fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia

Abstract

Schizophrenia is a highly heritable disorder that typically develops in early adult life. Structural imaging studies have indicated that patients with the illness, and to some extent their unaffected relatives, have subtle deficits in several brain regions, including prefrontal and temporal lobes. It is, however, not known how this inherited vulnerability leads to psychosis. This study used a covert verbal initiation fMRI task previously shown to elicit frontal and temporal activity (the Hayling sentence completion task) to examine this issue. A large (n = 69) number of young participants at high risk of developing schizophrenia for genetic reasons took part, together with a matched group of healthy controls (n = 21). At the time of investigation, none had any psychotic disorder, but on detailed interview some of the high-risk participants (n = 27) reported isolated psychotic symptoms. The study aimed to determine: (i) whether there were activation differences that occurred in all subjects with a genetic risk of schizophrenia (i.e. 'trait' effects); and (ii) whether there were activation differences that only occurred in those at high risk who had isolated psychotic symptoms ('state' effects). No activation differences were found in regions commonly reported to be abnormal in the established illness, namely the dorsolateral prefrontal cortex or in the temporal lobes, but group differences of apparent genetic cause were evident in medial prefrontal, thalamic and cerebellar regions. In addition, differences in activation in those with symptoms were found in the intraparietal sulcus. No significant differences in performance were found between the groups, and all subjects were antipsychotic naïve. These findings therefore suggest that vulnerability to schizophrenia may be inherited as a disruption in a fronto-thalamic-cerebellar network, and the earliest changes specific to the psychotic state may be related to hyperactivation in the parietal lobe.

Impact of a microRNA MIR137 Susceptibility Variant on Brain Function in People at High Genetic Risk of Schizophrenia or Bipolar Disorder

“…Participants performed the Hayling sentence completion paradigm in the scanner (see Burgess and Shallice, 1997;Whalley et al, 2004). Subjects were shown sentences with the last word missing and asked to silently think of an appropriate word to complete the sentence and press a button.…”

“…We examined the effect of variation in MIR137 (rs1625579) on brain activation in (i) those at high genetic risk of SCZ (n ¼ 44), (ii) those at high genetic risk of BD (n ¼ 90), and (iii) healthy controls (n ¼ 81), during performance of a sentence completion task. This task differentiates patients with SCZ, BD, and those at increased familial risk for both disorders, from healthy controls (Whalley et al, 2004McIntosh et al, 2008b). It activates language-related regions involved in the pathophysiology of both disorders (Lawrie and Abukmeil, 1998;Shenton et al, 2001;Glahn et al, 2008;Minzenberg et al, 2009).…”

Cerebellum volume and eyeblink conditioning in schizophrenia

“…Although few studies have examined the functional integrity of the cerebellum in schizophrenia, there is evidence of abnormalities from both functional MRI (Whalley et al, 2004;Takahashi et al, 2004) and positron emission tomography (Andreasen et al, 1996;Potkin et al, 2002). These functional imaging studies indicate that individuals with schizophrenia exhibit atypical cerebellar activation during sentence completion, affective processing, visual attention and verbal memory tasks.…”

An fMRI study of language processing in people at high genetic risk for schizophrenia

“…Crow et al, 1995;DeLisi et al, 1991). Recent fMRI studies provoking activation with a language production paradigm in patients who already have the diagnosis of acute or chronic schizophrenia (Boksman et al, 2005;Kircher et al, 2001Kircher et al, , 2005Koeda et al, 2006;Kubicki et al, 2003;Sommer et al, 2001Sommer et al, , 2003Weiss et al, 2006) and in those during the prodromal stage prior to illness onset and/or at high-genetic risk for illness (Whalley et al, 2004(Whalley et al, , 2005(Whalley et al, , 2006 have shown disruption in the normal lateralized activation in the frontal and temporal cortical circuits for language processing and further evidence that this pattern is heritable (Sommer et al, 2004). Other studies, mostly focusing on activation during tasks engaging working memory (Callicott et al, 2003;Keshavan et al, 2002;Seidman et al, 2006;Thermenos et al, 2004), attentional processes (Morey et al, 2005) in the prefrontal cortex, or facial expression and amygdala response (Habel et al, 2004), have suggested that these functional changes also occur early on and could be vulnerability markers for the illness.…”