Mapping effective connectivity in the human brain with concurrent intracranial electrical stimulation and BOLD-fMRI

BACKGROUND: Understanding brain function requires knowledge of how one brain region causally influences another. This information is difficult to obtain directly in the human brain, and is instead typically inferred from resting-state fMRI. NEW METHOD: Here, we demonstrate the safety and scientific promise of a novel and complementary approach: concurrent electrical stimulation and fMRI (es-fMRI) at 3 T in awake neurosurgical patients with implanted depth electrodes. RESULTS: We document the results of safety testing, actual experimental setup, and stimulation parameters, that safely and reliably evoke activation in distal structures through stimulation of amygdala, cingulate, or prefrontal cortex. We compare connectivity inferred from the evoked patterns of activation with that estimated from standard resting-state fMRI in the same patients: while connectivity patterns obtained with each approach are correlated, each method produces unique results. Response patterns were stable over the course of 11 min of es-fMRI runs. COMPARISON WITH EXISTING METHOD: es-fMRI in awake humans yields unique information about effective connectivity, complementing resting-state fMRI. Although our stimulations were below the level of inducing any apparent behavioral or perceptual effects, a next step would be to use es-fMRI to modulate task performances. This would reveal the acute network-level changes induced by the stimulation that mediate the behavioral and cognitive effects seen with brain stimulation. CONCLUSIONS: es-fMRI provides a novel and safe approach for mapping effective connectivity in the human brain in a clinical setting, and will inform treatments for psychiatric and neurodegenerative disorders that use deep brain stimulation

Hybrid Mechanical Systems

We discuss hybrid systems in which a mechanical oscillator is coupled to another (microscopic) quantum system, such as trapped atoms or ions, solid-state spin qubits, or superconducting devices. We summarize and compare different coupling schemes and describe first experimental implementations. Hybrid mechanical systems enable new approaches to quantum control of mechanical objects, precision sensing, and quantum information processing.Comment: To cite this review, please refer to the published book chapter (see Journal-ref and DOI). This v2 corresponds to the published versio

Cavity Induced Interfacing of Atoms and Light

This chapter introduces cavity-based light-matter quantum interfaces, with a single atom or ion in strong coupling to a high-finesse optical cavity. We discuss the deterministic generation of indistinguishable single photons from these systems; the atom-photon entanglement intractably linked to this process; and the information encoding using spatio-temporal modes within these photons. Furthermore, we show how to establish a time-reversal of the aforementioned emission process to use a coupled atom-cavity system as a quantum memory. Along the line, we also discuss the performance and characterisation of cavity photons in elementary linear-optics arrangements with single beam splitters for quantum-homodyne measurements.Comment: to appear as a book chapter in a compilation "Engineering the Atom-Photon Interaction" published by Springer in 2015, edited by A. Predojevic and M. W. Mitchel

An ethical exploration of the narratives surrounding substance use and pain management at the end of life: a discussion paper.

This discussion article examines narrative positioning related to pain management for people who use substances at the end of life. We explore how dominant narrative genres associated with biomedicine, such as 'restitution' and narratives common within the context of drug services such as 'recovery' can hinder effective pain management within this population. We argue that these discourses can marginalise the ethical self-identity of patients who use substances at the end of life. It can also trouble health and social care professionals in supporting patients and generating counter-narratives that challenge those often associated with substance use. Stigma is a common experience for this population with stereotyping as 'junkies' and associated with criminality. They are positioned as drug-seeking, and this requires more surveillance at the end of life when opioid therapy is potentially more available and authorised. This can make it challenging to generate 'companion' stories that are positive and maintain moral adequacy. Dominant biomedical narrative genres often prevent the recognition of the fractured stories that people using substances can often present with. This can lead to narrative silencing and to the under treatment of pain. The person's self-identity is invested in narratives of recovery, and opioid use symbolises their addicted past because for practitioners, this population is at clinical risk with the potential for drug seeking behaviours. Whilst not requiring formal ethical review this discussion paper was constructed in accordance with good scientific practice with the work of other researchers respected and cited appropriately

Triple-negative breast cancers are increased in black women regardless of age or body mass index

INTRODUCTION. We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population. We focused on triple-negative (Tneg) tumours (oestrogen receptor (ER), progesterone receptor (PR) and HER2 negative), which are associated with poor prognosis. METHODS. We identified female patients with invasive BC diagnosed between 1998 and 2006, with data available on tumor grade, stage, ER, PR and HER2 status, and patient age, body mass index (BMI) and self-identified racial/ethnic group. We determined associations between patient and tumour characteristics using contingency tables and multivariate logistic regression. RESULTS. 415 cases were identified. Patients were racially and ethnically diverse (born in 44 countries, 36% white, 43% black, 10% Hispanic and 11% other). 47% were obese (BMI > 30 kg/m2). 72% of tumours were ER+ and/or PR+, 20% were Tneg and 13% were HER2+. The odds of having a Tneg tumour were 3-fold higher (95% CI 1.6, 5.5; p = 0.0001) in black compared with white women. Tneg tumours were equally common in black women diagnosed before and after age 50 (31% vs 29%; p = NS), and who were obese and non-obese (29% vs 31%; p = NS). Considering all patients, as BMI increased, the proportion of Tneg tumours decreased (p = 0.08). CONCLUSIONS. Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI. Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis.LaPann Fund; Research Enhancement Fun

Evidence for a Novel Marine Harmful Algal Bloom: Cyanotoxin (Microcystin) Transfer from Land to Sea Otters

“Super-blooms” of cyanobacteria that produce potent and environmentally persistent biotoxins (microcystins) are an emerging global health issue in freshwater habitats. Monitoring of the marine environment for secondary impacts has been minimal, although microcystin-contaminated freshwater is known to be entering marine ecosystems. Here we confirm deaths of marine mammals from microcystin intoxication and provide evidence implicating land-sea flow with trophic transfer through marine invertebrates as the most likely route of exposure. This hypothesis was evaluated through environmental detection of potential freshwater and marine microcystin sources, sea otter necropsy with biochemical analysis of tissues and evaluation of bioaccumulation of freshwater microcystins by marine invertebrates. Ocean discharge of freshwater microcystins was confirmed for three nutrient-impaired rivers flowing into the Monterey Bay National Marine Sanctuary, and microcystin concentrations up to 2,900 ppm (2.9 million ppb) were detected in a freshwater lake and downstream tributaries to within 1 km of the ocean. Deaths of 21 southern sea otters, a federally listed threatened species, were linked to microcystin intoxication. Finally, farmed and free-living marine clams, mussels and oysters of species that are often consumed by sea otters and humans exhibited significant biomagnification (to 107 times ambient water levels) and slow depuration of freshwater cyanotoxins, suggesting a potentially serious environmental and public health threat that extends from the lowest trophic levels of nutrient-impaired freshwater habitat to apex marine predators. Microcystin-poisoned sea otters were commonly recovered near river mouths and harbors and contaminated marine bivalves were implicated as the most likely source of this potent hepatotoxin for wild otters. This is the first report of deaths of marine mammals due to cyanotoxins and confirms the existence of a novel class of marine “harmful algal bloom” in the Pacific coastal environment; that of hepatotoxic shellfish poisoning (HSP), suggesting that animals and humans are at risk from microcystin poisoning when consuming shellfish harvested at the land-sea interface

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis