Proton magnetic resonance spectroscopy of the substantia nigra in schizophrenia.

BACKGROUND: Converging evidence in schizophrenia points to disruption of the dopamine and glutamate neurotransmitter systems in the pathophysiology of the disorder. Dopamine is produced in the substantia nigra, but few neuroimaging studies have specifically targeted this structure. In fact, no studies of the substantia nigra in schizophrenia have used proton magnetic resonance spectroscopy (MRS). We sought to demonstrate the feasibility of acquiring single-voxel MRS measurements at 3T from the substantia nigra and to determine which metabolites could be reliably quantified in schizophrenia patients and healthy controls. METHODS: We used a turbo spin echo sequence with magnetization transfer contrast to visualize the substantia nigra and single-voxel proton MRS to quantify levels of N-acetylaspartate, glutamate and glutamine (Glx), and choline in the left substantia nigra of 35 people with schizophrenia and 22 healthy controls. RESULTS: We obtained spectra from the substantia nigra and quantified neurometabolites in both groups. We found no differences in levels of N-acetylaspartate/creatine, Glx/creatine, or choline/creatine between the groups. We found a significant correlation between Glx/creatine and overall cognitive performance, measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), in controls but not patients, a difference that was statistically significant. CONCLUSIONS: Our study demonstrates the feasibility of obtaining single-voxel MRS data from the substantia nigra in schizophrenia. Such measurements may prove useful in understanding the biochemistry underlying cellular function in a region implicated in the pathophysiology of schizophrenia.

Magnetic transfer contrast accurately localizes substantia nigra confirmed by histology.

BACKGROUND: Magnetic resonance imaging (MRI) has multiple contrast mechanisms. Like various staining techniques in histology, each contrast type reveals different information about the structure of the brain. However, it is not always clear how structures visible in MRI correspond to structures previously identified by histology. The purpose of this study was to determine if magnetic transfer contrast (MTC) or T2 contrast MRI was better at delineating the substantia nigra (SN). METHODS: MRI scans were acquired in vivo from two nonhuman primates (NHPs). The NHPs were subsequently euthanized, perfused, and their brains sectioned for histologic analyses. Each slice was photographed before sectioning. Each brain was sectioned into approximately 500 sections, 40 µm each, encompassing most of the cortex, midbrain, and dorsal parts of the hindbrain. Levels corresponding to anatomic MRI images were selected. From these, adjacent sections were stained using Kluver-Barrera (myelin and cell bodies) or tyrosine hydroxylase (dopaminergic neurons) immunohistochemistry. The resulting images were coregistered to the block-face images using a moving least squares algorithm with similarity transformations. MR images were similarly coregistered to the block-face images, allowing the structures on MRI to be identified with structures on the histologic images. RESULTS: We found that hyperintense (light) areas in MTC images were coextensive with the SN as delineated histologically. The hypointense (dark) areas in T2-weighted images were not coextensive with the SN but extended partially into the SN and partially into the cerebral peduncles. CONCLUSIONS: MTC is more accurate than T2-weighting for localizing the SN in vivo.

Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging.

BACKGROUND: Studies have shown that individuals with schizophrenia suffer from memory impairments. In this study, we combined proton magnetic resonance spectroscopy (¹H-MRS) and functional magnetic resonance imaging (fMRI) to clarify the neurobiology of memory deficits in schizophrenia. METHODS: We used single-voxel MRS acquired in the left hippocampus and fMRI during performance of a memory task to obtain measures of neurochemistry and functional response in 28 stable, medicated participants with schizophrenia (SZ) and 28 matched healthy controls (HC). RESULTS: The SZ group had significantly decreased blood oxygen level-dependent (BOLD) signal in left inferior frontal gyrus (IFG) during encoding and in the anterior cingulate cortex (ACC) and superior temporal gyrus (STG) during retrieval. We did not find significant differences in N-acetylaspartate/creatine (NAA/Cr) or glutamate+glutamine (Glx/Cr) levels between the groups, but did find a significant positive correlation between NAA/Cr and Glx/Cr in the HC group that was absent in the SZ group. There were no significant correlations between BOLD and MRS measured in the hippocampus. Further analyses revealed a negative correlation between left IFG BOLD and task performance in the SZ group. Finally, in the HC group, the left IFG BOLD was positively correlated with Glx/Cr. CONCLUSIONS: We replicated findings of reduced BOLD signal in left IFG and of an altered relationship between IFG BOLD response and task performance in the SZ. The absence of correlation between NAA/Cr and Glx/Cr levels in patients might suggest underlying pathologies of the glutamate-glutamine cycle and/or mitochondria.

Assessments of function and biochemistry of the anterior cingulate cortex in schizophrenia.

BACKGROUND: Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T. METHODS: We used single-voxel MRS acquired in the dorsal anterior cingulate cortex and fMRI during performance of a Stroop color-naming task to investigate the neurochemistry and functional response of the anterior cingulate cortex/medial frontal cortex in 26 stable, medicated subjects with schizophrenia and 23 matched healthy control subjects. RESULTS: In schizophrenia subjects, we found decreased blood oxygen level-dependent signal in the medial frontal wall, with significant clusters restricted to more dorsal regions compared with healthy subjects. In addition, we observed a trend-level decrease in N-acetylaspartate/creatine (NAA/Cr) levels and a significant positive correlation between NAA/Cr level and the blood oxygen level-dependent signal in schizophrenia subjects that did not exist in healthy subjects. Furthermore, in this group of medicated subjects, we did not find evidence of decreased glutamate + glutamine(Glx)/Cr levels, but there was a significant negative correlation between Glx/Cr levels and negative symptoms. CONCLUSIONS: Our results suggest that abnormal NAA levels, which may reflect a neuronal dysfunction related to schizophrenia, affect neuronal physiology, as evidenced by reduced blood oxygen level-dependent response.

Obese women show greater delay discounting than healthy-weight women.

Delay discounting (DD) is a measure of the degree to which an individual is driven by immediate gratification vs. the prospect of larger, but delayed, rewards. Because of hypothesized parallels between drug addiction and obesity, and reports of increased delay discounting in drug-dependent individuals, we hypothesized that obese individuals would show higher rates of discounting than controls. Obese and healthy-weight age-matched participants of both sexes completed two versions of a DD of money task, allowing us to calculate how subjective value of $1000 or $50,000 declined as delay until hypothetical delivery increased from 2 weeks to 10 years. On both tasks, obese women (N=29) showed greater delay discounting than control women did (N=26; P values <.02). Subsequent analyses showed that these differences were not related to differences in IQ or income. Obese (N=19) and healthy-weight (N=21) men did not differ significantly. Further research is needed to determine why greater delay discounting was not also observed in obese men.