Frontal lobe membrane phospholipid metabolism and ventricle to brain ratio in schizophrenia: preliminary 31P-MRS and CT studies

A number of studies employing in vivo phosphorous-31 magnetic resonance spectroscopy (³¹P-MRS) have demonstrated alterated measurements of frontal phospholipid and high energy phosphorus metabolism in schizophrenia. Enlargement of both the cerebroventricular system and the cortical sulci also has been reported as the most consistent pathological finding in schizophrenia by several investigators. To our knowledge, however, only two studies have simultaneously examined structural and functional aspects of the biological substrate of schizophrenia in the same patients. Moreover, they may have failed to find a significant correlation between these variables because of small sample sizes. The possible relationship between frontal lobe membrane phospholipid metabolism and ventricle-to-brain ratio (VBR) in patients with schizophrenia was investigated. In 31 schizophrenic patients, frontal lobe membrane phospholipid metabolism was measured by ³¹P-MRS, and VBR was measured by computed tomography (CT). Stepwise multiple regression analysis disclosed that VBR positively correlated only with increased phosphodiester (PDE) level (β = 0.381, p = 0.0345), but with no other metabolites. This finding may provide evidence for an association between structural brain abnormality and altered frontal lobe membrane metabolism in schizophrenic patients, although the p-value of the finding is not high. Received: 26 April 1999 / Accepted: 22 February 2000     

Basal ganglia high-energy phosphate metabolism in neuroleptic-naive patients with schizophrenia: a 31-phosphorus magnetic resonance spectroscopic study

OBJECTIVE: This study used 31-phosphorus magnetic resonance spectroscopy ((31)P MRS) to investigate basal ganglia abnormalities in neuroleptic-naive patients with schizophrenia. METHOD: Nineteen schizophrenia patients and 31 age- and sex-matched healthy comparison subjects underwent (31)P MRS. RESULTS: The phosphocreatine/total phosphorus and phosphocreatine/total ATP ratios in both basal ganglia were significantly lower in patients. CONCLUSIONS: Schizophrenia patients showed features of increased metabolism in the basal ganglia consistent with impaired activity of the frontostriatal pathways.     

Frontal lobe alterations in schizophrenia

Functional neuroimaging and neuropsychological performance indicate a prefrontal dysfunction in schizophrenia patients. Frontal morphological brain abnormalities are also evident in these patients, but the relationship between neuropsychology and neuroimaging findings remains unclear. In this study, thirty patients with schizophrenia and 30 control participants were assessed using a neuropsychological test battery sensitive to fronto–striatal system dysfunction. Computed tomography (CT) scans were used to calculate the distance from the corpus callosum to the frontal pole corrected for brain size (anterioposterior length) in the group of patients and in a group of control participants with negative radiological findings. Schizophrenia patients performed significantly worse than controls in all frontal lobe tests. Corrected length from the corpus callosum to the frontal pole was reduced in patients with schizophrenia. This easy–toperform measurement has not been used in previous studies, and indicates that schizophrenia patients have structural frontal abnormalities. However, correlations between structural and functional measures fail to show a clear relationship between the prefrontal performance and the main CT measures. As a rule, the trend observed in the correlation matrix pointed towards a relationship between CT parameters and a dysfunction on neuropsychological tests sensitive to frontal lobe damage.     

Neuronal dysfunction of the frontal lobe in schizophrenia

Localized in vivo proton magnetic resonance spectroscopy (MRS) was performed to evaluate metabolic alterations in the right and left frontal lobe before and after antipsychotic treatment of schizophrenic patients (n=24) and a group of healthy normal subjects (n=20). Proton metabolic ratios obtained from the 8 cm3 voxels in the right and left frontal lobes were compared with the clinical assessment for each subject. There was no significant difference in the metabolic ratios between the right and the left frontal lobes in either the schizophrenic group or the control group, indicating no laterality. Compared with those of the normal control group, NAA/Cr ratio of the schizophrenic patients showed significantly lower value. The NAA/Cr ratio of the schizophrenic patients was not changed after antipsychotic treatment. The present study supports the 'hypofrontality' hypothesis of schizophrenia.     

Investigation of frontal lobe subregions in first-episode schizophrenia

The evidence for frontal lobe structural abnormalities in schizophrenia using magnetic resonance (MR) imaging has been mixed, but most studies used either single slice measures or total volumes of a single frontal region, neither of which is sensitive to potential volume differences in more specific subregions. This study employed reliable methods for parcellation of the frontal lobes from MR images based on the sulcal anatomy. Following a cytoarchitectonic theory that distinguishes dorsomedial (archicortically derived) from ventrolateral (paleocortically derived) frontal subregions, we measured the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal region in 19 first-episode schizophrenia patients and 26 healthy comparison subjects. Results indicated that male patients had significantly larger right orbital frontal volume compared to their left orbital frontal volume and compared to healthy men. Among male patients larger right orbital frontal volume was significantly correlated with smaller right `archicortical' (i.e. anterior cingulate and superior frontal gyri) volume. Furthermore, the ratio of right orbital frontal to right `archicortical' volume was significantly and positively correlated with level of delusions among male patients. These findings suggest that there may be reciprocal controls on `archicortical' and `paleocortical' neurodevelopment among men with schizophrenia, and that larger paleocortical relative to archicortical volumes may be associated with increased delusions.     

Apathy in schizophrenia: reduced frontal lobe volume and neuropsychological deficits

OBJECTIVE: Apathy is a common negative symptom in schizophrenia. The authors investigated neuropsychological performance and regional brain volumes in schizophrenia patients with high versus low levels of apathy. METHOD: Schizophrenia patients with low apathy levels (N=18) and high apathy levels (N=20) and 12 healthy comparison subjects completed neuropsychological testing as well as magnetic resonance imaging scanning to obtain lobar volumes after total intracranial volume was controlled. RESULTS: The high apathy group scored lower than comparison subjects on rapid visuomotor sequencing and verbal learning/recall. The high apathy group had lower performance IQ scores than the low apathy and comparison groups. Only the high apathy group showed significantly reduced bilateral frontal lobe volumes relative to comparison subjects; both schizophrenia patient groups showed bilateral temporal lobe volume reductions. CONCLUSIONS: The present findings are consistent with studies in other disorders showing frontal lobe involvement in apathy.     

Longitudinal progression of frontal and temporal lobe changes in schizophrenia

On August 5-7, 2011, S?o Paulo was home to the first regional meeting of the Schizophrenia International Research Society (SIRS). Over 400 people from many countries attended the activities and contributed with around 200 submissions for oral and poster presentations. This article summarizes the data presented during the meeting, with an emphasis on the plenary talks and sessions for short oral presentations. For information on the poster presentations, readers are referred to the special issue of Revista de Psiquiatria Clínica (Brazil) dedicated to the conference (available at: http://www.hcnet.usp.br/ipq/revista/vol38/s1/).     

Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study.

BACKGROUND: (31)Phosphorous magnetic resonance spectroscopy has been widely used to evaluate schizophrenic patients in comparison to control subjects, because it allows the investigation of both phospholipid and energy metabolism in vivo; however, the results achieved so far are inconsistent. Chemical shift imaging (CSI) has the advantage that instead of only one or a few preselected voxels the tissue of a whole brain slice can be examined. The aim of the present investigation was to determine whether the results of previous studies of our group, showing that phosphodiesters (PDE) are decreased in the frontal lobe of schizophrenic patients as compared to control subjects, might be confirmed in an independent unmedicated patient sample using the CSI technique. METHODS: A carefully selected new cohort including 11 neuroleptic-free schizophrenic patients and 11 age- and gender-matched healthy control subjects was recruited. CSI was applied and an innovative analysis method for CSI data based on a general linear model was used. RESULTS: PDE, phosphocreatine, and adenosine triphosphate (ATP) were found to be significantly decreased in the frontal lobe of patients with schizophrenia. CONCLUSIONS: Because PDE was decreased in schizophrenic patients, the membrane phospholipid hypothesis of schizophrenia could not be corroborated. Further results indicate decreased ATP production in the frontal lobe of patients with schizophrenia.     

Multiple regression analysis of relationship between frontal lobe phosphorus metabolism and clinical symptoms in patients with schizophrenia

We investigated the differences among diagnostic types of 36 schizophrenic patients in the brain phosphorus metabolism in the frontal lobe. We performed phosphorus-31 magnetic resonance spectroscopy (³¹P-MRS) in the frontal region in patients with schizophrenia of the catatonic (n=4), disorganized (n=8), paranoid (n=10) and undifferentiated (n=14) types. In the disorganized type, the PME level was significantly decreased compared to those in the other three types, while the phosphodiester (PDE) level tended to be higher, although not significantly, than those in the other types. Using multiple regression analysis, we investigated whether or not the clinical symptoms were correlated with the brain phosphorus metabolism. An increased motor retardation factor score was significantly correlated with decreased PME level, whereas more severe emotional withdrawal and blunted affect were associated with increased PDE level. These results suggest that altered membrane phospholipid metabolism in the frontal region may be associated with negative symptoms and that schizophrenia of the disorganized type is associated with more severe negative symptoms and may present more severe brain abnormalities compared to the other types.     

Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis

Magnetic resonance imaging (MRI) and positron emission tomography (PET) studies of the frontal and temporal lobes in schizophrenia patients and healthy controls have proliferated over the past 2 decades, but there have been relatively few attempts to quantify the evidence. In this meta-analytic review, 155 studies on frontal and temporal lobe neurobiology were synthesized, reflecting results from 4043 schizophrenia patients and 3977 normal controls. Cohen's d was used to quantify case-control differences, and moderator variable analysis indexed the relation of sample and imaging characteristics to the magnitude of these differences. Frontal metabolic and blood flow deficiencies in conjunction with cognitive activation tasks ("hypofrontality") emerged as the strongest body of evidence, demonstrating abnormalities that distinguish approximately half of schizophrenia patients from healthy people. Most case-control comparisons with structural and functional imaging yield small and in many cases unstable findings. Technical scanning parameters like slice thickness and magnet strength did not vary with case-control differences consistently across the meta-analyses. However, patient sample characteristics including sample size, handedness and gender composition emerged frequently as moderators of brain-imaging effect sizes.     

Near-infrared spectroscopy analysis of frontal lobe dysfunction in schizophrenia.

BACKGROUND: Previous studies have shown that near-infrared spectroscopy (NIRS) has high temporal resolution, requires little restraint, and is suitable for examining the effect of psychological tasks on brain circulation. In the present study, frontal function in schizophrenic patients was analyzed by NIRS during random number generation (RNG), ruler-catching (RC), and sequential finger-to-thumb (SFT) tasks. METHODS: Two sets of NIRS probes were attached to the foreheads of 13 schizophrenic patients and 10 control subjects approximately at Fp1-F7 and Fp2-F8. Near-infrared spectroscopy was conducted at a sampling rate of 1 Hz, with the pathlength being determined by time-resolved spectroscopy with differential pathlength factor measurements. The absolute changes in oxygenated (oxy-Hb) and deoxygenated (deoxy-Hb) hemoglobin concentrations in response to each task were measured, and total hemoglobin (total-Hb) concentration was calculated as the sum of the two. RESULTS: During RNG task, total- and oxy-Hb concentrations increased, and deoxy-Hb decreased, but the responses were significantly smaller in schizophrenic patients. During RC task, oxy-Hb in schizophrenic patients tended to decrease, in contrast to the mostly increasing response in control subjects. No group difference was observed during SFT task. CONCLUSIONS: Task-dependent profile of functional abnormalities was observed in schizophrenic frontal brain metabolism. These results support the usefulness of NIRS data in investigating frontal lobe dysfunction and evaluating psychopathologic condition in schizophrenic patients.     

Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia

This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.     

Akinesia, tardive dysmentia, and frontal lobe disorder in schizophrenia

Two iatrogenic effects of antipsychotic medications other than tardive dyskinesia have been recently described in schizophrenic populations: akinesia and tardive dysmentia. These effects involve activational, cognitive, and affective rather than motor changes, and closely resemble two most common prefrontal syndromes: dorsolateral and fronto-orbital/mediobasal. It is possible that the widely reported "frontal lobe dysfunction" in some chronic schizophrenic patients at least in part reflects iatrogenic changes in the mesolimbic/mesocortical dopamine system, which projects extensively into prefrontal areas. The degree of iatrogenic versus genuine contribution to the frontal lobe dysfunction in schizophrenia needs to be ascertained further, and the heterogeneity of known frontal lobe syndromes must be taken into account in describing schizophrenic populations. The mechanisms of noniatrogenic contributions to the frontal lobe dysfunction in schizophrenia may reflect a variety of anatomical sources and require further examination.     

Thalamo‐frontal white matter alterations in chronic schizophrenia

Diffusion tensor imaging (DTI) and fiber tractography are useful tools for reconstructing white matter tracts (WMT) in the brain. Previous tractography studies have sought to segment reconstructed WMT into anatomical structures using several approaches, but quantification has been limited to extracting mean values of diffusion indices. Delineating WMT in schizophrenia is of particular interest because schizophrenia has been hypothesized to be a disorder of disrupted connectivity, especially between frontal and temporal regions of the brain. In this study, we aim to differentiate diffusion properties of thalamo‐frontal pathways in schizophrenia from normal controls. We present a quantitative group comparison method, which combines the strengths of both tractography‐based and voxel‐based studies. Our algorithm extracts white matter pathways using whole brain tractography. Functionally relevant bundles are selected and parsed from the resulting set of tracts, using an internal capsule (IC) region of interest (ROI) as “source”, and different Brodmann area (BA) ROIs as “targets”. The resulting bundles are then longitudinally parameterized so that diffusion properties can be measured and compared along the WMT. Using this processing pipeline, we were able to find altered diffusion properties in male patients with chronic schizophrenia in terms of fractional anisotropy (FA) decreases and mean diffusivity (MD) increases in precise and functionally relevant locations. These findings suggest that our method can enhance the regional and functional specificity of DTI group studies, thus improving our understanding of brain function. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Refractory symptomatic schizophrenia resulting from frontal lobe lesion: response to clozapine

A 34-year-old man with a 10-year history of persistent auditory hallucinations and passivity delusions had failed to respond to a variety of conventional antipsychotic medications. He had a history of head trauma 8 years before the onset of psychiatric symptoms. Recent investigations revealed a post-traumatic infarct, situated in the left frontal lobe, on a magnetic resonance imaging scan. Treatment with clozapine for more than 2 years resulted in a marked improvement in his psychotic symptoms. The localization of the brain lesion may be related to the etiology of his symptoms and to the clinical response to clozapine.     

Planning impairments in frontal lobe dementia and frontal lobe lesion patients

Patients with frontal lobe brain damage are reportedly impaired on tasks that require plan development and execution. In this study, we examined the performance of 15 patients diagnosed with frontal lobe dementia and 14 patients with focal frontal lobe lesions on the Tower of London planning task. Patients with frontal lobe dementia committed a significantly higher number of rule violations, made more moves, and demonstrated longer solution time latencies compared to their matched controls. Patients with frontal lobe lesions demonstrated significantly delayed solution times and also made more moves compared to their matched controls. Frontal lobe lesion patient performance suggests an impairment in execution-related processes, while frontal lobe dementia patients appear to be impaired in both plan development and execution. Despite these findings, the identification of a specific cognitive impairment that induces these planning problems remains elusive.     

Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy

In this pilot study, membrane phospholipid and high-energy phosphate metabolism were studied in the dorsal prefrontal cortex of 11 drug-naive, first-episode schizophrenic patients and compared with those of 10 healthy control volunteers comparable in age, education, and parental education. The schizophrenic patients had significantly reduced levels of phosphomonoesters and inorganic orthophosphate and significantly increased levels of phosphodiesters and adenosine triphosphate compared with the controls. The levels of phosphocreatine and adenosine diphosphate did not differ in the two subject groups. The adenosine triphosphate and inorganic orthophosphate findings suggest functional hypoactivity of the dorsal prefrontal cortex. The phosphomonoester and phosphodiester findings are compatible with either premature aging or an exaggeration of normal programmed regressive events occurring in the neural systems sampled.     

Volumetric analysis of frontal lobe regions in schizophrenia: relation to cognitive function and symptomatology.

BACKGROUND: The purpose of this study was to examine the structure of dorsolateral, medial, and orbital regions of the frontal lobe in schizophrenia, and to determine whether their volumetric measurements were related to cognitive function and symptomatology. METHODS: High resolution magnetic resonance imaging scans of the brains of 14 schizophrenic patients and 14 closely matched healthy controls were acquired. Volumes of gray and white matter of the left and right dorsolateral, medial, and orbital prefrontal brain regions were measured. Tests of verbal and visual memory and executive functions were used to assess cognitive function. The SANS and SAPS were used to obtain symptom ratings in patients. RESULTS: Data of 13 schizophrenic patients were analyzed. Patients showed a general, though not significant, decrease in volumes of frontal regions as compared to controls. In patients, but not in controls, smaller left and right prefrontal gray matter volumes were significantly correlated with impaired performance on immediate recall in verbal and visual memory and semantic fluency. Furthermore, in patients, smaller total orbitofrontal gray matter volume was significantly correlated with more severe negative symptomatology (rs = -.76, p = .006). CONCLUSIONS: These findings suggest that in schizophrenia, deficits in verbal and visual memory and semantic fluency and negative symptoms may be related to (subtle) abnormalities in frontal lobe structure.     

Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms

BACKGROUND: Previous research has provided evidence for brain abnormalities in schizophrenia, but their relationship to specific clinical symptoms and syndromes remains unclear. METHODS: With an all-male demographically similar sample of 53 schizophrenic patients and 29 normal control subjects, cerebral gray and white matter volumes (adjusted for intracranial volume and age were determined for regions in the prefrontal lobe and in the superficial and mesial temporal lobe using T1-weighted magnetic resonance imaging with 2.8-mm coronal slices. RESULTS: As a group, schizophrenic patients had wide-spread bilateral decrements in gray matter in the pre-frontal (7.4%) and temporal lobe regions (8.9%), but not in white matter in these regions. In the temporal lobe, gray matter reductions were found bilaterally in the superior temporal gyrus (6.0%), but not in the hippocampus and parahippocampus. While there were no overall group differences in white matter volumes, widespread decrements in prefrontal white matter in schizophrenic patients (n = 53) were related to higher levels of negative symptoms (partial r[49] = -0.42, P = .002), as measured by the Scale for the Assessment of Negative Symptoms. A post hoc analysis revealed that schizophrenic patients with high negative symptoms had generalized prefrontal white matter reductions (11.4%) that were most severe in the orbitofrontal subregion (15.1%). CONCLUSIONS: These results suggest that gray matter deficits may be a fairly common structural abnormality of schizophrenia, whereas reductions in prefrontal white matter may be associated with schizophrenic negative symptoms.