Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis.

Glioblastoma (grade IV glioma/GBM) is the most common primary adult malignant brain tumor with poor prognosis. To characterize molecular determinants of tumor-stroma interaction in GBM, we profiled 48 serum cytokines and identified macrophage colony-stimulating factor (MCSF) as one of the elevated cytokines in sera from GBM patients. Both MCSF transcript and protein were up-regulated in GBM tissue samples through a spleen tyrosine kinase (SYK)-dependent activation of the PI3K-NFκB pathway. Ectopic overexpression and silencing experiments revealed that glioma-secreted MCSF has no role in autocrine functions and M2 polarization of macrophages. In contrast, silencing expression of MCSF in glioma cells prevented tube formation of human umbilical vein endothelial cells elicited by the supernatant from monocytes/microglial cells treated with conditioned medium from glioma cells. Quantitative proteomics based on stable isotope labeling by amino acids in cell culture showed that glioma-derived MCSF induces changes in microglial secretome and identified insulin-like growth factor-binding protein 1 (IGFBP1) as one of the MCSF-regulated proteins secreted by microglia. Silencing IGFBP1 expression in microglial cells or its neutralization by an antibody reduced the ability of supernatants derived from microglial cells treated with glioma cell-conditioned medium to induce angiogenesis. In conclusion, this study shows up-regulation of MCSF in GBM via a SYK-PI3K-NFκB-dependent mechanism and identifies IGFBP1 released by microglial cells as a novel mediator of MCSF-induced angiogenesis, of potential interest for developing targeted therapy to prevent GBM progression.

Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth.

Glioblastoma (GBM) is the most aggressive type of brain tumor and shows very poor prognosis. Here, using genome-wide methylation analysis, we show that G-CIMP+ and G-CIMP-subtypes enrich distinct classes of biological processes. One of the hypermethylated genes in GBM, ULK2, an upstream autophagy inducer, was found to be down-regulated in GBM. Promoter hypermethylation of ULK2 was confirmed by bisulfite sequencing. GBM and glioma cell lines had low levels of ULK2 transcripts, which could be reversed upon methylation inhibitor treatment. ULK2 promoter methylation and transcript levels showed significant negative correlation. Ectopic overexpression of ULK2-induced autophagy, which further enhanced upon nutrient starvation or temozolomide chemotherapy. ULK2 also inhibited the growth of glioma cells, which required autophagy induction as kinase mutant of ULK2 failed to induce autophagy and inhibit growth. Furthermore, ULK2 induced autophagy and inhibited growth in Ras-transformed immortalized Baby Mouse Kidney (iBMK) ATG5(+/+) but not in autophagy-deficient ATG5(-/-) cells. Growth inhibition due to ULK2 induced high levels of autophagy under starvation or chemotherapy utilized apoptotic cell death but not at low levels of autophagy. Growth inhibition by ULK2 also appears to involve catalase degradation and reactive oxygen species generation. ULK2 overexpression inhibited anchorage independent growth, inhibited astrocyte transformation in vitro and tumor growth in vivo. Of all autophagy genes, we found ULK2 and its homologue ULK1 were only down-regulated in all grades of glioma. Thus these results altogether suggest that inhibition of autophagy by ULK1/2 down-regulation is essential for glioma development.

Homozygous 10q23/PTEN deletion and its impact on outcome in glioblastoma: a prospective translational study on a uniformly treated cohort of adult patients.

Tumors from a prospective cohort of adult patients with newly diagnosed glioblastoma (n=73), treated uniformly with radiochemotherapy, were examined for 10q23/PTEN deletion by fluorescence in situ hybridization (FISH). Statistical methods were employed to evaluate the degree of association between 10q23/PTEN deletion status and patient age. Survival analysis was performed using Kaplan-Meier log-rank test and multivariable Cox models to assess the prognostic value of 10q23/PTEN deletion. Interestingly, 10q23/PTEN homozygous deletion was frequent in patients >45 years of age (P=0.034) and the median age of patients harboring PTEN homozygous deletions was significantly higher than those with the retained status (P=0.019). 10q23/PTEN homozygous deletion was associated with shorter survival in the entire cohort as well in patients >45 years (P<0.05), indicating that loss of 10q23/PTEN showed clinical importance in elderly patients. Our study highlights the independent prognostic/predictive value of 10q23/PTEN deletion status as identified by FISH, particularly in glioblastoma patients aged >45 years.

Mixed-density extradural hematomas on computed tomography-prognostic significance.

BACKGROUND: It has been variably reported that patients who acutely present with low- or mixed-density blood on CT scan are associated with poor clinical outcome. The aim of the study was to correlate the presence or absence of mixed density within EDHs on CT scanning with the clinical outcome. METHODS: This is a retrospective study of a total of 109 patients with EDHs who were operated on from August 2001 to August 2002. The CT scans were reviewed and classified into 2 categories-predominantly hyperdense and mixed density. This was correlated with clinical details and outcome. RESULTS: In all, 43.2% (16/37) of patients in the mixed-density category presented with GCS of no more than 8 as compared with 23.6% (17/72) of patients in the hyperdense group (P < .05). Mean hematoma volume in the mixed-density group was 72 cm(3) as compared with 42 cm(3) in the hyperdense group (P < .05). Mortality rate was significantly higher in the mixed-density category (21.6% vs 4.2%, P < .05). CONCLUSION: The study portends mixed density in EDH as a potent poor prognostic indicator. The mixed density of the clot probably indicates that the clot is rapidly increasing in size and requires even earlier and more aggressive treatment.

Pediatric infratentorial subdural empyema: analysis of 14 cases.

OBJECT: Pediatric cases of infratentorial subdural empyema (SDE) are both rare and associated with high rates of morbidity and mortality. The goal of this study was to report patient characteristics, treatment, and outcome in an exclusively pediatric series of SDE cases. METHODS: A series of 14 pediatric cases of infratentorial SDE was retrospectively analyzed. All patients were treated between 1994 and 2004. Sixty-four percent of the patients were boys; the majority of cases occurred during the summer months. Clinical features included headache, fever, vomiting, meningism, and otorrhea. Cerebellar signs were found only in 21% of patients. In 85.7% of the cases, the patients presented with a depressed level of consciousness (Glasgow Coma Scale Scores 11-15). In 79.6%, pus collection was seen over the cerebellar convexity; interhemispheric and tentorial collections were also observed in some cases. Hydrocephalus was present in 92.9% of patients. Five patients required external ventricular drainage during surgery or postoperatively. Shunt placement was required in 21% of cases. All patients were treated with antibiotic therapy and surgery (bur holes in 21% of the cases, craniectomy in 79%). Pus cultures demonstrated microbial infection in 71.4%, and polymicrobial infection in 21%. Four patients required repeated surgery for reaccumulation of pus. Minor postoperative complications developed in three patients. All 14 patients survived. At follow up, the Glasgow Outcome Scale scores were 4 or 5 in all cases. CONCLUSIONS: Early diagnosis and prompt surgical treatment are crucial in cases of SDE. With appropriate surgery, antibiotic therapy, and management of hydrocephalus, good outcome can be expected.

An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals.

Glioblastomas (GBM) are largely incurable as they diffusely infiltrate adjacent brain tissues and are difficult to diagnose at early stages. Biomarkers derived from serum, which can be obtained by minimally invasive procedures, may help in early diagnosis, prognosis and treatment monitoring. To develop a serum cytokine signature, we profiled 48 cytokines in sera derived from normal healthy individuals (n = 26) and different grades of glioma patients (n = 194). We divided the normal and grade IV glioma/GBM serum samples randomly into equal sized training and test sets. In the training set, the Prediction Analysis for Microarrays (PAM) identified a panel of 18 cytokines that could discriminate GBM sera from normal sera with maximum accuracy (95.40%) and minimum error (4.60%). The 18-cytokine signature obtained in the training set discriminated GBM sera from normal sera in the test set as well (accuracy 96.55%; error 3.45%). Interestingly, the 18-cytokine signature also differentiated grade II/Diffuse Astrocytoma (DA) and grade III/Anaplastic Astrocytoma (AA) sera from normal sera very efficiently (DA vs. normal-accuracy 96.00%, error 4.00%; AA vs. normal-accuracy 95.83%, error 4.17%). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using 18 cytokines resulted in the enrichment of two pathways, cytokine-cytokine receptor interaction and JAK-STAT pathways with high significance. Thus our study identified an 18-cytokine signature for distinguishing glioma sera from normal healthy individual sera and also demonstrated the importance of their differential abundance in glioma biology.

Definition of a serum marker panel for glioblastoma discrimination and identification of Interleukin 1ß in the microglial secretome as a novel mediator of endothelial cell survival induced by C-reactive protein.

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. We profiled 724 cancer-associated proteins in sera of healthy individuals (n=27) and GBM (n=28) using antibody microarray. While 69 proteins exhibited differential abundance in GBM sera, a three-marker panel (LYAM1, BHE40 and CRP) could discriminate GBM sera from that of healthy donors with an accuracy of 89.7% and p<0.0001. The high abundance of C-reactive protein (CRP) in GBM sera was confirmed in 264 independent samples. High levels of CRP protein was seen in GBM but without a change in transcript levels suggesting a non-tumoral origin. Glioma-secreted Interleukin 6 (IL6) was found to induce hepatocytes to secrete CRP, involving JAK-STAT pathway. The culture supernatant from CRP-treated microglial cells induced endothelial cell survival under nutrient-deprivation condition involving CRP-FcγRIII signaling cascade. Transcript profiling of CRP-treated microglial cells identified Interleukin 1ß (IL1ß) present in the microglial secretome as the key mediator of CRP-induced endothelial cell survival. IL1ß neutralization by antibody-binding or siRNA-mediated silencing in microglial cells reduced the ability of the supernatant from CRP-treated microglial cells to induce endothelial cell survival. Thus our study identifies a serum based three-marker panel for GBM diagnosis and provides leads for developing targeted therapies. Biological significance A complex antibody microarray based serum marker profiling identified a three-marker panel - LYAM1, BHE40 and CRP as an accurate discriminator of glioblastoma sera from that of healthy individuals. CRP protein is seen in high levels without a concomitant increase of CRP transcripts in glioblastoma. Glioma-secreted IL6 induced hepatocytes to produce CRP in a JAK-STAT signaling dependent manner. CRP induced microglial cells to release IL1ß which in turn promoted endothelial cell survival. This study, besides defining a serum panel for glioblastoma discrimination, identified IL1ß as a potential candidate for developing targeted therapy.

Reduced contribution of executive functions in impaired working memory performance in mild traumatic brain injury patients.

AIM: Mild traumatic brain injury (MTBI) is associated with often selective impairment of both working memory (WM) and the executive functions (EFs). Research indicates that one of the commonest deficits present in MTBI patients falls in the domain of WM. We aimed to investigate the role of EFs in WM impairment following MTBI. METHODS: Performance on the tests of EFs and the verbal and visuo-spatial WM of 30 consecutive MTBI patients were compared with age/education/IQ matched 30 normal healthy control participants. Correlation between EFs and WM was studied separately for the MTBI and the control group. RESULTS: The MTBI and control group were tested on a range of EF tests and WM. The MTBI group was demonstrated impairment on verbal and visuo-spatial WM and category fluency tests only. Furthermore, the MTBI group had fewer significant correlations between the WM and EFs (5 out of 54 possible correlations) than in the control group (13 out of 54 possible correlations). CONCLUSIONS: We suggest that MTBI may lead to WM deficits as the contribution of executive processes to support the WM is diminished following MTBI. Such an understanding of the poor WM performance in MTBI patients will be helpful when planning appropriate strategies for cognitive rehabilitation.

A DNA methylation prognostic signature of glioblastoma: identification of NPTX2-PTEN-NF-κB nexus.

Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n = 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-κB pathway association with high-risk group. NF-κB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-κB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-κB activity by inhibiting AKT through a p53-PTEN-dependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-κB-activated high-risk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-κB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target.

Outcome of lesionectomy in medically refractory epilepsy due to non-mesial temporal sclerosis (non-MTS) lesions.

OBJECTIVES: To analyze the seizure outcome of lesionectomy for refractory epilepsy secondary to non-mesial temporal sclerosis (non-MTS) lesions. METHODS: Sixty-eight patients with non-MTS lesions (M:F=42:26; age at onset: 11.7±9.6 years; age at surgery: 21.1±9.4 years), who underwent lesionectomy for refractory epilepsy were analyzed. The age at onset, frequency/type of seizure, MRI findings, video-EEG, histopathology and Engel's grading at 1 year/last follow up were recorded. RESULTS: The duration of epilepsy at surgery was 9.9±6.9 years. The location of lesions were: temporal: 41 (60.3%); frontal: 21 (30.9%); parietal: 6 (8.8%). The type of lesionectomies performed were temporal 41 (60.3%), extra-temporal: 25 (36.8%), temporo-frontal and temporo-parietal: 1 (1.5%) patient each. The histopathological diagnosis were neoplastic: 32 (47.1%), cortical dysplasia: 19 (27.9%), other focal lesions: 17 (25%). At mean follow up of 2.9±2.1 years (median: 2.6 years), outcome was - Engel's class I: 43 (63.2%), IIa: 14 (20.6%), III: 7 (10.3%), IV: 4 (5.9%). Good seizure control (Engel's class I/IIa) was achieved in 57 (83.8%) patients. The good prognostic markers included temporal seizures, extended lesionectomy and AEDs after surgery while poor prognostic marker was gliotic lesion on histopathology. CONCLUSION: Following lesionectomy due to non-MTS lesions, seizure freedom (Engel I) was noted in about 63.2% of patients, which is comparable to other series and reiterates the effectiveness of lesionectomy for seizure control.

Traumatic epidural and subdural hematomas and extensive brain infarcts in a patient with pial arteriovenous malformation: Mechanisms underlying clinical and radiological findings.

We report a rare case of a patient with a pial arteriovenous malformation (AVM) who presented in altered sensorium. He was found to have large epidural and subdural hematomas overlying a pial AVM. He underwent evacuation of these hematomas and postop computed tomography showed infarcts deep to the site of hematoma evacuation. These infarcts were postulated to be due to a steal phenomenon combined with raised intracranial pressure. The management and possible mechanisms for this rare combination are discussed.

IDH1 mutations in diffusely infiltrating astrocytomas: grade specificity, association with protein expression, and clinical relevance.

IDH1 mutations are frequent genetic alterations in low-grade diffuse gliomas and secondary glioblastoma (GBM). To validate mutation frequency, IDH1 gene at codon 132 was sequenced in 74 diffusely infiltrating astrocytomas: diffuse astrocytoma (DA; World Health Organization [WHO] grade II), anaplastic astrocytoma (AA; WHO grade III), and GBM (WHO grade IV). All cases were immunostained with IDH1-R132H monoclonal antibody. Mutational status was correlated with mutant protein expression, patient age, duration of symptoms, and prognosis of patients with GBM. We detected 31 (41.9%) heterozygous IDH1 mutations resulting in arginine-to-histidine substitution (R132H;CGT-CAT). All 12 DAs (100%), 13 of 14 AAs (92.9%), and 6 of 48 GBMs (12.5%) (5/6 [83.3%] secondary, and 1/42 [2.4%] primary) harbored IDH1 mutations. The correlation between mutational status and protein expression was significant (P < . 001). IDH1 mutation status, though not associated with prognosis of patients with GBM, showed significant association with younger age and longer duration of symptoms in the whole cohort (P < .001). Our study validates IDH1 mutant protein expression across various grades of astrocytoma, and demonstrates a high incidence of IDH1 mutations in DA, AA, and secondary GBM.

Predictive model for survival among neurosurgical intensive care patients.

BACKGROUND: Models for prediction of outcome of intensive care patients greatly help the physician to make decisions and are also important for risk stratification in clinical research and quality improvement. At present, there are no major predictive models for neurosurgical intensive care unit (NSICU) patients. This study aimed to develop a predictive model for survival in NSICU patients. METHODS: This is a prospective observational study in the NSICU at a tertiary-care university hospital. The data were collected within 24 hours of admission in all patients admitted to the NSICU. The parameters collected were demographic variables, systolic blood pressure, arterial oxygen tension after resuscitation (PaO2), Glasgow coma score (GCS) and pupillary signs, blood urea, creatinine, albumin, glucose, sodium, potassium, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, hemoglobin concentration, leukocyte count, platelet count, temperature, and evidence of infection. Mortality or discharge from NSICU was the primary outcome variable. All patients were provided full care until death or discharge from the ICU. Life support was not withdrawn in any of the patient based on the perception of outcome by the treating physician. All variables were compared between survivors and nonsurvivors. Significant variables were analyzed by multivariate logistic regression and a prediction model was developed. RESULTS: Four hundred six patients were included in the study. Three hundred two patients survived and 104 died (mortality of 25.6%). Significant variables on univariate analysis include primary reason for admission, GCS, pupillary reaction, systolic blood pressure, serum albumin, glucose, serum sodium concentration, hypothermia, and infection at the time of admission. Multivariate analysis showed that the significant independent factors for predicting outcome in NSICU patients are age, diagnosis, GCS, pupillary status, albumin, and serum sodium concentration. The predictive model has good discrimination (receiver operating characteristic curve=0.796) and good calibration (P=0.937). The overall accuracy of the model was 81%. CONCLUSIONS: In the current model of prediction of survival in a neurosurgical ICU, age, diagnosis, GCS, pupillary status, serum albumin, and serum sodium are independent predictors of survival in NSICU patients.

Glioblastoma-specific protein interaction network identifies PP1A and CSK21 as connecting molecules between cell cycle-associated genes.

Glioblastoma (GBM; grade IV astrocytoma) is a very aggressive form of brain cancer with a poor survival and few qualified predictive markers. This study integrates experimentally validated genes that showed specific upregulation in GBM along with their protein-protein interaction information. A system level analysis was used to construct GBM-specific network. Computation of topological parameters of networks showed scale-free pattern and hierarchical organization. From the large network involving 1,447 proteins, we synthesized subnetworks and annotated them with highly enriched biological processes. A careful dissection of the functional modules, important nodes, and their connections identified two novel intermediary molecules CSK21 and protein phosphatase 1 alpha (PP1A) connecting the two subnetworks CDC2-PTEN-TOP2A-CAV1-P53 and CDC2-CAV1-RB-P53-PTEN, respectively. Real-time quantitative reverse transcription-PCR analysis revealed CSK21 to be moderately upregulated and PP1A to be overexpressed by 20-fold in GBM tumor samples. Immunohistochemical staining revealed nuclear expression of PP1A only in GBM samples. Thus, CSK21 and PP1A, whose functions are intimately associated with cell cycle regulation, might play key role in gliomagenesis.

Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis.

BACKGROUND: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM). METHODS: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins. Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients. RESULTS: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs. RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes. With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues. Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot. GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 0.0001). Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis. CONCLUSIONS: Several novel potential serum biomarkers of GBM are identified and validated. High serum OPN level is found as a poor prognostic indicator in GBMs. IMPACT: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis.

Grade-specific expression of insulin-like growth factor-binding proteins-2, -3, and -5 in astrocytomas: IGFBP-3 emerges as a strong predictor of survival in patients with newly diagnosed glioblastoma.

BACKGROUND: Insulin-like growth factor (IGF)-binding protein (IGFBP) isoforms have been implicated in the pathogenesis of human neoplasms including glioma. In view of this, we evaluated the expression of IGFBP isoforms (IGFBP-2, -3, and -5) during malignant progression of astrocytoma and their prognostic significance in glioblastoma. METHODS: The expression of IGFBP isoforms was analyzed in diffusely infiltrating astrocytomas by real-time quantitative PCR (n = 203) and immunohistochemistry (n = 256). Statistical methods were used to assess their grade-specific expression pattern and mRNA-protein intercorrelation. Survival analyses were done on a uniformly treated, prospective cohort of adult patients with newly diagnosed glioblastoma (n = 136) by using Cox regression models. RESULTS: The mean transcript levels of IGFBP-2 and -3 were significantly higher in glioblastomas (GBM) relative to anaplastic astrocytoma (AA), diffuse astrocytoma (DA), and controls whereas IGFBP-5 mRNA was higher in GBM relative to AA and controls (P < 0.05). By immunohistochemistry, the mean labeling index of all isoforms was significantly higher in GBM compared with AA, DA, and control (P < 0.05). A strong positive correlation was observed between their respective mRNA and protein expressions (P < 0.01). Multivariate analysis revealed IGFBP-3 expression (hazard ratio, 1.021; P = 0.030) and patient age (hazard ratio, 1.027; P = 0.007) to be associated with shorter survival in glioblastoma. CONCLUSIONS: This study shows the associations of IGFBP-2, -3, and -5 expression with increasing grades of malignancy in astrocytomas. IGFBP-3 is identified as a novel prognostic glioblastoma biomarker. The strong correlation between their mRNA and protein expression patterns suggests their role in the pathogenesis of these tumors. IMPACT: IGFBP isoforms have emerged as biomarkers with diagnostic and prognostic utility in astrocytomas.

Reduction of functional brain connectivity in mild traumatic brain injury during working memory.

Working memory deficits are present in patients with mild traumatic brain injury (MTBI). Functional connectivity of different brain regions is required for adequate working memory. Brain injury is associated with disrupted connectivity due to microscopic axonal damage. In this investigation, we sought to investigate functional brain connectivity during working memory in MTBI patients. A sample of 30 MTBI patients and 30 age-, education-, and gender-matched normal controls were studied. Working memory was assessed with the Sternberg's verbal and visuo-spatial working memory tasks. Electro-encephalography (EEG) was recorded from 128 channels while subjects performed working memory tasks and during eyes closed resting condition. EEG coherence was computed in theta; lower and upper alpha; and lower and upper beta frequency bands during the encoding, retention, and retrieval stages of working memory as well as during eyes-closed rest. We found that the MTBI patients had impaired verbal and visuo-spatial working memory. The different stages of working memory were associated with poor intrahemispheric coherence in long-range (fronto-parietal) and mid-range (fronto-temporal and temporo-parietal) regions as well as poor interhemispheric coherence in the frontal and temporal regions in the MTBI patients. The deficit in coherence was present in theta, alpha, and beta frequency bands. However, the MTBI and the control group had comparable coherence values in intra- and inter-hemispheric regions during eyes closed rest. We suggest that the inter- and intra-hemispheric functional connectivity is impaired in MTBI during working memory performance.

Sensory gating impairment in development of post-concussive symptoms in mild head injury.

Post-concussive symptoms reported by mild head injury (MHI) patients have been inadequately understood. Post-concussive symptoms reported by patients with MHI have so far been explained in terms of impairment in neurocognitive functions or deficits in modulation of flow of information. There are no studies that have looked into sensory gating impairment in MHI and its relation to post-concussive symptoms. The purpose of the present paper was to investigate the role of sensory gating impairment in post-concussive symptoms in mild head injury patients. Thirty MHI patients were evaluated for their neuropsychological functions, sensory gating deficits, and post-concussive symptoms. Neuropsychological functions were in the domain of attention, executive functions, and learning and memory. Sensory gating was assessed by Structured Interview for Assessing Perceptual Anomalies and post-concussive symptoms were assessed using the Neurobehavioral Rating Scale. Multiple regression method was used to identify predictors for post-concussive symptoms. Post-concussive symptoms were predicted by sensory gating deficits when sensory gating deficit was one of the predictors along with neuropsychological functions. Post-concussive symptoms were predicted by scores of Digit Vigilance and Digit Symbol Substitution Test, when predictors were restricted to neuropsychological functions. Sensory gating deficits were correlated with performance on Digit Symbol Substitution test. Post-concussive symptoms reported by MHI patients are the result of poor modulation of incoming sensory information.