Faculty Bibliography

Pathological avoidance behavior in anxiety and anxiety-related disorders has a large role in the persistence and severity of disease. Individuals are cued to avoid potential aversive events by learned danger and safety signals in the environment. Individuals with anxiety demonstrate a bias to utilize danger signals more than safety signals, in contrast to those without these disorders. Therefore, the present study investigated if danger and safety signals differentially influenced persistent avoidance in an animal model of anxiety-vulnerability, the Wistar Kyoto (WKY) rat, relative to the outbred Sprague Dawley (SD) rat. Persistent avoidance was assessed using extinction protocols. When danger or safety signals were present during extinction, WKY rats were slower to extinguish the avoidance response compared to SD rats. In contrast, when danger and safety signals were both present during extinction, WKY and SD rats extinguished at a similar rate. Differences in contextual and configural learning were explored as potential causes of the strain differences in the use of safety and danger signals in avoidance extinction. Strains did not differ in avoidance extinction when context was manipulated. However, WKY rats were impaired in configural learning using a negative patterning task. The results indicate that danger and safety signals may impair avoidance extinction in anxiety-vulnerable individuals due to impaired configural learning. These findings have important implications for understanding the etiology of anxiety disorders and may improve their diagnosis and treatment.

OBJECTIVE:With this prospective, observational study, we aimed to determine whether noninvasive language tasks, developed specifically for children, could reliably identify the hemisphere of seizure onset in pediatric epilepsy. METHODS:analyses and odds ratios were used to examine classification of left vs right hemisphere epilepsy for individual patients based on test performance. RESULTS:= 0.004). The odds of left hemisphere epilepsy were 4.2 times higher (95% confidence interval 1.4-11.7) than the odds of right hemisphere epilepsy with poor auditory naming performance. In the subset of patients with temporal lobe epilepsy (TLE), the odds of left TLE were 11.3 times higher (95% confidence interval 2.00-63.17) than the odds of right TLE with poor auditory naming performance. CONCLUSION/CONCLUSIONS:Contrary to previous findings, naming performance can lateralize hemisphere of seizure onset in children with epilepsy, thereby assisting in the preoperative workup for pediatric epilepsy surgery.

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.

OBJECTIVE:We aimed to determine the rates and predictors of resection and seizure freedom after bilateral stereo-electroencephalography (SEEG) implantation. METHODS:We reviewed 184 patients who underwent bilateral SEEG implantation (2009-2015). Noninvasive and invasive evaluation findings were collected. Outcomes of interest included subsequent resection and seizure freedom. Statistical analyses employed multivariable logistic regression and proportional hazard modeling. Preoperative and postoperative seizure frequency, severity, and quality of life scales were also compared. RESULTS:Following bilateral SEEG implantation, 106 of 184 patients (58%) underwent resection. Single seizure type (P = 0.007), a family history of epilepsy (P = 0.003), 10 or more seizures per month (P = 0.004), lower number of electrodes (P = 0.02), or sentinel electrode placement (P = 0.04) was predictive of undergoing a resection, as were lack of nonlocalized (P < 0.0001) or bilateral (P < 0.0001) ictal-onset zones on SEEG. Twenty-six of 81 patients (32% with follow-up greater than 1 year) remained seizure-free. Predictors of seizure freedom were single seizure type (P = 0.01), short epilepsy duration (P = 0.008), use of 2 or fewer antiepileptic drugs (AEDs) at the time of surgery (P = 0.0006), primary localization hypothesis involving the frontal lobe (P = 0.002), sentinel electrode placement only (P = 0.02), and lack of overlap between ictal-onset zone and eloquent cortex (P = 0.04), along with epilepsy substrate histopathology (P = 0.007). Complete resection of a suspected focal cortical dysplasia showed a trend to increased likelihood of seizure freedom (P = 0.09). The 44 of 55 patients (80%) who underwent resection and experienced seizure recurrence had >50% seizure reduction, as opposed to 26 of 45 patients (58%) who continued medical therapy alone (P = 0.003). Seventy-two percent of patients had a clinically meaningful quality of life improvement (>10% decrease in the Quality of Life in Epilepsy [QOLIE-10] score) at 1 year. SIGNIFICANCE/CONCLUSIONS:A strong preimplantation hypothesis of a suspected unifocal epilepsy increases the odds of resection and seizure freedom. We discuss a tailored approach, taking into account localization hypothesis and suspected epilepsy etiology in guiding implantation and subsequent surgical strategy.

Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in Gba^L444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations. Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type.

Although there is an increasing agreement that hypertension is associated with cerebrovascular compromise, relationships between blood pressure (BP) and cerebral blood flow are not fully understood. It is not known what BP level, and consequently what therapeutic goal, is optimal for brain perfusion. Moreover, there is limited data on how BP affects hippocampal perfusion, a structure critically involved in memory. We conducted a cross-sectional (n=445) and longitudinal (n=185) study of adults and elderly without dementia or clinically apparent stroke, who underwent clinical examination and brain perfusion assessment (age 69.2±7.5 years, 62% women, 45% hypertensive). Linear models were used to test baseline BP-blood flow relationship and to examine how changes in BP influence changes in perfusion. In the entire group, systolic BP (SBP) was negatively related to cortical (β=-0.13, P=0.005) and hippocampal blood flow (β=-0.12, P=0.01). Notably, this negative relationship was apparent already in subjects without hypertension. Hypertensive subjects showed a quadratic relationship between SBP and hippocampal blood flow (β=-1.55, P=0.03): Perfusion was the highest in subjects with mid-range SBP around 125 mm Hg. Longitudinally, in hypertensive subjects perfusion increased with increased SBP at low baseline SBP but increased with decreased SBP at high baseline SBP. Cortical and hippocampal perfusion decrease with increasing SBP across the entire BP spectrum. However, in hypertension, there seems to be a window of mid-range SBP which maximizes perfusion.

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy^1,2, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease^3-10. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging^11,12, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost^13,14. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2^1,2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

Clinical interpretation of cerebral positron emission tomography with 2-deoxy-2[F-18]fluoro-d-glucose (FDG-PET) images often relies on evaluation of regional asymmetries. This study was designed to establish age-related variations in regional cortical glucose metabolism asymmetries in the developing human brain. FDG-PET scans of 58 children (age: 1-18 years) were selected from a large single-center pediatric PET database. All children had a history of epilepsy, normal MRI, and normal pattern of glucose metabolism on visual evaluation. PET images were analyzed objectively by statistical parametric mapping with the use of age-specific FDG-PET templates. Regional FDG uptake was measured in 35 cortical regions in both hemispheres using an automated anatomical labeling atlas, and left/right ratios were correlated with age, gender, and epilepsy variables. Cortical glucose metabolism was mostly symmetric in young children and became increasingly asymmetric in older subjects. Specifically, several frontal cortical regions showed an age-related increase of left > right asymmetries (mean: up to 10%), while right > left asymmetries emerged in posterior cortex (including portions of the occipital, parietal, and temporal lobe) in older children (up to 9%). Similar trends were seen in a subgroup of 39 children with known right-handedness. Age-related correlations of regional metabolic asymmetries showed no robust gender differences and were not affected by epilepsy variables. These data demonstrate a region-specific emergence of cortical metabolic asymmetries between age 1-18 years, with left > right asymmetry in frontal and right > left asymmetry in posterior regions. The findings can facilitate correct interpretation of cortical regional asymmetries on pediatric FDG-PET images across a wide age range.

Healthcare reform, including the focus on chronic illness, the growing role of neuroscience, the emphasis on collaborative interprofessional care, and more recently, on integrated medical and behavioral healthcare, have important implications for social work education and practice. Parkinson's disease, a chronic neurodegenerative illness exemplifying these trends, is an area in which social workers are increasingly involved. This paper provides (1) an overview of Parkinson's disease and its complexity, (2) a summary of role and functions identified in a survey of health social workers working with Parkinson's disease and/or neurology, and (3) education and practice recommendations for the social work profession.

BACKGROUND:Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). OBJECTIVE:We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. METHODS:I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. RESULTS:We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. CONCLUSIONS:These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.