Resting quantitative cerebral blood flow in schizophrenia measured by pulsed arterial spin labeling perfusion MRI
Introduction
Studies of cerebral blood flow (CBF) in schizophrenia have been of interest since Kety and Schmidt first applied their nitrous oxide inhalation method to study the disorder (Kety et al., 1948). While Kety and Schmidt failed to find differences between patients and healthy individuals in CBF for the brain as a whole, they proposed that regional differences could provide clues to neural substrates of schizophrenia. Several years and technological advances later, this expectation was supported by the development of nuclear medicine techniques for measuring regional CBF such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT), which have revealed more focal and nuanced abnormalities in the CBF of individuals with schizophrenia.
Although variable, results have largely highlighted decreased CBF in specific brain areas such as frontal and temporal regions (Erkwoh et al., 1999, Taylor et al., 1999, Esel et al., 2000, Malaspina et al., 2004). In regard to frontal regions, and perhaps contributing to inconsistencies in results, hypofrontality appears to be most pronounced during active engagement in cognitive tasks (for reviews, see (Andreasen et al., 1992, Chua and McKenna, 1995, Gur and Gur, 1995, Weinberger and Berman, 1996; for a meta-analysis, see Hill et al., 2004). Additional findings include abnormal hemispheric laterality (Sheppard et al., 1983, Gur et al., 1985) and abnormal anterior posterior gradients that may contribute to findings of hypofrontality (Mathew et al., 1988); for reviews see (Gur, 1995, Bachneff, 1996). Utilization of these methods has also clarified the relationships between symptomatology and regional hyper- and hypoperfusion at rest. Specifically, increased severity of negative symptoms has been associated with reduced CBF in frontal and temporal regions as well as the thalamus (Lewis et al., 1992, Sabri et al., 1997, Min et al., 1999, Esel et al., 2000), and positive symptoms have been associated with increased CBF in temporal (Mathew et al., 1988, Parellada et al., 1998, Esel et al., 2000, Kohno et al., 2006, Horn et al., 2009), parietal (Mathew et al., 1988, Erkwoh et al., 1999, Esel et al., 2000, Franck et al., 2002), and frontal regions (Erkwoh et al., 1999, Horn et al., 2009), as well as decreased CBF in posterior cingulate gyrus and lingual gyrus (Liddle et al., 1992, Franck et al., 2002).
Despite the value of PET and SPECT in informing the neurobiology of schizophrenia, both are limited by invasiveness, reliance on radioactive tracer material, and expense. These limitations make PET and SPECT imaging difficult to implement in large-scale, multi-site studies. A promising alternative can be found in arterial spin labeling (ASL) imaging. ASL measures CBF by using magnetically labeled arterial blood water as an endogenous tracer (Detre et al., 1992, Williams et al., 1992) and offers several advantages over other techniques. First, the noninvasive nature of ASL allows for repeated measurements with limited discomfort to participants aside from those typically associated with MRI such as loud noise, feelings of claustrophobia, and vibration. Work examining the reproducibility of ASL CBF measurements over time shows good stability and reliability across sessions with healthy individuals (Yen et al., 2002, Parkes et al., 2004, Hermes et al., 2007, Petersen et al., 2010, Pfefferbaum et al., 2010b, Wang et al., 2011) and suggests that ASL may be particularly useful for longitudinal studies of schizophrenia that assess changes over time due to symptom remission/exacerbation or behavioral/psychopharamacological intervention. It should be noted, however, that a debate about the long-term reproducibility of ASL measurements is currently open, as some studies suggest that reproducibility estimates decline over longer time periods (Parkes et al., 2004, Gevers et al., 2009) whereas others do not (Hermes et al., 2007, Petersen et al., 2010). Second, as opposed to fMRI techniques such as blood oxygenation level dependent (BOLD) imaging that focus on task-related activation, ASL provides quantitative measurement of CBF, an advantage that makes ASL optimal for assessing resting or baseline states. Third, ASL can be acquired quickly and easily in conjunction with other structural and functional MR information. These utilities offer a unique opportunity to provide a measurable and meaningful baseline to be integrated with blood oxygenation level dependent with BOLD paradigms.
To our knowledge, two studies have utilized ASL to examine CBF in schizophrenia. Horn et al. (2009) found no group differences in CBF between patients and healthy controls but did report a significant correlation between severity of thought disorder and increased blood flow in left superior temporal gyrus, left anterior insula, and left inferior frontal gyrus. Additionally, in an examination of unmedicated patients, Scheef et al. (2010) found reduced perfusion in bilateral frontal and parietal lobes and middle and anterior cingulate gyrus in patients but increased perfusion in cerebellum, thalamus, and brainstem as compared to healthy controls. While informative, these early studies utilized small samples, and the examination of correlations with symptoms was limited to thought disorder.
Thus, given the benefits of ASL and the promising findings of these initial studies, we utilized this method to examine resting CBF in a relatively large sample of healthy control individuals and individuals with schizophrenia. Our goals were as follows: 1) to quantify resting CBF in individuals with schizophrenia, 2) to assess differences in resting CBF between patients and healthy individuals, and 3) to examine the relationship between resting CBF and psychiatric symptoms. We expected that the quantitative CBF values obtained for both controls and patients would be comparable to those obtained with both nuclear medicine techniques and previous ASL investigations of healthy individuals. We also hypothesized that patients would show reduced CBF in frontal and temporal regions as compared to control participants; however, because participants were only assessed at rest, we expected these differences to be modest in comparison to those reported by previous studies that have utilized a cognitive task. Finally, consistent with previous reports reviewed above, we hypothesized that increased severity of negative symptoms would be related to reduced CBF in frontal and temporal regions and that increased severity of positive symptoms would be related to increased CBF in frontal, temporal, and parietal regions. Furthermore, in using a voxel-wise analysis of these quantitative images, we intended to expand upon previous work by better localizing brain regions linked to more severe symptomatology.
Section snippets
Subjects
The original sample included 26 healthy control individuals and 31 individuals diagnosed with schizophrenia or schizoaffective disorder. Data from two controls and one patient were excluded due to excessive motion during scanning (> 3 mm). The final sample included 24 controls and 30 patients. Groups did not significantly differ in gender (χ2 = 0.19, p = 0.67), handedness (χ2 = 0.18, p = 0.94), ethnicity (χ2 = 1.35, p = 0.51), age (t(52) = 0.35, p = 0.73), personal education (t(52) = 1.71, p = 0.09), parental
Group differences in CBF
Quantification of CBF produced gray matter values that on average were 2–3 times higher than white matter values, resulting in a mean gray to white matter ratio of 2.37 (± 0.45) for controls and 2.32 (± 0.68) for patients. Mean gray matter CBF (including cortical and subcortical gray matter) for controls and patients was 69.11 (± 16.53) and 67.51 (± 13.27) ml/100 g/min, respectively, and mean white matter CBF was 30.28 (± 10.05) and 30.57 (± 8.38) ml/100 g/min, respectively. These values did not
Discussion
Results from this study support the feasibility and utility of implementing ASL perfusion imaging in the study of schizophrenia. The quantitative CBF values reported here are consistent with those provided by nuclear medicine techniques (Ariel et al., 1983, Gur et al., 1983, Lassen, 1985, Leenders et al., 1990) and demonstrate the validity of ASL for providing quantitative and meaningful indices of CBF. Similarly, the findings from comparing CBF in patients with schizophrenia to healthy
Acknowledgments
This work was supported by the following grants from the National Institute of Mental Health (NIMH) at the University of Pennsylvania: T32-MH019112, T32-NS054575, and R01-MH060722. We thank Drs. John Detre, Jiongjiong Wang, and Ze Wang from the Center for Functional Neuroimaging at the University of Pennsylvania for their assistance in protocol implementation and data analysis consultation.
References (71)
See me, hear me, touch me: multisensory integration in lateral occipital–temporal cortex
Current Opinion in Neurobiology
(2005)- et al.
Pathways to functional outcomes in schizophrenia: the role of premorbid functioning, negative symptoms and intelligence
Schizophrenia Research
(2009) - et al.
Audio–visual integration in schizophrenia
Schizophrenia Research
(2003) - et al.
Meta-analysis of diffusion tensor imaging studies in schizophrenia
Schizophrenia Research
(2009) - et al.
Active and remitted schizophrenia: psychopathological and regional cerebral blood flow findings
Psychiatry Research
(1999) - et al.
The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: evidence from a partial correlation network analysis
NeuroImage
(2008) - et al.
Hypofrontality in schizophrenia: RIP
Lancet
(1995) - et al.
Localization of cerebral functional deficits in treatment-naive, first-episode schizophrenia using resting-state fMRI
NeuroImage
(2010) - et al.
Left temporal perfusion associated with suspiciousness score on the Brief Psychiatric Rating Scale in schizophrenia
Psychiatry Research
(2006) - et al.
Resting neural activity distinguishes subgroups of schizophrenia patients
Biological Psychiatry
(2004)