Decreased entorhinal cortex volumes in schizophrenia
Introduction
The human entorhinal cortex (EC) is located in the rostral half of the ventromedial temporal lobe and corresponds to the anteromedial parahippocampal gyrus (Brodmann's areas 28 and 34) (Insausti et al., 1998, Pruessner et al., 2002). It modulates multiple interactions between the limbic structures and the neocortex. More specifically, it is considered to be the most important gateway of neocortical polysensory information to the hippocampus (Sim et al., 2006). It is crucial for memory processing (Fransén, 2005), associative learning (Fyhn et al., 2004) and spatial navigation (Charles et al., 2004, Hafting et al., 2005). Furthermore, the entorhinal projections to the amygdala provide the neural pathway for the association between olfaction, emotional states and memory (Turetsky et al., 2003). All of these higher-level cognitive dimensions are compromised in patients with schizophrenia. As a result, it has always been believed that the entorhinal cortex is involved in the pathophysiology of this illness (Arnold, 1999, Arnold, 2000a, Arnold, 2000b, Lisman and Otmakhova, 2001).
Up to now, four magnetic resonance imaging (MRI) investigations have reported on reduced volumes of the entorhinal cortex in patients with schizophrenia compared to healthy individuals (Joyal et al., 2002, Pearlson et al., 1997, Prasad et al., 2004, Turetsky et al., 2003). On the contrary, no significant differences were found in three other MRI studies (Kalus et al., 2005, Nasrallah et al., 1997, Sim et al., 2006). However, early onset patients had smaller entorhinal cortex volumes than late-onset patients in one of these studies (Nasrallah et al., 1997). Therefore, the literature is still controversial on entorhinal cortex size in patients suffering from schizophrenia.
Nonetheless, several post-mortem studies support the role of entorhinal cortex in schizophrenia, showing subtle cytoarchitectural changes, such as smaller neuronal size (Arnold et al., 1995, Arnold et al., 1997) and neuronal displacement (Falkai et al., 2000, Jakob and Beckmann, 1986, Jakob and Beckmann, 1989, Jakob and Beckmann, 1994). These findings indicate that the entorhinal cortex is involved in a pattern of neurodevelopmental abnormalities (Kovalenko et al., 2003), which have also been observed in animal models of schizophrenia (Cunningham et al., 2006, Talamini et al., 1998). Also, neurophysiologic studies suggest that the entorhinal cortex plays a major role in the psychopathology and neuropsychology of schizophrenia (Cunningham et al., 2006). For instance, entorhinal cortex volumes were positively correlated with psychotic symptoms, especially with delusions (Prasad et al., 2004). In this regard, it has been hypothesized that the entorhinal cortex could retrieve corrupted memories (Prasad and Keshavan, 2003), consecutively processed as false conclusions by a dysfunctional circuitry involving the hippocampus (Benes and Berretta, 2000, Lisman and Otmakhova, 2001). Therefore, there is evidence that the cytoarchitecture and the function of the entorhinal cortex is impaired in schizophrenia, potentially participating in sustaining symptoms and cognitive disturbances.
In conclusion, some MRI studies exploring entorhinal cortex size in patients suffering from schizophrenia, provided conflicting findings. In this study, we investigated entorhinal cortex volumes in a large community-based population of patients with schizophrenia, representative of those living in the geographically defined catchment area of South Verona (100,000 inhabitants), Italy. Based on previous literature, we expected that patients suffering from schizophrenia would have decreased entorhinal cortex volumes compared to normal controls. Since the entorhinal cortex is part of the medial temporal lobe, we also explored the size of hippocampus in this dataset.
Section snippets
Subjects
Seventy patients with DSM-IV schizophrenia were studied (Table 1). They were recruited from the geographically defined catchment area of South Verona (i.e. 100,000 inhabitants) and were being treated by the South Verona Community-based Mental Health Service (CMHS) and by other clinics reporting to the South Verona Psychiatric Care Register (PCR) (Ammadeo et al., 1997, Tansella and Burti, 2003). Diagnoses for schizophrenia were obtained using the Item Group Checklist of the Schedule for Clinical
Results
The two groups significantly differed for total entorhinal cortex volumes, with patients having smaller volumes than normal controls (F = 6.24, p = 0.01; ANCOVA, age, gender and ICV as covariates). Also, a significant group × hemisphere interaction was found; indeed, patients with schizophrenia had significantly reduced right entorhinal cortex volumes compared to normal controls (F = 9.76; p = 0.002; ANCOVA, age, gender, and ICV as covariates) (Table 2 and Fig. 2), even when education was included as a
Discussion
Our study confirmed the presence of abnormally decreased entorhinal cortex volumes in schizophrenia, particularly on the right side (p = 0.002). This is consistent with the findings of four previous reports which found smaller entorhinal volumes in patients with schizophrenia when compared to healthy controls (Pearlson et al., 1997, Turetsky et al., 2003), even in neuroleptic–naive first-episode patients (Joyal et al., 2002, Prasad et al., 2004). Also, microstructural impairments of entorihnal
Role of the funding source
This work was partly supported by grants from the American Psychiatric Institute for Research and Education (APIRE/AstraZeneca Young Minds in Psychiatry Award), the Italian Ministry for Education, Universities and Research (PRIN n. 2005068874), the StartCup Veneto 2007 to Dr. Brambilla and by a grant from the Veneto Region, Italy, (159/03, DGRV n. 4087). None of these funding agencies had any further role in the study design; in the collection, analysis and interpretation of data; in the
Contributors
Monica Baiano managed the literature searches and wrote the manuscript draft.
Cinzia Perlini coordinated patient and control recruitment and scale administration.
Gianluca Rambaldelli managed MRI data post-processing.
Roberto Cerini and Roberto Pozzi Mucelli collected MRI data.
Marcella Bellani and Nicola Dusi recruited patients.
Giorgia Spezzapria traced the entorhinal cortex.
Amelia Versace supervised the entorhinal cortex tracing.
Matteo Balestrieri and Michele Tansella supervised subject
Conflict of interest
No authors of this manuscript have fees and grants from, employment by, consultancy for, shared ownership in, or any close relationship with, an organization whose interests, financial or otherwise, may by affected by the publication of the paper.
Acknowledgements
We thank Dr Konasale Prasad for his very helpful comments on the earlier versions of this manuscript and all subjects who participated.
This work was partly supported by grants from the American Psychiatric Institute for Research and Education (APIRE Young Minds in Psychiatry Award), the Italian Ministry for University and Research (PRIN n. 2005068874), the StartCup Veneto 2007 to Dr. Brambilla and by a grant from the Veneto Region, Italy, (159/03, DGRV n. 4087).
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