Betsy Schaefer

Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia

BACKGROUND Thalamic glutamine loss and grey matter reduction suggest neurodegeneration in first-episode schizophrenia, but the duration is unknown. AIMS To observe glutamine and glutamate levels, grey matter volumes and social functioning in patients with schizophrenia followed to 80 months after diagnosis. METHOD Grey matter volumes and proton magnetic resonance spectroscopy metabolites in left anterior cingulate and left thalamus were measured in 17 patients with schizophrenia before medication and 10 and 80 months after diagnosis. Social functioning was assessed with the Life Skills Profile Rating Scale (LSPRS) at 80 months. RESULTS The sum of thalamic glutamate and glutamine levels decreased over 80 months, and correlated inversely with the LSPRS. Thalamic glutamine and grey matter loss were significantly correlated in frontal, parietal, temporal and limbic regions. CONCLUSIONS Brain metabolite loss is correlated with deteriorated social functioning and grey matter losses in schizophrenia, consistent with neurodegeneration.

Duration of untreated psychosis vs. N-acetylaspartate and choline in first episode schizophrenia: a 1H magnetic resonance spectroscopy study at 4.0 Tesla.

N-acetylaspartate (NAA) has been associated with neuronal integrity and function, and choline-containing compounds have been linked to neuronal membrane integrity. This study examined the influence of the duration of untreated psychosis, duration of prodromal symptoms and total length of untreated illness on these markers of neuronal loss or damage. In vivo 1H magnetic resonance spectroscopy data were acquired from 1.5-cc volumes in the left anterior cingulate and left thalamus of 19 never-treated first episode schizophrenic subjects using STEAM20 at 4.0 Tesla. Duration of untreated psychosis, prodrome and total length of untreated illness were correlated with levels of NAA and choline. No significant correlation was observed between NAA and duration of untreated psychosis and untreated illness in both regions examined. Thalamic NAA negatively correlated with duration of prodromal symptoms. A positive correlation between choline and duration of untreated psychosis was identified in both regions studied. Delays in treatment of psychotic symptoms of schizophrenia were not associated with a reduction in markers of neuronal integrity or function in contrast to longer prodromal periods, which were associated with lower NAA. Neuronal damage, potentially detectable via lower NAA, may be occurring before the onset of psychosis. Increased choline is associated with longer duration of untreated psychosis and could indicate that psychosis-related membrane alterations precede the appearance of NAA reductions observed by studies of chronic schizophrenia.

Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: anterior cingulate activity during a color-word Stroop task

Background:Glutamate abnormalities have been suggested to be associated with symptoms of schizophrenia. Using functional magnetic resonance spectroscopy (1H-fMRS), it is possible to monitor glutamate dynamically in the activated brain areas, which has yet to be reported in schizophrenia. It was hypothesized that subjects with schizophrenia would have weaker glutamatergic responses in the anterior cingulate to a color-word Stroop Task.AIMS:The aim of this study was to gain insight into the health of GLU neurotransmission and the GLU-GLN cycle in SZ using a 1H-fMRS protocol.Methods:Spectra were acquired from the anterior cingulate of 16 participants with schizophrenia, 16 healthy controls and 16 participants with major depressive disorder (MDD) while performing the Stroop task in a 7T magnetic resonance imaging scanner. 1H-fMRS spectra were acquired for 20 min in which there were three 4-min blocks of cross fixation interleaved with two 4-min blocks of the Stroop paradigm.Results:A repeated-measures analysis of variance revealed a main effect of time for glutamate concentrations of all groups (P<0.001). The healthy control group increased glutamate concentrations in the first run of the Stroop task (P=0.006) followed by a decrease in the recovery period (P=0.007). Neither the schizophrenia (P=0.107) nor MDD (P=0.081) groups had significant glutamate changes in the first run of the task, while the schizophrenia group had a significant increase in glutamine (P=0.005). The MDD group decreased glutamate concentrations in the second run of the task (P=0.003), as did all the groups combined (P=0.003).Conclusions:1H-fMRS data were successfully acquired from psychiatric subjects with schizophrenia and mood disorder using a cognitive paradigm for the first time. Future study designs should further elucidate the glutamatergic response to functional activation in schizophrenia.

A Pilot Study of Marital Therapy as a Treatment for Depression.

Abstract Seventeen depressed married women were assigned to marital therapy or a waiting list control group. The couples received 10 sessions of Enhancing Marital Intimacy Therapy (EMIT), a structured technique involving the self-disclosure of personal constructs. The marital therapy group had a significant reduction in depressive symptomatology compared to the control group in this pilot study. EMIT may be a viable treatment for women whose depressive symptoms are initiated by the loss of hope of developing a close, confiding relationship.

Increased glutamate levels observed upon functional activation in the anterior cingulate cortex using the Stroop Task and functional spectroscopy

It has been shown in recent studies that it is possible to detect changes in the main excitatory neurotransmitter, glutamate, upon functional activation with visual and motor paradigms using a 7 T MRI and functional magnetic resonance spectroscopy. A cognitive task would be desirable for this technique because it could then be used to examine psychiatric disorders that have cognitive deficiencies. The aim of the work presented here was to use functional magnetic resonance spectroscopy with a 7 T MRI to show that increases in glutamate can be observed within the anterior cingulate cortex using the Stroop Task as the activation paradigm in healthy controls. Significant glutamate increases (0.24±0.09 µmol/g, P<0.025), comparable with what has been reported in the studies of the occipital cortex and motor cortex, were observed when the participants (n=7) performed the task, followed by a trend toward returning to baseline in the post-task recovery period (−0.23±0.13 µmol/g). This method would be ideal for the study of neuropsychiatric disorders that have been shown to have abnormal resting glutamate levels and cognitive deficiencies in the anterior cingulate cortex, such as schizophrenia. This exploratory study is the first to demonstrate functional magnetic resonance spectroscopy in the anterior cingulate with a cognitive task using a 7 T MRI.

Comparative study of proton and phosphorus magnetic resonance spectroscopy in schizophrenia at 4 Tesla

This study used high-field magnetic resonance spectroscopy to examine the correlation of 1H and 31P metabolite levels in patients with schizophrenia and normal controls. 1H and 31P in vivo spectra were acquired successively from the left anterior cingulate and left thalamus of nine chronic schizophrenic patients and eight comparable healthy controls. A significant positive correlation between glutamine (Gln) and phosphoethanolamine (PEtn) was found in the left anterior cingulate of patients. In the left thalamus of patients, a significant negative correlation between N-acetylaspartate (NAA) and glycerophosphocholine (GroPCho) was found. No significant correlations were found in controls. The correlation between glutamine and phosphoethanolamine may reflect a link between neurotransmission alterations and membrane phospholipid metabolism alterations. The negative correlation between N-acetylaspartate and glycerophosphocholine may reflect the presence of neurodegeneration.

Longitudinal 4.0 Tesla 31P magnetic resonance spectroscopy changes in the anterior cingulate and left thalamus in first episode schizophrenia

Progressive volumetric losses in schizophrenia may be preceded by abnormal cell membrane metabolism. Longitudinal changes in membrane metabolites were quantified with (31)P MRS in the anterior cingulate and left thalamus of 13 first episode schizophrenic patients and 13 healthy volunteers at baseline and 30 months. Glycerophosphocholine was higher in patients at baseline in the anterior cingulate and glycerophosphoethanolamine was lower in the left thalamus at 30 months compared with patients at baseline and volunteers at 30 months. These observations suggest longitudinal changes in membrane metabolites consistent with a neurodegenerative process in certain cases of schizophrenia.

Medial Prefrontal and Anterior Insular Connectivity in Early Schizophrenia and Major Depressive Disorder: A Resting Functional MRI Evaluation of Large-Scale Brain Network Models

Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.

Progressive membrane phospholipid changes in first episode schizophrenia with high field magnetic resonance spectroscopy

Patients with a first episode of schizophrenia generally have increased phospholipid membrane breakdown products within the brain, while findings in chronic patients have been inconsistent. In this study we examine progressive changes in phosphorus membrane metabolites in the same patient group through the early years of schizophrenia in brain regions associated with the disease. Sixteen never-treated and medicated first episode schizophrenic patients were assessed at 10 months and 52 months after diagnosis. Sixteen matched volunteers were assessed at baseline and after 35 months. Phospholipid membrane metabolism was assessed with phosphorous magnetic resonance spectroscopy in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex, parieto-occipital cortex, superior temporal gyrus and temporal pole. At 10 months, glycerophosphocholine was increased in the anterior cingulate in patients as compared to controls. Glycerophosphocholine was decreased in the anterior cingulate and increased in the posterior cingulate and left superior temporal gyrus; glycerophosphoethanolamine was decreased in the left thalamus and increased in the left hippocampus within patients over time. At 52 months, compared to controls phosphocholine was increased in the left thalamus and glycerophosphoethanolamine was increased in the left hippocampus. These results imply a gradual inclusion of brain regions in schizophrenia where an initial increase, followed by a decrease in phospholipid membrane metabolites was observed. This pattern, observed in the early years of schizophrenia, is consistent with excitotoxic neural membrane breakdown in these regions.

Relationship of site of seizure focus to psychiatric morbidity

Abstract We evaluated patients with demonstrated right (n = 25) or left (n = 25) temporal lobe seizure foci and compared their prevalence of psychopathology with that of patients with nontemporal lobe foci (n = 25) or multifocal seizure onset (n = 19). We also investigated the relation between foci laterality and psychiatric disturbance. Fifty-three patients (56.3%) had psychiatric morbidity. When Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) case status was used for comparison, no significant differences were evident among the three groups. Patients with right hemisphere foci were more likely to have psychiatric morbidity than those with left hemisphere foci, but this finding was not statistically significant.