Anterior thalamic radiation integrity in schizophrenia: A diffusion-tensor imaging study
Introduction
Dysfunction of the thalamus has been associated with the pathophysiology of schizophrenia due in part to its dense reciprocal connections with the cerebral cortex (Andreasen, 1997, Byne et al., 2009). Many structural studies have shown decreased size of the thalamus in schizophrenia (Wright et al., 2000, Konick and Friedman, 2001), although negative studies have also been reported (Portas et al., 1998). In our previous studies, using deformation-based shape analysis, thalamic abnormalities were localized to regions that included the anterior extremes of the structure (Csernansky et al., 2004, Harms et al., 2007). The anterior and mediodorsal nuclei have been associated with cognitive functions (Van der Werf et al., 2003), and postmortem studies have shown a reduction in neuronal population in these regions among individuals with schizophrenia (Young et al., 2000). The anterior thalamic nucleus receives hippocampal afferents and projects information to the anterior cingulate cortex, and can influence the encoding of new stimuli (Mitchell et al., 2002, Van der Werf et al., 2003). The mediodorsal thalamic nucleus has reciprocal connections with the prefrontal cortex, and structural and functional abnormalities in this area have been linked to dysfunction in executive processes pertaining to declarative memory (Van der Werf et al., 2003).
A major efferent tract of the thalamus is the anterior limb of the internal capsule (ALIC). The ALIC carries two major fiber systems: the anterior thalamic radiation (ATR) and the frontopontine tract (Kahle et al., 2002). To a lesser degree thalamo-striate and striato-striate fibers are also present (Axer and Keyserlingk, 2000, Cunningham, 1903) in the ALIC. The ATR consists of fibers between mediodorsal thalamic nuclei and the frontal cortex, and fibers between anterior thalamic nuclei and the anterior cingulate cortices (Kahle et al., 2002, Zhou et al., 2003). Frontopontine fibers are descending cortical fibers, which have motor functions (Hendelman, 2006). Although the distinct fiber systems intermingle to a degree in the ALIC (Axer and Keyserlingk, 2000, Axer et al., 1999), the anterior thalamic radiation fibers tend to course medial to the frontopontine tracts in at least some deep brain regions superior to the anterior commissure (Wright and Locke, 1971, Meyer et al., 1947, Wakana et al., 2004). At more inferior regions near the level of the anterior commissure, the ALIC consists almost exclusively of anterior thalamic radiation fibers (Spalteholz, 1923).
In recent years an increasingly valuable tool for evaluating the integrity of the ALIC and other white matter tracts has been diffusion-tensor imaging (DTI) (Basser et al., 1994). DTI measures the diffusivity of water molecules within living brain and can characterize the organization of underlying tissue structure using scalar measures of anisotropy (Basser et al., 1994, Conturo et al., 1996). In healthy white matter, water is constrained to diffuse primarily along the axis of the fibers resulting in a high anisotropy, while in gray matter diffusion is less directional yielding a relatively low anisotropy (Pierpaoli et al., 1996, Le Bihan et al., 2001). Anisotropy refers to the extent to which water diffusion is direction-dependent within the tissue microstructure, and is considered a marker of white matter integrity. Therefore DTI can evaluate the integrity and directionality of white matter tracts in vivo. Previous DTI studies of schizophrenia have generally shown decreased anisotropy in various white matter structures as well as a loss of normal left–right asymmetry (Kanaan et al., 2005, Kubicki et al., 2007). The anisotropy of the ALIC has been previously reported to be decreased in schizophrenia using both voxel based morphometry (Sussmann et al., 2009, Munoz Maniega et al., 2008) and region-of-interest (ROI) based methods (Zou et al., 2008, Mitelman et al., 2007, Sussmann et al., 2009). In addition, reduced anisotropy has been found in unaffected siblings of patients (Munoz Maniega et al., 2008).
The goal of the current study was to determine if selective measurement of the anterior thalamic radiation may provide increased sensitivity to detect anisotropy changes in schizophrenia relative to the ALIC as a whole. We also sought to determine if those changes have a relationship with specific symptoms and cognitive features of schizophrenia. We hypothesize that weighting the anisotropy measurements to the anterior thalamic radiation by measuring the more medial part of the ALIC will yield a more significant reduction in schizophrenia subjects than when measuring the total ALIC. This hypothesis is based on the premise that anterior thalamic radiation, and not frontopontine fibers, is disrupted in schizophrenia, due to decreased neuronal density in thalamic nuclei that project through the ATR (Young et al., 2000). Also, since the anterior thalamic radiation is associated with memory encoding and executive functioning (as described above), we hypothesize a relationship of fiber integrity to cognitive performance.
Section snippets
Subjects
The study was approved by the local Institutional Review Board (IRB). Informed consent was obtained in all subjects. Two groups of subjects were recruited by advertising in local area psychiatric clinics and in the community: schizophrenia probands (SCZ; n = 39) and healthy controls (CON; n = 33). From an initial group of potential subjects that fit inclusion criteria (see below), the final group of study subjects were those from whom DTI scans were generated and whose MR scans did not have
ROI volumes
For each subject, the volume of the specific ROIs outlined in each axial section was summed across sections to calculate the total ROI volumes. This calculation was used as a quality-control check on the ROI tracing procedure, and to test for differences in tALIC volume between groups. Because anisotropy images demonstrate the full thickness of the internal capsule compared to conventional T1- or T2-weighted images (Shimony et al., 1999), we assessed the tALIC volume using the volumes of the
Discussion
In this study, we found evidence for decreased anisotropy in the anterior limb of the internal capsule (ALIC) in patients with schizophrenia, compared to controls. Anisotropy decreases could be due to decreased myelination, neuronal fiber density, or directional coherence (Basser, 1995). A possible explanation for the right ALIC finding is decreased neuronal fiber density, which would be consistent with histopathologic observations showing decreased neuronal density in thalamic neurons that
Acknowledgements
This research was funded by federal NIH grants P20 MH062130 and P50 MH071616 (Conte Center for the Neuroscience of Mental Disorders), R01 MH056584, R01 NS039538, and R01 NS065480.
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