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Selective attention is impaired in first-episode psychosis (FEP). Selective attention effects can be detected during auditory tasks as increased sensory activity. We previously reported electroencephalography scalp-measured N100 enhancement is reduced in FEP. Here, we localized magnetoencephalography (MEG) M100 source activity within the auditory cortex, making novel use of the Human Connectome Project multimodal parcellation (HCP-MMP) to identify precise auditory cortical areas involved in attention modulation and its impairment in FEP. MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while individuals either ignored frequent standard and rare oddball tones while watching a silent movie or attended tones by pressing a button to oddballs. Because M100 arises mainly in the auditory cortices, MEG activity during the M100 interval was projected to the auditory sensory cortices defined by the HCP-MMP (A1, lateral belt, and parabelt parcels). FEP had less auditory sensory cortex M100 activity in both conditions. In addition, there was a significant interaction between group and attention. HC enhanced source activity with attention, but FEP did not. These results demonstrate deficits in both sensory processing and attentional modulation of the M100 in FEP. Novel use of the HCP-MMP revealed the precise cortical areas underlying attention modulation of auditory sensory activity in healthy individuals and impairments in FEP. The sensory reduction and attention modulation impairment indicate local and systems-level pathophysiology proximal to disease onset that may be critical for etiology. Further, M100 and N100 enhancement may serve as outcome variables for targeted intervention to improve attention in early psychosis.

PDF - 72K, Expression of monocyte phenotype markers and IL-10 in malignant gliomas.

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PDF - 69K, Gene-specific primers and probes for QRT-PCR.

PDF - 102K, Assessment of the expression of mRNAs specific for the Treg marker FoxP3 and CMV IL-10 in glioma tissues and epilepsy specimens.

PDF - 66K, Co-staining of GBM specimens for the astrocyte/glioma cell marker GFAP and IL-10.

PDF - 47K, Heat map representation of the expression of select genes associated with M1-M2 monocyte polarization.

Purpose: This study is directed at identifying the cell source(s) of immunomodulatory cytokines in high-grade gliomas and establishing whether the analysis of associated markers has implications for tumor grading.Experimental Design: Glioma specimens classified as WHO grade II–IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade.Results: The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high-grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade.Conclusions: Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163+ cells distinguishes grade III astrocytoma subsets with different prognosis. Clin Cancer Res; 19(14); 3776–86. ©2013 AACR.

PDF - 45K, Summary of clinical characteristics from archived tissues analyzed

PDF - 73K, Correlation between expression levels of IL-10, TGF-beta1, TGF-beta2 and GBM-assorted genes in primary GBM tissues.

Granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis, is a small- and medium-vessel autoimmune vasculitis. Rare presentations of GPA can manifest as ophthalmologic and endocrinological deficits with sellar enhancement on imaging. While GPA typically presents distinct in appearance from other sellar pathologies, such as pituitary adenoma, we report the case of a 41-year-old woman with GPA of the pituitary that was initially diagnosed as pituitary macroadenoma with apoplexy and treated with two surgical resections without improvement of clinical symptoms. Pathology analysis of the second resection specimen revealed an inflammatory process consistent with GPA. After the pathologic and clinical diagnosis of GPA was established, treatment with steroid and steroid-sparing immunosuppressants resulted in improvements both on imaging and symptomatically. We discuss important aspects of the diagnosis and treatment of this rare presentation of GPA.

Purpose: Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma. Patients and Methods: This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies. Results: Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted. Conclusions: IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates with a higher risk of recurrence of resected WHO grade I meningiomas. The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion. Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI [1.2534, 3.764]; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI [1.41, 4.6364]; p = 0.002). WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.

Early course schizophrenia is associated with reduced gray matter. The specific structures affected first and how deficits impact symptoms and cognition remain unresolved. We used the Human Connectome Project multimodal parcellation (HCP‐MMP) to precisely identify cortical areas and investigate thickness abnormalities in discovery and replication samples of first‐episode schizophrenia spectrum individuals (FESz). In the discovery sample, T1w scans were acquired from 31 FESz and 31 matched healthy controls (HC). Thickness was calculated for 360 regions in Freesurfer. In the replication sample, high‐resolution T1w, T2w, and BOLD‐rest scans were acquired from 23 FESz and 32 HC and processed with HCP protocols. Thickness was calculated for regions significant in the discovery sample. After FDR correction (q, The early course schizophrenia is associated with reduced gray matter, but the specific structures affected first and how gray matter deficits impact symptoms and cognition remain unresolved. The novel use of the Human Connectome Project multimodal parcellation in two independent first episode schizophrenia‐spectrum samples revealed thinner bilateral parahippocampal area 3, suggesting this byway between cortical and limbic processing is a critical site of pathology near the emergence of psychosis.

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.

Pineal parenchymal tumors are rare neoplasms, ranging from WHO Grade I to IV. There are few studies characterizing the molecular profiles of these tumors. ATRX alterations are strongly associated with the presence of the alternative lengthening of telomeres (ALT) phenotype, and within the central nervous system they tend to occur in subsets of gliomas, including those with IDH, NF1, or histone (H3 K27M or G34) mutations. Here, we identified ATRX frameshift mutations by next generation sequencing associated with corresponding protein loss in 2 cases of pineal parenchymal tumors of intermediate differentiation (PPTID) developing in a 21-year-old woman and a 64-year-old man. In contrast, we identified partial ATRX loss in 1 pineoblastoma, among 14 pineal parenchymal tumors of various grades (6 pineoblastomas, 4 pineocytomas, and 4 PPTID) using tissue microarrays; ALT was absent in these cases. Evaluating the cBioPortal database, an ATRX mutation was identified in one (of 3 total) PPTIDs analyzed. Thus, ATRX mutations associated with protein loss and ALT develop in a small subset of pineal parenchymal tumors and may be limited to those with intermediate differentiation. The clinical significance of these alterations requires further study.

BACKGROUND Cushing’s disease (CD) remains a challenging condition to diagnose and treat. This case study highlights the challenges of diagnosing CD when faced with discrepant clinical, biochemical, and radiological findings. OBSERVATIONS A 62-year-old man presented with rapid evolution of symptoms, including depression, fatigue, and extreme muscle atrophy, which resulted in the patient being a wheelchair user over the course of a few months. His rapid clinical course in conjunction with hypercortisolemia in the setting of a pituitary macroadenoma involving the cavernous sinus, two large pulmonary nodules, and urine-free cortisol levels in the thousands suggested an aggressive ectopic adrenocorticotropic hormone (ACTH) source. After extensive testing ruled out CD from an ectopic source and because of the patient’s abrupt clinical deterioration, the authors concluded that the source was likely an aggressive pituitary adenoma. Therefore, the authors performed an endonasal transsphenoidal approach for resection of the pituitary adenoma involving the cavernous sinus, and the patient was scheduled for radiosurgery to control tumor progression. LESSONS Although extremely high levels of cortisol and ACTH are associated with ectopic Cushing’s syndrome, they may also indicate an aggressive form of CD. Suspicion should be maintained for hypercortisolemia from a pituitary source even when faced with discrepant information that may suggest an ectopic source.

INTRODUCTION: Ganglion cysts are benign soft tissue lesions, usually arising from periarticular connective tissue. These are very rarely reported in the spine, but when seen can cause radiculopathy or myelopathy. CASE PRESENTATION: A 68-year-old female patient presented with worsening radiculopathy and right foot drop and imaging noted a right L5–S1 foraminal mass. The lesion was gross totally resected. Histological analysis revealed myxoid degeneration and inflammation, without a synovial lining, consistent with ganglion cyst. DISCUSSION: While uncommon, intra-foraminal ganglion cysts can be distinguished from synovial cysts through imaging and histology and are typically amenable to surgical resection. Greater knowledge and insight about differentiating ganglion versus synovial cyst may prevent resection of facet joints and prevent a fusion procedure.

Background Pitch and duration mismatch negativity (pMMN/dMMN) are related to left Heschl’s gyrus gray matter volumes in first-episode schizophrenia (FESz). Previous methods were unable to delineate functional subregions within and outside Heschl’s gyrus. The Human Connectome Project multimodal parcellation (HCP-MMP) atlas overcomes this limitation by parcellating these functional subregions. Further, MMN has generators in inferior frontal cortex, and therefore, may be associated with inferior frontal cortex pathology. With the novel use of the HCP-MMP to precisely parcellate auditory and inferior frontal cortex, we investigated relationships between gray matter and pMMN and dMMN in FESz. Methods pMMN and dMMN were measured at Fz from 27 FESz and 27 matched healthy controls. T1-weighted MRI scans were acquired. The HCP-MMP atlas was applied to individuals, and gray matter volumes were calculated for bilateral auditory and inferior frontal cortex parcels and correlated with MMN. FDR correction was used for multiple comparisons. Results In FESz only, pMMN was negatively correlated with left medial belt in auditory cortex and area 47L in inferior frontal cortex. Duration MMN negatively correlated with the following auditory parcels: left medial belt, lateral belt, parabelt, TA2, and right A5. Further, dMMN was associated with left area 47L, right area 44, and right area 47L in inferior frontal cortex. Conclusions The novel approach revealed overlapping and distinct gray matter associations for pMMN and dMMN in auditory and inferior frontal cortex in FESz. Thus, pMMN and dMMN may serve as biomarkers of underlying pathological deficits in both similar and slightly different cortical areas.

To describe a patient with orbital neuroendocrine neoplasm (NEN)/carcinoid tumor and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported ocular adnexal (OA) NENs.A systematic literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of OA NENs.Final analysis yielded 94 patients with OA NENs, 50 females (53%) and 44 (47%) males with an average age of 63 years (range 14-86). Of 91 patients with known information, the most common presenting signs were proptosis (56/91, 61%) and visual disturbances (42/91, 47%), induced by a mass most commonly associated with an extraocular muscle (49/63, 78%). The majority of tumors (88/94, 94%) were metastases, most commonly from the gastrointestinal tract (52/88, 59%). OA NEN metastasis presented following detection of primary tumor in 73/94 (78%) patients (median time to metastasis 36 months, range 0-288 months) and as an initial manifestation of disease in 15/94 (16%) patients (median time to primary detection 18 months, range 1-108 months). Systemic work-up included extra-OA NEN biopsy (37/54, 69%), multimodal imaging (42/54, 78%), and other laboratory studies (32/54, 59%). Resection with or without adjuvant chemotherapy, radiotherapy, and biologics was the most common intervention for OA NENs (36/82, 44%). Of 67 patients with available follow-up, the median survival was 108 months (95% CI 55-161 months) and the absolute 5-year survival rate was 68%.OA NENs are almost exclusively metastases and can precede detection of primary tumor by many months, requiring appropriate diagnostic work-up.

Patients with grade III anaplastic astrocytomas (AA) separate into survival cohorts based on the presence or absence of mutations in isocitrate dehydrogenase (IDH). Progression to glioblastoma (GBM), morphologically distinguishable by elevated microvascular proliferation, necrosis, and cell division in tumor tissues, is considerably more rapid in IDH wild-type tumors such that their diagnosis as AA is relatively rare. More often initially presenting as GBM, these contain higher numbers of tumor-associated macrophages (TAMs) than most AA, and GBM patients also have higher levels of circulating M2 monocytes. TAM and M2 monocytes share functional properties inhibitory for antitumor immunity. Yet, although there is a wealth of data implicating TAM in tumor-immune evasion, there has been limited analysis of the impact of the circulating M2 monocytes. In the current study, immune parameters in sera, circulating cells, and tumor tissues from patients with primary gliomas morphologically diagnosed as AA were assessed. Profound differences in serum cytokines, glioma extracellular vesicle cross-reactive Abs, and gene expression by circulating cells identified two distinct patient cohorts. Evidence of type 2–immune bias was most often seen in patients with IDH wild-type AA, whereas a type 1 bias was common in patients with tumors expressing the IDH1R132H mutation. Nevertheless, a patient’s immune profile was better correlated with the extent of tumor vascular enhancement on magnetic resonance imaging than IDH mutational status. Regardless of IDH genotype, AA progression appears to be associated with a switch in systemic immune bias from type 1 to type 2 and the loss of tumor vasculature integrity.

Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating single-nucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment. Experimental Design: Transgenic Ido2+/+ and Ido2−/− mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N = 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data. Results: PDAC development was notably decreased in the Ido2−/− mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy. Conclusions: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.

Stroke is a leading cause of long-term disability, though current rehabilitative strategies fail to yield complete recovery. Focused training of the impaired limb improves functional outcome in rodents, but these strategies require intensive training that is difficult to practice in humans. Because aerobic exercise has been found to induce beneficial changes in the brain, it is a promising rehabilitative strategy after stroke. The current study investigated the effect of voluntary poststroke aerobic exercise on functional outcome in young and aged mice. Mice were trained on a skilled reaching task before receiving focal ischemic stroke and being subdivided into 3 different groups for rehabilitative training: traditional skilled reach rehabilitation, aerobic exercise, and control procedures. Both young and aged mice benefited from aerobic exercise after stroke, though the behavioral profile somewhat differed. Aerobic exercise in young mice yielded poststroke performance levels that were equivalent to preinjury levels. In aged mice, aerobic exercise accelerated improvement in motor performance without an effect on the absolute level of performance compared with controls. Our results suggest that aerobic exercise may be an effective alternative or adjunctive rehabilitative strategy after stroke. Potential mechanisms of this effect need to be further investigated. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Background Biphenotypic sinonasal sarcoma is a recently described malignancy showing dual differentiation with both myogenic and neural elements. Due to its histologic similarities to other sinonasal malignancies, it is a diagnostic challenge. Objective The main purpose of this article is to report a case of biphenotypic sinonasal sarcoma and to consolidate data and provide a comprehensive review regarding pathological differences between biphenotypic sarcoma and other sinonasal malignancies and diagnostic modalities used for biphenotypic sarcoma. Material and Methods A systematic review of all cases of biphenotypic sinonasal sarcoma was performed using electronic databases (PubMed and Medline). Data collected included age, gender, symptoms, sub-site of origin, immunophenotyping, metastasis, recurrence, treatment, duration of follow-up, and survival outcomes. Results Ninety-five cases of biphenotypic sarcoma were found with mean age at diagnosis of 52.36 years (range, 24–87 years). Female to male ratio was 2.27:1. Extra-sinonasal extension was present in 28%. Immunophenotyping revealed that S-100 and SMA (smooth muscle actin) were consistently positive, while SOX-10 was consistently negative. PAX3-MAML3 fusion [t (2; 4) (q35; q31.1)] was the most common genetic rearrangement. Surgical excision with or without adjuvant radiotherapy was the most frequent treatment modality used. Recurrence was observed in 32% of cases with follow-up. None of the cases reported metastasis. Three patients had died at the time of publication that included one case with intracranial extension. Conclusion Biphenotypic sarcoma is distinct sinonasal malignancy with unique clinicopathological features. Testing involving a battery of myogenic and neural immunomarkers is essential for diagnostic confirmation and is a clinically useful endeavor when clinical suspicion is high.

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic reprogramming. This is underscored by the detection of functional, somatic IDH1 mutations frequently found in secondary glioblastoma. To our knowledge, there has never been a reported, validated case of an IDH1 mutation in a pancreatic ductal adenocarcinoma (PDA). Herein, we present a case of a patient with metastatic PDA that harbored a potentially actionable, albeit rare, IDH1 mutation. As part of the Know Your Tumor project (Pancreatic Cancer Action Network), a 48-year-old female was diagnosed with metastatic PDA and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. This mutation was confirmed by an independent sequencing reaction from the tumor sample, and by immunohistochemistry using an antibody specific for the IDH1 R132H mutation. The patient subsequently received a mutant IDH1 inhibitor (AG-120, Agios Pharmaceuticals, Cambridge, MA), but with no response. IDH1 mutations are common in certain cancer types, but have not been reported in PDA. We report the first case of an IDH1 mutation in this tumor type, perhaps providing a rare opportunity for a targeted therapy as a treatment option for PDA.

PURPOSE To evaluate the clinical behavior of spheno-orbital meningiomas with regard to World Health Organization (WHO) tumor grade and Ki-67, a cellular marker of proliferation. METHODS A retrospective review over a 16-year period of the demographic, clinical, radiographic, and surgical data of all patients with spheno-orbital meningioma who underwent surgical resection. Tumor specimens were examined histologically using the current WHO 2016 classification and immunohistochemically using Ki-67/MIB-1 monoclonal antibody. RESULTS Thirty-eight patients met all inclusion criteria: 78.9% of tumors were WHO grade I with a mean Ki-67 of 3.76, and 93% of patients were clinically stable at last follow up; 10.5% of lesions were WHO grade II (atypical) with a mean Ki-67 of 14.93, and 10.5% of lesions were WHO grade III (anaplastic) with a mean Ki-67 of 58.3. All grade II and III meningiomas exhibited an aggressive clinical course. There were statistically significant correlations between disease clinical progression and WHO tumor grade (p < 0.001), between disease clinical progression and Ki-67 (p < 0.001), and between increasing Ki-67 index and higher WHO grade (p < 0.001). For WHO grade I lesions, a Ki-67 of ≥3.3 correlated with recurrence (p = 0.0256). Overall, disease-specific mortality occurred in 5 (13%) patients. CONCLUSIONS Ki-67 index is a valuable marker to use in conjunction with WHO grade to predict meningioma behavior, particularly in histologically borderline lesions, and possibly to identify a subset of WHO grade I tumors at risk of recurrence. This combination of methods can aid in tailoring treatment and surveillance strategies.

Background Language impairments are a core feature of schizophrenia. Category fluency is severely impacted, even as early as the first-episode of psychosis (FEP). It remains unclear which brain regions in the early course of schizophrenia are dysfunctional during category fluency. Therefore, we investigated differences in fMRI bold activity during a category fluency task in FEP, with particular attention to left temporo-parietal junction (TPJ) and inferior frontal gyrus (IFG), areas critical to verbal fluency. Our hypothesis was that left TPJ would show overactivity in FEP due to functional dysconnectivity with IFG, thought to modulate TPJ activation. Methods Twenty-seven FEP and 25 matched healthy controls (HC) completed an overt category fluency task (animal naming) from the MATRICS Consensus Cognitive Battery (MCCB), and a covert category fluency task while BOLD fMRI was acquired. The fMRI task had a total of 10 blocks (30s duration) with two alternating conditions: category and rest. At the beginning of the category condition, a category name (birds, breeds of dogs, fruits and vegetables, fish, flowers and trees) was displayed on the screen, and individuals were instructed to think of items within that category. At the beginning of the rest condition, individuals were instructed to silently repeat the word “rest” to themselves. To isolate the activity related to category exemplar generation, the rest condition and the category condition fMRI data were contrasted using SPM12. An uncorrected cluster-defining primary threshold of p Results FEP (47.3±12.1) were significantly less fluent compared to HC (55.8±11.3) in the overt MCCB category fluency task (p =.017). In the fMRI covert fluency task, several regions were activated during the category condition (FWE p Discussion FEP have impaired overt category fluency performance, and appear to have deficient deactivation in a region of the left TPJ language area during a category fluency task. TPJ is thought to communicate with Wernicke’s area to translate thoughts into words. Temporal language areas are also thought to be deactivated by IFG during verbal fluency tasks. This fMRI finding is consistent with dysconnectivity between IFG and TPJ during verbal fluency, although future work is needed to definitively address this possible network dysfunction.

Background Mismatch negativity (MMN) is an event-related potential (ERP) that is severely impaired in long-term schizophrenia. However, though largely debated, numerous electroencephalography (EEG) studies suggest that MMN is less reduced in individuals at their first episode of psychosis (FEP). Pitch MMN (pMMN) is not reduced, although duration MMN (dMMN) may be reduced compared to healthy controls (HC), and may show left hemisphere deficits early on. Few MMN studies in FEP have utilized magnetoencephalography (MEG). MEG could potentially be more sensitive to circumscribed differences, given its ability to more effectively localize MMN sources within the auditory cortex. Using MEG, we compared pMMN and dMMN between FEP and HC to identify potential source location- and timing-dependent differences in early disease course. Methods Simultaneous MEG and EEG recordings of pMMN and dMMN were obtained with an oddball paradigm from 15 FEP and 19 HC. Of those, 12 FEP and 11 HC had usable EEG recordings, with the remainder lost due to a circuit board failure. MMN was calculated by subtraction of the sensor-space average to the standard tones from the average to the deviant tones. For EEG, mean amplitudes across fronto-central electrodes (F1, Fz, F2, FC1, FCz, FC2) were calculated over a 30 msec window at group peak latency. For MEG data, source activity was determined in Brainstorm using minimum norm estimation, multisphere head models, and individual MRI cortical surface reconstructions. Using the HCP Brain Atlas, regions of interest (ROIs) were determined based on areas of peak activity at two time windows for each task: an Early time window of 105–115 ms for both pMMN and dMMN, and a Late time window of 125–135 ms for pMMN and 155–165 ms for dMMN. Mean amplitudes were calculated over six auditory cortex ROIs: A1, Brodmann’s Area 43, Brodmann’s Area 52, Lateral Belt, Medial Belt, and Parabelt. Mixed-model ANOVA was then used to compare groups, regions, hemispheres, time windows, and tasks using SPSS software. Results For EEG peak MMNs, there were no significant differences between groups in pMMN or dMMN (p’s > 0.1). For MEG sources, however, ANOVA indicated a Region x Hemisphere x Group interaction (p = 0.038), but no significant regional differences between Pitch and Duration or for either Early or Late time windows (p’s > 0.1). When ROI data were averaged across tasks and time windows, the right hemisphere showed no difference between groups, whereas the left hemisphere showed a trend for reduced MMN activity in FEP (p = 0.069). Post-hoc comparisons of the six left hemisphere ROIs revealed that all regions but Brodmann’s Area 43 showed significant reduction in FEP (p’s < 0.05). Discussion These findings support previous literature that indicate relatively preserved EEG scalp measures of MMN in FEP. However, the MEG source data indicate a deficit in the left hemisphere auditory cortex of FEP. This left hemisphere reduction was observed in 5 out of 6 source regions and at both time windows. This suggests broad left hemisphere auditory cortex pathophysiology early in disease course to which EEG may be relatively less sensitive by comparison with MEG. In conclusion, FEP may be associated with a selective left hemisphere MMN deficit in auditory regions on the superior temporal plane, but not the opercular cortex (i.e. Brodmann’s Area 43).

Background Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. Methods We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. Results Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. Conclusions Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.