Cagri Yuksel

Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders.

In mood disorders, there is growing evidence for glutamatergic abnormalities derived from peripheral measures of glutamatergic metabolites in patients, postmortem studies on glutamate-related markers, and animal studies on the mechanism of action of available treatments. Magnetic resonance spectroscopy (MRS) has the potential to corroborate and extend these findings with the advantage of in vivo assessment of glutamate-related metabolites in different disease states, in response to treatment, and in relation with functional imaging data. In this article, we first review the biological significance of glutamate, glutamine, and Glx (composed mainly of glutamate and glutamine). Next, we review the MRS literature in mood disorders, examining these glutamate-related metabolites. Here, we find a highly consistent pattern of Glx-level reductions in major depressive disorder and elevations in bipolar disorder. In addition, studies of depression, regardless of diagnosis, provide suggestive evidence for reduced glutamine/glutamate ratio and in mania for elevated glutamine/glutamate ratio. These patterns suggest that the glutamate-related metabolite pool (not all of it necessarily relevant to neurotransmission) is constricted in major depressive disorder and expanded in bipolar disorder. Depressive and manic episodes may be characterized by modulation of the glutamine/glutamate ratio in opposite directions, possibly suggesting reduced versus elevated glutamate conversion to glutamine by glial cells, respectively. We discuss the implications of these results for the pathophysiology of mood disorders and suggest future directions for MRS studies.

The history of childhood trauma among individuals with ultra high risk for psychosis is as common as among patients with first-episode schizophrenia

Childhood trauma (CT) is more common in patients with psychosis than in general population and is found to be related to the severity of symptoms. The objective of this study was to investigate the severity of CT, and its relationship with clinical features in two different groups: first‐episode schizophrenia (FES) and ultra high risk for psychosis (UHR) groups.

Gray matter volume in schizophrenia and bipolar disorder with psychotic features

There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD.

Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder

Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using 31P magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.

Cognitive deficits in clinical and familial high risk groups for psychosis are common as in first episode schizophrenia

The aim of this study is to compare the neurocognitive functions in individuals with clinical or genetic risk for psychosis, in patients with first-episode schizophrenia (FES) and in healthy controls. We compared cognitive functions of 52 individuals at ultra high risk (UHR) for psychosis, 53 patients with FES, their 30 healthy siblings (familial high risk group, FHR) and controls. FES group had worse neuropsychological performance than controls in all of the domains. UHR group had worse performance in verbal learning, attention, and working memory than controls. Additionally, individuals at UHR with familial risk had worse performance on executive functions than the control group. FES group had lower global composite score than UHR group, and worse sustained attention than FHR group. FHR group had worse performance on executive functions and attention than controls. We found no difference in cognitive performances of UHR and FHR groups. Cognitive deficits in UHR and FHR groups were largely similar to those with FES. These findings support that cognitive deficits may arise before the first episode of schizophrenia.

Gray matter abnormalities in patients with social anxiety disorder: A voxel-based morphometry study

The main objective of this study was to investigate the gray matter volume (GMV) differences between the patients with social anxiety disorder (SAD) and healthy controls, using VBM analysis. A total of 27 consecutive patients (15 women and 12 men) with SAD and 27 age and sex-matched healthy control subjects were included in this study. With magnetic resonance imaging, we examined GMV differences between SAD and healthy control groups. We found that GMV in the right middle and inferior temporal, left superior parietal, left precuneus and right fusiform areas were significantly greater in patients with SAD than in healthy controls. In addition, GMV in the right inferior and middle temporal regions were positively correlated with the social avoidance and total social anxiety scores of the participants in the SAD group. Lastly, greater GMV in the left superior parietal and precuneal regions were correlated with the higher disability in the social life of the patients with SAD. Our results suggest that the regions that showed significant GMV differences between the two groups play an important role in the pathophysiology of SAD and increased GMV in these regions might reflect a pathological process of neural abnormalities in this disorder.

Brain bioenergetics and redox state measured by 31P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders

BACKGROUND Brain bioenergetic anomalies and redox dysregulation have been implicated in the pathophysiology of psychotic disorders. The present study examined brain energy-related metabolites and the balance between nicotinamide adenine dinucleotide metabolites (oxidized NAD+ and reduced NADH) using 31P-magnetic resonance spectroscopy (31P-MRS) in unaffected siblings, compared to first episode psychosis (FEP) patients and healthy controls. METHODS 21 unaffected siblings, 32 FEP patients (including schizophrenia spectrum and affective psychoses), and 21 controls underwent 31P-MRS in the frontal lobe (6×6×4cm3) on a 4T MR scanner, using custom-designed dual-tuned surface coil with outer volume suppression. Brain parenchymal pH and steady-state metabolite ratios of high energy phosphate compounds were measured. NAD+ and NADH levels were determined using a 31P-MRS fitting algorithm. 13 unaffected sibling-patient pairs were related; other patients and siblings were unrelated. ANCOVA analyses were used to examine 31P-MRS measures, with age and gender as covariates. RESULTS The phosphocreatine/adenosine triphosphate ratio was significantly reduced in both unaffected siblings and FEP patients, compared to controls. NAD+/NADH ratio was significantly reduced in patients compared to siblings and controls, with siblings showing a reduction in NAD+/NADH compared to controls that was not statistically significant. Compared to patients and controls, siblings showed significantly reduced levels of NAD+. Siblings did not differ from patients or controls on brain pH. DISCUSSION Our results indicate that unaffected siblings show some, but not all the same abnormalities in brain energy metabolites and redox state as FEP patients. Thus, 31P-MRS studies may identify factors related both to risk and expression of psychosis.

McLean OnTrack: a transdiagnostic program for early intervention in first-episode psychosis

Most programs specializing in the treatment of first‐episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first‐episode psychosis.

Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies

Converging evidence from molecular to neuroimaging studies suggests brain energy metabolism abnormalities in both schizophrenia and bipolar disorder. One emerging hypothesis is: decreased oxidative phosphorylation leading to accumulation of lactic acid from glycolysis and subsequent acidification of tissue. In this regard, integrating lactate and pH data from magnetic resonance spectroscopy (MRS) studies in both diseases may help us understand underlying neurobiological mechanisms. In order to achieve this goal, we performed a systematic search of case–control studies examining brain lactate or pH among schizophrenia and/or bipolar patients by using MRS. Medline/Pubmed and EBSCO databases were searched separately for both diseases and outcomes. Our search yielded 33 studies in total composed of 7 lactate and 26 pH studies. In bipolar disorder, 5 out of 6 studies have found elevated lactate levels especially in the cingulate cortex and 4 out of 13 studies reported reduced pH in the frontal lobe. In contrast, in schizophrenia a single study has examined lactate and reported elevation, while only 2 out of 13 studies examining pH have reported reduction in this measure. There were no consistent patterns for the relationship between lactate or pH levels and medication use, disease type, mood state, and other clinical variables. We highlight the need for future studies combining 1H-MRS and 31P-MRS approaches, using longitudinal designs to examine lactate and pH in disease progression across both schizophrenia and bipolar disorders.

Proton Magnetic Resonance Spectroscopy in Social Anxiety Disorder

In the present study, 24 nonmedicated patients with social anxiety disorder (SAD) were compared with 24 healthy control subjects to assess metabolite levels in the anterior cingulate, insula, caudate, and putamen using proton magnetic resonance spectroscopy. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was significantly higher in patients with SAD than in healthy control subjects in the anterior cingulate and insula. NAA/Cr ratios in the insula correlated positively with the Liebowitz Social Anxiety Scale total scores in patients with SAD. Our results support the significance and biochemical involvement of the anterior cingulate and insula in the pathophysiology of SAD.