effect of long-term cannabis exposure (Bolla et al., 2002, Solowij et al., 2002, Roser et al., 2010).

Numerous studies reported a close relationship between chronic cannabis use and schizophrenia (D'Souza, 2007, Moore et al., 2007). In healthy subjects, cannabis use represents an environmental risk factor for the development of psychotic symptoms, particularly in subjects with an underlying genetic predisposition for psychosis (Henquet et al., 2005a, Henquet et al., 2005b). Moreover, repeated cannabis use may increase the risk for psychosis by impacting on the persistence of psychotic symptoms, independent of age, gender, socioeconomic status, use of other drugs, urban environment, and childhood trauma (Kuepper et al., 2011). With regard to the clinical symptomatology, many psychotropic effects caused by cannabis use closely resemble the signs and symptoms of schizophrenia (D'Souza et al., 2009). Acute administration of Δ⁹-THC to healthy subjects induced characteristic positive, negative, and cognitive schizophrenia-like symptoms (D'Souza et al., 2004). In schizophrenia patients, acute administration of Δ⁹-THC was associated with a transient exacerbation of core psychotic symptoms and cognitive deficits (D'Souza et al., 2005). Moreover, chronic cannabis use has been demonstrated to worsen positive symptoms of schizophrenia and to result in a poor outcome and greater liability to relapse (Linszen et al., 1994, Bersani et al., 2002). However, the question of a causal relationship between cannabis use and schizophrenia remains unresolved (Arseneault et al., 2004).

Social cognitive impairments, including deficits to attribute mental states to others, are a common feature in schizophrenia (Brüne, 2005, Green et al., in press). The ability to explain other people's behavior in terms of their beliefs, intentions, and dispositions, has been referred to as “theory of mind” (ToM) (Frith and Frith, 1999; for a more recent overview of ToM deficits in neuropsychiatric disorders, see Brüne and Brüne-Cohrs, 2006). Mental state attribution or ToM has extensively been studied in schizophrenia and found consistently impaired, with some differences between syndromal subtypes (Abdel-Hamid et al., 2009). In addition, functional brain imaging studies have shown that patients with schizophrenia often underactivate brain regions involved in ToM performance, foremost areas of the prefrontal cortex and the anterior cingulate cortex, with more inconsistent findings regarding posterior regions such as the temporoparietal junction (Brunet-Gouet and Decety, 2006, Brüne et al., 2008, Brüne et al., 2011).

Anomalous patterns of brain activation during ToM task performance have also been shown in at-risk stages of psychosis (Modinos et al., 2010, Brüne et al., 2011). This suggests that people who are at increased genetic risk of developing psychosis, or who fulfill the criteria for clinical at-risk states according to the Structured Interview for Prodromal Symptoms (SIPS; Miller et al., 2002), activate the ToM network differently when compared with psychologically healthy subjects, and this may also be the case in individuals with chronic cannabis use.

Accordingly, the present study sought to investigate the brain activity of cannabis users during ToM performance. We predicted that, similar to what has been described in at-risk stages of schizophrenia, subjects with chronic cannabis use would deviate in activating the ToM network compared to a control group who had never used cannabis.