Gray Matter Volume In Patients Research Articles

Combined omega-3 fatty acids, aerobic exercise and cognitive stimulation prevents decline in gray matter volume of the frontal, parietal and cingulate cortex in patients with mild cognitive impairment

Previous studies in older adults suggested beneficial effects of omega-3 fatty acid (FA) supplementation, aerobic exercise, or cognitive stimulation on brain structure and function. However, combined effects of these interventions in patients suffering from mild cognitive impairment (MCI) are unknown. Using a randomized interventional design, we evaluated the effect of combined omega-3 FA supplementation, aerobic exercise and cognitive stimulation (target intervention) versus omega-3 FA supplementation and non-aerobic exercise (control intervention) on cognitive function and gray matter volume in patients with MCI. Moreover, we analyzed potential vascular, metabolic or inflammatory mechanisms underlying these effects. Twenty-two MCI patients (8 females; 60–80years) successfully completed six months of omega-3 FA intake, aerobic cycling training and cognitive stimulation (n=13) or omega-3 FA intake and non-aerobic stretching and toning (n=9). Before and after the interventions, cognitive performance, magnetic resonance imaging of the brain at 3T (n=20), intima-media thickness of the internal carotid artery and serum markers of glucose control, lipid and B-vitamin metabolism, and inflammation were assessed. Intervention-related changes in gray matter volume of Alzheimer's disease (AD)-related brain regions, i.e., frontal, parietal, temporal and cingulate cortex were examined using voxel-based morphometry of high resolution T1-weighted images.After the intervention period, significant differences emerged in brain structure between groups: Gray matter volume decreased in the frontal, parietal and cingulate cortex of patients in the control intervention, while gray matter volume in these areas was preserved or even increased after the target intervention. Decreases in homocysteine levels in the target intervention group were associated with increases in gray matter volume in the middle frontal cortex (p=0.010). No significant differences in cognitive performance or other vascular, metabolic and inflammatory parameters were observed between groups. This pilot study provides preliminary evidence that omega-3 FA intake combined with aerobic exercise and cognitive stimulation prevents atrophy in AD-related brain regions in MCI patients, compared to omega-3 FA intake plus the control condition of stretching and toning. These promising findings should now be validated in a larger interventional trial.

Gray matter volumes in patients with bipolar disorder and their first-degree relatives

Bipolar disorder (BD) is highly heritable. First-degree relatives of BD patient have an increased risk to develop the disease. We investigated abnormalities in gray matter (GM) volumes in healthy first-degree relatives of BD patients to identify possible brain structural endophenotypes for the disorder. 3D T1-weighted magnetic resonance images were obtained from 25 DSM-IV BD type I patients, 23 unaffected relatives, and 27 healthy controls (HC). A voxel-based morphometry protocol was used to compare differences in GM volumes between groups. BD patients presented reduced GM volumes bilaterally in the thalamus compared with HC. Relatives presented no global or regional GM differences compared with HC. Our negative results do not support the role of GM volume abnormalities as endophenotypes for BD. Thalamic volume abnormalities may be associated the pathophysiology of the disease.

Differences in gray matter volume corresponding to delusion and hallucination in patients with schizophrenia compared with patients who have bipolar disorder.

BackgroundAlthough schizophrenia and bipolar disorder (BD) are classified as different disease entities, they share critical pathognomonic symptoms in terms of hallucination and delusion. Because the characteristics of clinical symptoms are not sufficient to differentiate schizophrenia from BD, several studies have applied brain imaging methods to provide biological evidence of differences. We compared gray matter (GM) volume differences in schizophrenia and BD patients and examined volumetric differences associated with hallucination and delusion in these two groups.MethodsNinety-three schizophrenia patients and 75 BD patients who were followed for at least 3 years in an outpatient department were recruited for this study. Magnetic resonance data from 71 schizophrenia patients and 44 BD patients were obtained using a 3.0 T scanner. Volumetric differences were analyzed using Matlab 8.0.0 and SPM8 software.ResultsThe results showed that delusion symptoms were negatively correlated with GM volume within both frontal and both temporal cortices in the schizophrenia group and were negatively correlated with GM volume within the bilateral frontal cortices in the BD group. Hallucination symptoms were negatively correlated with GM volume within the bilateral frontal, bilateral temporal, and left parietal cortices in the schizophrenia group and were negatively correlated with GM volume within the bilateral frontal, right parietal, occipital, and insular cortices in the BD group.ConclusionDelusions in schizophrenia were correlated with GM volume in multiple brain regions, including the frontal, temporal, and parietal cortices, compared to those in patients with BD. Hallucination was associated with temporal lobe GM volume in patients with schizophrenia and with insular cortex GM volume in patients with BD.

Three-way interaction of 5-HTTLPR, BDNF Vall66Met and COMT Val158Met polymorphisms and its effect on regional gray matter volume in patients with Major Depressive Disorder (P2.156)

Three-way interaction of 5-HTTLPR, BDNF Vall66Met and COMT Val158Met polymorphisms and its effect on regional gray matter volume in patients with Major Depressive Disorder (P2.156)

A longitudinal study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis. (P6.170)

A longitudinal study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis. (P6.170)

Absence of change in the gray matter volume of patients with ulcerative colitis in remission: a voxel based morphometry study.

BackgroundRecent neuroimaging studies have investigated the brain involvement in patients with Crohn's disease (CD) and Ulcerative Colitis (UC). Functional studies found abnormalities in cognitive and emotional functions in CD and UC, while a voxel based morphometry (VBM) study found morphological changes in CD. We conducted a VBM study to compare the gray matter (GM) volume of UC patients and controls.MethodsEighteen UC patients in remission and eighteen healthy controls underwent structural MRI. VBM is a fully automated technique allowing identification of regional differences in the amount of GM, which enables an objective analysis of the whole brain. VBM was used for comparisons between patients and controls.ResultsUC patients were all in remission and had a mild clinical course. There were no differences between patients and controls in GM volume.ConclusionThe brain morphology of patients with UC in remission is similar to controls. The lack of GM abnormalities in UC patients might reflect the mild clinical course of the inflammatory bowel disorder. Further research involving patients with different degrees of disease severity or during flares could shed more light on potential brain structural changes in UC.

Correlations between homocysteine and grey matter volume in patients with Alzheimer's disease.

Previous studies have reported that elevated total homocysteine levels are associated with cognitive dysfunction. However, few studies have examined the radiological markers of associated neuropathology in Alzheimer's disease (AD). We hypothesized that elevated levels of homocysteine are associated with cerebral grey matter volume loss. We compared the grey matter in a high homocysteine group and a normal homocysteine group using an optimized voxel-based morphometry. The study included 79 patients with AD who were divided into two groups: a high homocysteine group and a normal homocysteine group. The participants underwent brain magnetic resonance imaging using a standardized protocol and neurocognitive evaluation. Homocysteine tests and other routine laboratory examinations for dementia assessment were carried out in all patients. There was no significant difference in grey matter volume between the patients with high homocysteine levels and those with normal homocysteine levels. A multiple regression analysis also revealed that the levels of homocysteine were not associated with the grey matter volume in patients with AD. Homocysteine levels were not correlated significantly with Mini-Mental State Examination, Global Deterioration Scale, or Clinical Dementia Rating. Our results showed that elevated homocysteine levels are not associated with reduced cerebral grey matter volume in AD. Larger samples will be needed to assess potential correlations between homocysteine and neuroanatomical pathology in the future.

Gray matter volumes in patients with chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by profound fatigue with uncertain pathologic mechanism. Neuroimage may be an important key to unveil the central nervous system (CNS) mechanism in CFS. Although most of the studies found gray matter (GM) volumes reduced in some brain regions in CFS, there are many factors that could affect GM volumes in CFS, including chronic pain, stress, psychiatric disorder, physical activity, and insomnia, which may bias the results. In this paper, through reviewing recent literatures, we discussed these interferential factors, which overlap with the symptoms of CFS.

Grey matter alterations in patients with depersonalization disorder: a voxel-based morphometry study.

To our knowledge, no whole brain investigation of morphological aberrations in dissociative disorder is available to date. Previous region-of-interest studies focused exclusively on amygdalar, hippocampal and parahippocampal grey matter volumes and did not include patients with depersonalization disorder (DPD). We therefore carried out an explorative whole brain study on structural brain aberrations in patients with DPD. We acquired whole brain, structural MRI data for patients with DPD and healthy controls. Voxel-based morphometry was carried out to test for group differences, and correlations with symptom severity scores were computed for grey matter volume. Our study included 25 patients with DPD and 23 controls. Patients exhibited volume reductions in the right caudate, right thalamus and right cuneus as well as volume increases in the left dorsomedial prefrontal cortex and right somatosensory region that are not a direct function of anxiety or depression symptoms. To ensure ecological validity, we included patients with comorbid disorders and patients taking psychotropic medication. The results of this first whole brain investigation of grey matter volume in patients with a dissociative disorder identified structural alterations in regions subserving the emergence of conscious perception. It remains unknown if these alterations are best understood as risk factors for or results of the disorder.

Subcortical grey matter changes in untreated, early stage Parkinson's disease without dementia

Previous MRI studies have investigated cortical or subcortical grey matter changes in patients with Parkinson's disease (PD), yielding inconsistent findings between the studies. We therefore sought to determine whether focal cortical or subcortical grey matter changes may be present from the early disease stage. We recruited 49 untreated, early stage PD patients without dementia and 53 control subjects. Voxel-based morphometry was used to evaluate cortical grey matter changes, and automated volumetry and shape analysis were used to assess volume changes and shape deformation of the subcortical grey matter structures, respectively. Voxel-based morphometry showed neither reductions nor increases in grey matter volume in patients compared to controls. Compared to controls, PD patients had significant reductions in adjusted volumes of putamen, nucleus accumbens, and hippocampus (corrected p<0.05). Vertex-based shape analysis showed regionally contracted area on the posterolateral and ventromedial putamen bilaterally in PD patients (corrected p<0.05). No correlations were found between cortical and subcortical grey matter and clinical variables representing disease duration and severity. Our results suggest that untreated, early stage PD without dementia is associated with volume reduction and shape deformation of subcortical grey matter, but not with cortical grey matter reduction. Our findings of structural changes in the posterolateral putamen and ventromedial putamen/nucleus accumbens could provide neuroanatomical basis for the involvement of motor and limbic striatum, further implicating motor and non-motor symptoms in PD, respectively. Early hippocampal involvement might be related to the risk for developing dementia in PD patients.

Effect of early stress on hippocampal gray matter is influenced by a functional polymorphism in EAAT2 in bipolar disorder

Current views on the pathogenesis of psychiatric disorders focus on the interplay between genetic and environmental factors, with individual variation in vulnerability and resilience to hazards being part of the multifactorial development of illness. The aim of the study is to investigate the effect of glutamate transporter polymorphism SLC1A2-181A>C and exposure to Adverse Childhood Experiences (ACE) on hippocampal gray matter volume of patients with bipolar disorder (BD). Patients exposed to higher levels of ACE reported lower gray matter volume. The effect of SLC1A2-181A>C revealed itself only among patients exposed to lower levels of ACE, with T/T homozygotes showing the lowest, and G/G the highest, gray matter volume. The greatest difference between high and low exposures to ACE was observed in carriers of the G allele. Since the mutant G allele has been associated with a reduced transcriptional activity and expression of the transporter protein, we could hypothesize that after exposure to highest levels of ACE G/G homozygotes are more vulnerable to stress reporting the highest brain damage as a consequence of an excess of free glutamate.

Hippocampal and orbital inferior frontal gray matter volume abnormalities and cognitive deficit in treatment-naive, first-episode patients with schizophrenia

BackgroundCognitive impairment is a core feature of schizophrenia. Some evidence suggests an association between cognition deficits and gray matter reductions. In this study, we investigated the relationship between cognitive performance and gray matter volumes in patients with treatment-naïve, first-episode schizophrenia. MethodFirst-episode patients with treatment-naïve schizophrenia and healthy controls went through brain imaging scan using high resolution magnetic resonance imaging. A neuropsychological battery including 8 neurocognitive tests was used to assess cognitive function. Voxel-based methods were used for volumetric measure in the brain. ResultsFifty-one patients and 41 healthy controls were included in the analysis. Patients exhibited a poorer performance on all 7 cognitive function tests compared with healthy controls (ps<0.006). There were significant gray matter volume differences between the two groups in bilateral hippocampus gyri, right superior temporal gyrus, left fusiform gyrus and orbital inferior frontal gyri (FDR, ps<0.05). Within the schizophrenia group, multiple regression analysis demonstrated that poorer performance on the working memory, verbal learning and visual learning was associated with smaller hippocampal gray matter volume, and poorer executive function was associated with smaller left orbital inferior frontal gray matter volume after controlling for potential confounding variables (β≥0.420, ps≤0.010). ConclusionsOur findings suggest that cognitive deficits are associated with hippocampal and orbital inferior frontal gray matter volume abnormalities in treatment-naïve, first-episode patients with schizophrenia.

EPA-0799 - Postcentral gyrus in patients at first episode of schizophrenia: A longitudinal structural mri study

Postcentral gyus (PoCG) has received little attention in brain imaging literature compared to others brain regions. In spite of that, some structural magnetic resonance (sMRI) studies have detected the presence of structural and functional abnormalities in schizophrenia. 1 year longitudinal study assessing PoCG morphometry in First Episode Schizophrenia (FES) patients and in healthy comparison (HC) We aimed to assess PoCG volumes differences and to explore possible changes over time, by means of sMRI. Also, we aimed to investigate the relationships between PoCG morphometry and clinical and cognitive variables. 56 FES patients, selected through the PAFIP Program, carefully assessed for dimensional psychopathology and cognitive functioning, and matched HC (n=56), underwent two sMRI at 1,5 T (interscan interval=1 year). PoCG grey matter (GM) volumes were measured. We found a significant reduction in right PoCG GM volume in patients at follow up (Tab.1) and a trend of interaction time x group in male right PoCG. We found positive correlations between right PoCG and SAPS total scores and disorganized symptoms. Finally, we observed inverse correlations between left PoCG and WAIS BD at baseline and between bilateral PoCG and CPT scores at follow up. Table 1 Results about volume comparions at baseline, at follow up and the interaction time for group. baseline follow-up FES Patients (n=56) Healthy Subjects (n=56) FES Patients (n=56) Healthy Subjects (n=56) timexgroup interaction Mean±SD Mean±SD F Mean±SD Mean±SD F F Left PoCG 15.35±2.60 15.49±3.64 0.04 14.90±2.07 15.23±2.09 0.79 0.26 Right PoCG 15.16±2.37 15.46±2.30 0.50 14.57±2.09 15.24±1.93 4.20 ** 2.64 Total PoCG 30.51±4.54 30.95±5.42 0.21 29.46±3.82 30.48±3.70 2.54 1.12 ** p value < 0.05 this is the first study focusing on PoCG in FES patients. Our results suggest a greater decrease of right PoCG, at a trend level, in male patients than in HC, sustaining that PoCG morphometry change in the first year of the illness, possibly sustaining the symptomatology and the cognitive impairment.

EPA-1018 - Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal brain structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. In this study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. 'source-based morphometry' (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a lower expression of medial and inferior frontal as well as bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with 'physical' AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

Relationship of clinical and cognitive variables with brain morphometric abnormalities in Alzheimer's disease: a voxel based morphometric study using 3-tesla MRI.

Alzheimer's disease (AD) is associated with widespread structural and functional brain alterations. The current study examined the gray matter (GM) voxel based morphometric (VBM) correlates of cognitive and clinical severity scores in patients with AD. The study included 34 patients with AD according to NINCDS/ADRDA AD criteria and 28 matched elderly controls. All subjects were clinically evaluated using Hindi Mental Status Examination (HMSE), Everyday Abilities Scale for India (EASI) and the Clinical Dementia Rating (CDR) scale. The structural Magnetic Resonance Imaging (MRI) data were acquired using a 3 Tesla MRI scanner and VBM analysis was performed using VBM5.1 toolbox. The patients with AD had significantly lower GM volume, white matter volume and total brain volume as compared to controls. The HMSE scores were positively correlated (p=0.009) and EASI (p=0.04) & CDR (p=0.0004) were negatively correlated with the total GM volumes in patients with AD. The VBM analysis revealed diffuse GM atrophy in patients with AD. Frontal& temporal GM volumes were positively correlated with the HMSE scores. Thus the results of the study replicate the previous observations of generalized GM atrophy, in an Indian sample with AD. The cognitive decline, clinical dementia severity and impairment in activities of daily living were correlated whole brain GM and WM volumes as well as with specific brain regional atrophy in AD. However further studies with larger samples & with more detailed cognitive evaluation are required for confirmation & validation of the relationship between regional morphometric abnormalities and cognitive deficits in AD.

Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. This study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. "source-based morphometry" (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a reduction of medial and inferior frontal, insular and bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with "physical" AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal, insular and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

Constructional Apraxia as a Distinctive Cognitive and Structural Brain Feature of Pre-Senile Alzheimer's Disease

Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy.

ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies.

Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.

Magnetic resonance morphometry of the loss of gray matter volume in Parkinson's disease patients.

Voxel-based morphometry can be used to quantitatively compare structural differences and func-tional changes of gray matter in subjects. In the present study, we compared gray matter images of 32 patients with Parkinson's disease and 25 healthy controls using voxel-based morphometry based on 3.0 T high-field magnetic resonance T1-weighted imaging and clinical neurological scale scores. Results showed that the scores in Mini-Mental State Examination and Montreal Cognitive Assessment were lower in patients compared with controls. In particular, the scores of visuospa-tial/executive function items in Montreal Cognitive Assessment were significantly reduced, but mean scores of non-motor symptoms significantly increased, in patients with Parkinson's disease. In dition, gray matter volume was significantly diminished in Parkinson's disease patients compared with normal controls, including bilateral temporal lobe, bilateral occipital lobe, bilateral parietal lobe, bilateral frontal lobe, bilateral insular lobe, bilateral parahippocampal gyrus, bilateral amygdale, right uncus, and right posterior lobe of the cerebellum. These findings indicate that voxel-based phometry can accurately and quantitatively assess the loss of gray matter volume in patients with Parkinson' disease, and provide essential neuroimaging evidence for multisystem pathological mechanisms involved in Parkinson's disease.

A meta-analysis of voxel-based morphometry studies on gray matter volume alteration in juvenile myoclonic epilepsy

The findings of structural neuroimaging studies on gray matter volume (GMV) of juvenile myoclonic epilepsy (JME) with voxel-based morphometry (VBM) were inconsistent. We aim to evaluate consistent gray matter changes in JME quantitatively. A systematic review of VBM studies on GMV of patients with JME and healthy control (HC) subjects indexed in PubMed and EMBASE from January 1990 to June 2012 was conducted. Coordinates were extracted from clusters of significant GMV difference between patients with JME and HC subjects. Meta-analysis was performed using Effect Size Signed Differential Mapping (ES-SDM). Seven studies with a total of 211 JME patients and 241 HC subjects were included in the meta-analysis. Increased GMV were observed in the bilateral medial frontal gyrus and anterior cingulate, whereas decreased GMV in the bilateral thalamus. The findings remain largely unchanged in the jackknife sensitivity analyses. The meta-analysis not only identified consistent changes in some regions of gray matter in patients with JME, but also supports the notion of thalamocortical circuitry involved in the pathogenesis of JME.