How can I investigate causal brain networks with iEEG?

While many human imaging methodologies probe the structural and functional connectivity of the brain, techniques to investigate cortical networks in a causal and directional manner are critical but limited. The use of iEEG enables several approaches to directly characterize brain regions that are functionally connected and in some cases also establish directionality of these connections. In this chapter we focus on the basis, method and application of the cortico-cortical evoked potential (CCEP), whereby electrical pulses applied to one set of intracranial electrodes yields an electrically-induced brain response at local and remote regions. In this chapter, CCEPs are first contextualized within common brain connectivity methods used to define cortical networks and how CCEP adds unique information. Second, the practical and analytical considerations when using CCEP are discussed. Third, we review the neurophysiology underlying CCEPs and the applications of CCEPs including exploring functional and pathological brain networks and probing brain plasticity. Finally, we end with a discussion of limitations, caveats, and directions to improve CCEP utilization in the future.Comment: Forthcoming chapter in "Intracranial EEG for Cognitive Neuroscience

Cultivating Healthy Communities: Refugee Urban Farmers in Providence, RI: Report No. 2 of Land Conservation and Inequality Series

Urban farming programs for refugees have become more common across the U.S. (Jean, 2015). Access to agricultural space, whether community gardens or market farms, can lead to improved health for those who have faced forced displacement, violence, and difficulties associated with resettlement. Community gardens in particular offer a range of benefits to refugees, including improvements to physical and mental health, food security, and social support (e.g., Malberg Dyg, 2020). Community gardens also provide refugees with opportunities for economic development (e.g., Banulescu-Bogdan, 2020). However, access to agricultural space in a dense urban area is challenging, particularly for groups from marginalized backgrounds, such as refugees. To better meet the needs of refugee farmers in urban areas, it is critical to identify the barriers that impede access to agricultural space. This report explains the challenges and needs related to farmland access among a group of refugees in Providence, Rhode Island. This report comes from a larger study investigating inequality and environmental justice in the context of farm and open space conservation. Distributional Impacts of Farm and Open Space Conservation is funded by the U.S. Department of Agriculture (NIFA Award No. 2018-67024-27695). Principal investigator is Corey Lang in the Department of Environmental & Natural Resource Economics at the University of Rhode Island, with co-investigator Amy Ando in the Department of Agricultural Economics at the University of Illinois-Urbana-Champaign, and co-investigator Julie C. Keller in the Department of Sociology & Anthropology at the University of Rhode Island

Diversity, Equity, and Inclusion at New England Land Trusts: Report No. 1 of Land Conservation and Inequality Series

With over 1,200 organizations registered with the Land Trust Alliance (LTA 2021), land trusts are often viewed as successful models of market-based solutions to environmental and social problems. Yet, the role of these organizations in making open space and farmland accessible to groups from marginalized backgrounds remains unclear. This report (No. 1) discusses findings from interviews conducted in 2021 with key experts at 15 land trusts in New England. The goal of the research was to understand organizational engagement with diversity, equity, and inclusion (DEI) values, with a special emphasis on how land trusts facilitate access to land for underrepresented groups. Interviewees and organizations are referred to using pseudonyms throughout the report. This report comes from a larger study investigating inequality and environmental justice in the context of farm and open space conservation. Distributional Impacts of Farm and Open Space Conservation is funded by the U.S. Department of Agriculture (NIFA Award No. 2018-67024-27695). Principal investigator is Corey Lang in the Department of Environmental & Natural Resource Economics at the University of Rhode Island, with coinvestigator Amy Ando in the Department of Agricultural Economics at the University of Illinois-Urbana-Champaign, and co-investigator Julie C. Keller in the Department of Sociology & Anthropology at the University of Rhode Island

RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model

BACKGROUND Docetaxel induces an anti-tumor response in men with advanced prostate cancer (PCa); however, the side effects associated with docetaxel treatment can be severe, resulting in discontinuation of therapy. Thus, identification of an effective adjuvant therapy to allow lower doses of docetaxel is needed. Advanced PCa is typically accompanied by skeletal metastasis. Receptor activator of NFkB ligand (RANKL) is a key pro-osteoclastic factor. Targeting RANKL decreases establishment and progression of PCa growth in bone in murine models. METHODS The efficacy of inhibiting RANKL, using a recombinant soluble RANK extracellular domain fused with the immunoglobulin Fc domain (RANK-Fc), was tested as an adjuvant therapy with docetaxel for PCa bone metastasis in a murine intra-tibial model. RESULT The combination of RANK-Fc and docetaxel reduced tumor burden in bone greater than either treatment alone. CONCLUSION The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa. Prostate 68:820–829, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58561/1/20744_ftp.pd

Corticocortical evoked potentials reveal projectors and integrators in human brain networks.

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter- regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks

Clinical prediction models for treatment outcomes in newly diagnosed epilepsy: A systematic review.

Up to 35% of individuals diagnosed with epilepsy continue to have seizures despite treatment, commonly referred to as drug-resistant epilepsy. Uncontrolled seizures can directly, or indirectly, negatively impact an individual's quality of life. To inform clinical management and life decisions, it is important to be able to predict the likelihood of seizure control. Those likely to achieve seizure control will be able to return sooner to their usual work and leisure activities and require less follow-up, whereas those with a poor prognosis will need more frequent clinical attendance and earlier consideration of epilepsy surgery. This is a systematic review aimed at identifying demographic, clinical, physiological (e.g., electroencephalographic), and imaging (e.g., magnetic resonance imaging) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). MEDLINE and Embase were searched for prediction models of treatment outcomes in patients with NDE. Study characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST (Prediction Model Risk of Bias Assessment Tool) tool. Baseline variables associated with treatment outcomes are reported as prognostic factors. After screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally scored high for susceptibility to bias. Outcomes reported fit broadly into four categories: drug resistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics/types, epilepsy history, and age at onset. Antiseizure medication response was often included as a baseline variable, potentially obscuring other factor relationships at baseline. Currently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) practices. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE

Personalized rTMS for Depression: A Review

Personalized treatments are gaining momentum across all fields of medicine. Precision medicine can be applied to neuromodulatory techniques, where focused brain stimulation treatments such as repetitive transcranial magnetic stimulation (rTMS) are used to modulate brain circuits and alleviate clinical symptoms. rTMS is well-tolerated and clinically effective for treatment-resistant depression (TRD) and other neuropsychiatric disorders. However, despite its wide stimulation parameter space (location, angle, pattern, frequency, and intensity can be adjusted), rTMS is currently applied in a one-size-fits-all manner, potentially contributing to its suboptimal clinical response (~50%). In this review, we examine components of rTMS that can be optimized to account for inter-individual variability in neural function and anatomy. We discuss current treatment options for TRD, the neural mechanisms thought to underlie treatment, differences in FDA-cleared devices, targeting strategies, stimulation parameter selection, and adaptive closed-loop rTMS to improve treatment outcomes. We suggest that better understanding of the wide and modifiable parameter space of rTMS will greatly improve clinical outcome

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC

Compartmentalization of Calcium Extrusion Mechanisms in the Outer and Inner Segments of Photoreceptors

AbstractDifferential localization of calcium channel subtypes in divergent regions of individual neurons strongly suggests that calcium signaling and regulation could be compartmentalized. Region-specific expression of calcium extrusion transporters would serve also to partition calcium regulation within single cells. Little is known about selective localization of the calcium extrusion transporters, nor has compartmentalized calcium regulation within single neurons been studied in detail. Sensory neurons provide an experimentally tractable preparation to investigate this functional compartmentalization. We studied calcium regulation in the outer segment (OS) and inner segment/synaptic terminal (IS/ST) regions of rods and cones. We report these areas can function as separate compartments. Moreover, ionic, pharmacological, and immunolocalization results show that a Ca-ATPase, but not the Na+/K+, Ca2+ exchanger found in the OSs, extrudes calcium from the IS/ST region. The compartmentalization of calcium regulation in the photoreceptor outer and inner segments implies that transduction and synaptic signaling can be independently controlled. Similar separation of calcium-dependent functions is likely to apply in many types of neuron