Alterations in brain structures underlying language function in young adults at high familial risk for schizophrenia

Abstract

Introduction

Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia.

Methods

T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N = 46) and controls with no family history of illness (i.e. at low genetic risk LRC; N = 31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered.

Results

No significant differences were observed between groups on any language measures. Controlling intracranial volume, significantly smaller left pars triangularis (PT) (p < 0.01) and right pars orbitalis (PO) (p < 0.01) volumes and reversal of the L > R pars orbitalis (p < 0.001) lateralization were observed in FHR subjects. In addition, the L pars triangularis and R pars orbitalis correlated with performance on tests of linguistic function in the FHR group.

Conclusions

Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studies would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function.

Introduction

Increasing evidence suggests that brain alterations and subtle neurocognitive abnormalities may predate the manifestations of the clinical features of schizophrenia (SZ) by several years or may reflect the vulnerability for illness that may only be expressed when other risk factors are involved. Investigating such potential precursors is important for distinguishing vulnerability characteristics from those of the illness itself. An important strategy to address this issue is to examine subjects who are at high familial risk (FHR) for the illness by having close family relatives with illness, as well as still being within the age range of risk for the disease. Young relatives of schizophrenia patients are an invaluable group of “at risk” subjects that may shed light on the indicators of vulnerability. The risk for developing schizophrenia or related psychotic disorders is 10–16% in first-degree relatives as compared with less than 1% among the general population (Gottesman and Shields, 1982). Studying these subjects also avoids confounds associated with medications and psychosis invariably associated with studies of patients.

One of the key impairments in SZ is linguistic function and this dimension may also be affected in young FHR individuals (Agnew-Blais and Seidman, in press, 2012). Magnetic Resonance Imaging (MRI) studies have implicated several brain regions underlying language function in the pathophysiology of schizophrenia (reviewed in Shenton et al., 2001, Kubicki et al., 2007, Whitford et al., 2007) and although many of these alterations have been reported in relatives of people with schizophrenia (Boos et al., 2007: meta-analysis), there is a relative paucity of studies investigating the neuroanatomical substrates of language in the illness. In the extant FHR literature (see Table 1), only four publications from two research groups (from Pittsburgh and Edinburgh) have reported on the neural substrates of language in FHR individuals. They report significant decreases in the volumes of the pars triangularis (BA 45) (Bhojraj et al., 2009, Bhojraj, Francis et al., 2011, Bhojraj, Sweeney et al., 2011), prefrontal cortex (McIntosh et al., 2011), supramarginal gyrus, (Bhojraj et al., 2009, Bhojraj, Francis et al., 2011, Bhojraj, Sweeney et al., 2011), and/or angular gyrus (BA 40) (Bhojraj et al., 2009, Bhojraj, Sweeney et al., 2011, Bhojraj, Sweeney et al., 2011). Of these, the Pittsburgh group (Bhojraj and colleagues) had a broad definition of FHR (needing only 1 relative with SZ, not necessarily first degree). The Edinburgh study (McIntosh et al., 2011) found a relationship of these volume deficits to conversion to psychosis (N = 17). The Pittsburgh study (Bhojraj et al., 2009) related structural deficits to a language measure (verbal fluency) underscoring the need for more studies examining these two domains. In this study involving an independent sample of FHR subjects, we addressed more extensive components of language, including phonological awareness.

The anatomy of the language system includes the inferior frontal gyrus (IFG), consisting of the pars triangularis, and orbitalis; inferior parietal cortex (IPC) consisting of the supramarginal and angular gyri; and the superior temporal gyrus (STG) including Heschl's gyrus and Wernicke's area. The IFG is has been shown to mediate the expressive aspects of language (Price et al., 1997, Shalom and Poeppel, 2008) of which verbal fluency is one (Hirshorn and Thompson-Schill, 2006, Kircher et al., 2009, Lux et al., 2008, Pearlson et al., 1996). The left IFG mediates aspects of language such as phonology, morphology and semantics in addition to syntax (Bookheimer, 2002, Hagoort, 2005) and it plays a more general role in supporting cognitive functions that are not specific to language (Miller, 2000), but in which language plays a role such as memory retrieval, cognitive control, or processes of selection and/or competition (Thompson-Schill et al., 1999, Moss et al., 2005). The right IFG mediates language prosody (Gandour et al., 2003). The supramarginal gyrus has been shown to be the neural substrate for grammatical processing (Rogalski et al., 2010), and visual word recognition (Stoeckel et al., 2009) while the angular gyrus has been implicated in symbolic processing (Price and Ansari, 2011), and character- to phonological conversion in letter perception (Callan et al., 2005). Finally, the STG, including Heschl's gyrus and Wernicke's area has been implicated in word recognition (Mainy et al., 2008) and auditory language comprehension (Friederici et al., 2010) (Fig 1).

Crow et al., (1989, 1990) proposed a theory that schizophrenia arises out of an abnormality in the genetic control for the development of normal cerebral asymmetry that in turn underlies language processing. He further proposed this as the underlying basis for the symptoms of schizophrenia (Crow, 1997, DeLisi, 2001). Some evidence exists from fMRI studies that the processing of language may be abnormal in both people with schizophrenia and their young FHR relatives (Li, Craig et al., 2007, Li, Branch et al., 2007; Rajarethinam et al., 2011). These studies make a compelling case for further exploration of language related brain anatomy in people at FHR for schizophrenia.

Most family studies of brain structure, with some exceptions (Lawrie et al., 2008, Keshavan et al., 2010, Rosso et al., 2010, Bhojraj, Francis et al., 2011, Bhojraj, Sweeney et al., 2011) do not separate out those family members who are in the typical age range for onset of schizophrenia (and thus still at increased risk for illness) from those who are older (e.g., 18–35 for peak risk period versus older). In addition, many of these studies define genetic risk broadly—i.e. as needing only one ill first-degree relative (“simplex”), or even just second degree, to be at risk. By contrast, in families that have multiple affected members (e.g., two or more with psychosis), there is a greater likelihood of transmission of genetic risk across generations. Whereas in simplex families, the possibility exists of non-transmission of a new mutation that has not yet appeared in the germline or an environmental cause. Most studies do not distinguish this characteristic and it is likely to be important. For example, in Seidman et al. (2002), in an older group of relatives (mean age 40), nonpsychotic relatives from multiple affected families had more substantial volume reductions in the left hippocampus and had more severe neuropsychological impairments than relatives from simplex families (Faraone et al., 2000). Although, younger relatives l within the age of risk for schizophrenia were not studied to see if this abnormality could predict who later developed schizophrenia, finding hippocampal volume reduction in older well relatives suggests that hippocampal volume reduction may be a familial vulnerability marker that does not necessarily lead to illness.

Deficits in neuropsychological test scores for language functioning have been shown to correlate with reduced brain lateralization in people with schizophrenia (Hoff et al., 1992). Structural MRI studies (O'Donnell et al., 1995, Blackwood et al., 1991, McCarley et al., 2002; Meisenzahl et al., 2008, Lee et al., 2007) have shown lateralization deficits to be associated with language dysfunction in schizophrenia. Recently Oertel et al (2010) found reduced laterality in the planum temporale but not in Heschl's gyrus of FHR subjects. The focus of the present study was to extend the small number of FHR studies to a sample of young people at FHR for schizophrenia who have a high likelihood of inherited vulnerability for illness, and who are studied prior to being considered at ultra-high clinical risk for schizophrenia or in the prodromal stage (DeLisi, 2008, Keshavan et al., 2008, Seidman et al., 2010), yet while they are still within the peak age of risk for illness. Our specific hypotheses were as follows:

• Brain regions mediating language would be altered in the FHR subjects in comparison to low familial risk (LRC) subjects. Some of these regions may show altered lateralization.

• Language regions would be correlated with linguistic functions as measured by standardized neurocognitive tests of language.

• Language functions would be significantly impaired in the FHR group.