Emerging Neurotechnologies: Implications for Professional Relations and Communication.

Rapid advances in neurotechnology and neurosurgery are positioned to revolutionize care for patients suffering from debilitating neurological and psychiatric disease. Enthusiasm for the adoption of these technologies is tempered by ethical dilemmas regarding resource allocation, provision of care, communication with patients and other providers, and other potential pitfalls. In the present work, we discuss bioethical implications of novel neurotechnologies for medical practice. In particular, we examine the implications of neurotechnological advancement through the lens of professional communication. Emerging challenges within this domain are presented in the context of physician interactions with four key partners: (i) patients; (ii) other physicians; (iii) industry; and (iv) society-at-large. Anticipated issues as well as mitigation strategies are discussed as they relate to communication with these stakeholders.

Neuroinflammatory transcriptional programs induced in rhesus pre-frontal cortex white matter during acute SHIV infection.

BACKGROUND: Immunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505). METHODS: We performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays. RESULTS: RNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS. CONCLUSIONS: Our data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.

Nose to brain delivery of Efavirenz nanosuspension for effective neuro AIDS therapy: in-vitro, in-vivo and pharmacokinetic assessment.

Efavirenz is inhibitor of non-nucleoside reverse transcriptase enzyme; BCS class II drug. The objective of the present research was to prepare and evaluate nanosuspension of Efavirenz for the treatment of neuro-AIDS. Efavirenz is the substrate for drug resistant proteins at BBB prone to efflux and could not reach brain with effective levels. Current need of the therapy is to develop drug delivery systems targeting viral reservoirs at effective concentration in the brain. With this need we developed Efavirenz nanosuspension for nose to brain drug transport to bypass blood brain barrier. Nanosuspension prepared with high-pressure homogenization had a mean particle size of 223 nm, PDI of 0.2 and -21.2 mV zeta potential. Histopathology study on goat nasal mucosa showed no adverse effects of formulation on nasal tissues. Gamma scintigraphy study and in-vivo study on Wistar rat model reveals drug transport to the CNS after nasal administration. Pharmacokinetic parameters and drug targeting potential of 99.46 % suggest direct nose to brain transport of Efavirenz nanoparticle. Results reveal that nose to brain delivery of Efavirenz is the best possible alternative for neuro -AIDS treatment.

Stroke and HIV-associated neurological complications: A retrospective nationwide study.

There is an increased risk of stroke and other neurological complications in human immunodeficiency virus (HIV) infected patients with no large population-based studies in the literature. We aim to evaluate the prevalence of stroke, HIV-associated neurological complications, and identify risk factors associated with poor outcomes of stroke among HIV admissions in the United States. In the nationwide inpatient sample with adult HIV hospitalizations, patients with primary cerebrovascular disease (CeVDs) and HIV-associated neurological complications were identified by ICD-9-CM codes. We performed a retrospective study with weighted analysis to evaluate the prevalence of stroke and neurological complications and outcomes of stroke among HIV patients. We included 1,559,351 HIV admissions from 2003 to 2014, of which 22470 (1.4%) patients had CeVDs (transient ischemic attack [TIA]: 3240 [0.2%], acute ischemic stroke [AIS]: 14895 [0.93%], and hemorrhagic stroke [HS]: 4334 [0.27%]), 7781 (0.49%) had neurosyphilis, 29,925 (1.87%) meningitis, 39,190 (2.45%) cytomegalovirus encephalitis, 4699 (0.29%) toxoplasmosis, 9964 (0.62%) progressive multifocal leukoencephalopathy, and 142,910 (8.94%) epilepsy. There is increased overall prevalence trend for CeVDs (TIA: 0.17%-0.24%; AIS: 0.62%-1.29%; HS: 0.26%-0.31%; pTrend < .0001) from 2003 to 2014. Among HIV admissions, variables associated with AIS were neurosyphilis (odds ratio: 4.38; 95% confidence interval: 3.21-5.97), meningitis (4.87 [4.10-5.79]), and central nervous system tuberculosis (6.72 [3.85-11.71]). Toxoplasmosis [4.27 [2.34-7.76]), meningitis (2.91 [2.09-4.06)], and cytomegalovirus encephalitis (1.62 [1.11-2.37]) were associated with higher odds of HS compared to patients without HS. There was an increasing trend of CeVDs over time among HIV hospitalizations. HIV-associated neurological complications were associated with the risk of stroke, together with increased mortality, morbidity, disability, and discharge to long-term care facilities. Further research would clarify stroke risk factors in HIV patients to mitigate adverse outcomes.

Intranasal chitosan-g-HPßCD nanoparticles of efavirenz for the CNS targeting.

Incompetence of antiretrovirals (ARV) in complete eradication of HIV from the CNS is the biggest issue in neuro-AIDS treatment. The ineffectiveness is largely due to the poor penetration of ARV. Hence, the present study is attempted to enhance the CNS uptake of efavirenz (EFV) by designing intranasal EFV nanoparticles (EFV-NPs). EFV-NPs were fabricated using chitosan-g-HPßCD by ionic gelation method and optimized using quadratic response surface methodology (RSM) employing two-factor, five-level circumscribed central composite design. NPs containing drug: polymer ratio (1.25:0.79) were spherical with 198 ± 4.4 nm size, 23.28 ± 1.5% drug loading and 38 ± 1.43% entrapment efficiency. NPs showed sustained drug release (99.03 ± 0.30% in 8 h) and followed Fickian diffusion mechanism. It gave 4.76 times greater permeability than plain drug solution through porcine nasal mucosa. Enhanced CNS bioavailability (12.40-fold that of i.v solution) of EFV, high drug-targeting percentage (99.24%) and drug-targeting index (141.3) post-intranasal administration of NPs was observed. These results are corroborated by gamma scintigraphy images, which revealed high CNS uptake. NPs appeared histocompatible with porcine nasal mucosa and non-toxic to L929 cell line. Thus, CS-g-HPßCD served as a potential carrier in developing intranasal mucoadhesive EFV-NPs for the CNS targeting.

Loss of cerebellar neurons in the progression of lentiviral disease: effects of CNS-permeant antiretroviral therapy.

BACKGROUND: The majority of investigations on HIV-associated neurocognitive disorders (HAND) neglect the cerebellum in spite of emerging evidence for its role in higher cognitive functions and dysfunctions in common neurodegenerative diseases. METHODS: We systematically investigated the molecular and cellular responses of the cerebellum as contributors to lentiviral infection-induced neurodegeneration, in the simian immunodeficiency virus (SIV)-infected rhesus macaque model for HIV infection and HAND. Four cohorts of animals were studied: non-infected controls, SIV-infected asymptomatic animals, and SIV-infected AIDS-diseased animals with and without brain-permeant antiretroviral treatment. The antiretroviral utilized was 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG), a CNS-permeable nucleoside reverse transcriptase inhibitor. Quantitation of granule cells and Purkinje cells, of an established biomarker of SIV infection (gp41), of microglial/monocyte/macrophage markers (IBA-1, CD68, CD163), and of the astroglial marker (GFAP) were used to reveal cell-specific cerebellar responses to lentiviral infection and antiretroviral therapy (ART). The macromolecular integrity of the blood brain barrier was tested by albumin immunohistochemistry. RESULTS: Productive CNS infection was observed in the symptomatic stage of disease, and correlated with extensive microglial/macrophage and astrocyte activation, and widespread macromolecular blood brain barrier defects. Signs of productive infection, and inflammation, were reversed upon treatment with 6-Cl-ddG, except for a residual low-grade activation of microglial cells and astrocytes. There was an extensive loss of granule cells in the SIV-infected asymptomatic cohort, which was further increased in the symptomatic stage of the disease and persisted after 6-Cl-ddG (administered after the onset of symptoms of AIDS). In the symptomatic stage, Purkinje cell density was reduced. Purkinje cell loss was likewise unaffected by 6-Cl-ddG treatment at this time. CONCLUSIONS: Our findings suggest that neurodegenerative mechanisms are triggered by SIV infection early in the disease process, i. e., preceding large-scale cerebellar productive infection and marked neuroinflammation. These affect primarily granule cells early in disease, with later involvement of Purkinje cells, indicating differential vulnerability of the two neuronal populations. The results presented here indicate a role for the cerebellum in neuro-AIDS. They also support the conclusion that, in order to attenuate the development of motor and cognitive dysfunctions in HIV-positive individuals, CNS-permeant antiretroviral therapy combined with anti-inflammatory and neuroprotective treatment is indicated even before overt signs of CNS inflammation occur.

Neurological complications in late-stage hospitalized patients with HIV disease.

BACKGROUND AND OBJECTIVE: The nervous system is the most frequent and serious targets of human immunodeficiency virus (HIV) infection. In spite of a wide prevalence of neurological manifestations in HIV there are not many studies to look into it, especially from this part of the world. We investigated various neurological manifestations of HIV and their association with CD4 and CD8 counts at the time of presentation. MATERIALS AND METHODS: All HIV-infected patients who presented to 750 bedded teaching hospital in North India were subjected to thorough neurological and neuropsychological evaluation. Wherever indicated, neuroimaging, cerebrospinal fluid study, electromyography, and nerve-conduction studies were performed to confirm the diagnosis. CD4 and CD8 counts were calculated. RESULTS: A total of 416 HIV-positive patients were seen. Of them 269 were males. A total of 312 neurological events were identified in 268 patients having evidence of neurological involvement. HIV-associated dementia (HAD) was the most common cause of morbidity (33.65%), followed by CNS infections (21.63%). Most common CNS infection was tuberculosis (65.56%). CD4 counts in CNS infections and HAD were 64.8/µl and 83.52/µl, respectively. Most of the patients in our study had low scores on MMSE (22.32). CONCLUSIONS: Even in the absence of overt neurological disease, subclinical involvement in the form of subtle cognitive and motor decline is found to occur with greater frequency. Most of these patients have lower CD4 and CD8 counts, thus substantiating the proposition that neuroAIDS is a late manifestation. Significant correlation exists between CD4 counts and type of neurological manifestation. We concluded that neuropsychological assessment should be mandatory for all HIV-positive patients.

Manifestaciones neurológicas en pacientes pediátricos y adolescentes mexicanos infectados con VIH/SIDA: Experiencia del Hospital Infantil de México Federico Gómez / Neurological manifestations in Mexican pediatric and adolescent patients infected with HIV/AIDS: Experience in the Hospital Infantil de Mexico Federico Gomez

Introducción. Objetivo: describir las principales manifestaciones neurológicas que presentan los pacientes pediátricos y adolescentes infectados por VIH/SIDA atendidos en el Hospital Infantil de México Federico Gómez. Métodos. Se realizó un estudio retrospectivo con la revisión de pacientes pediátricos con diagnóstico de infección por VIH/ SIDA, donde se tomaron en cuenta variables demográficas, epidemiológicas, manifestaciones clínicas neurológicas y estudios de laboratorio y gabinete. Además, se valoraron los índices de desarrollo neuromotor. Resultados. Se revisaron 127 pacientes, 62 masculinos y 65 femeninos, con edad promedio de 7 años y edad promedio del inicio de la enfermedad de 1 año 6 meses. La forma de transmisión de la enfermedad en 72% de los casos fue por vía vertical. Se observó la presencia de manifestaciones neurológicas clínicas, por imagen o electroencefalograma (EEG) en 40 casos (31.5%), de los cuales 25 (62.5%) presentaban datos de encefalopatía manifestada por retardo en los hitos del desarrollo, atrofia cortical y principalmente retardo en el desarrollo del lenguaje. Los estudios de imagen presentaban datos de atrofia cerebral (cortical o central), calcificación de ganglios basales y alteraciones desmielinizantes. Los EEG mostraban enlentecimiento del ritmo de fondo y actividad epiléptica, y únicamente en 4 se observaron crisis parciales. Más de la mitad de los casos presentaban un desarrollo académico normal. Conclusión. Uno de cada 3 pacientes infectados por el VIH presentaba alguna manifestación neurológica, la cual puede observarse desde los primeros meses de la enfermedad. Esto define la necesidad de establecer un seguimiento neurológico desde la detección de la enfermedad, ayudando a prevenir de manera más temprana las alteraciones neurológicas, y favoreciendo el inicio de las rehabilitaciones correspondientes.

Introduction. Objective: Describe the main neurological manifestations present in pediatric and adolescent patients with HIV-AIDS seen at the Hospital Infantil de Mexico Federico Gomez. Methods. In a retrospective study, we analyzed patients with a diagnosis of HIV-AIDS seen at the Hospital Infantil de Mexico Federico Gomez, where we searched for multiple specific variables such as demographic, epidemiologic, neurological manifestations and laboratory studies. Moreover, we analyzed the neurodevelopment index. Results. We analyzed 127 patients, 62 males and 65 females with a median age of 7 years who initiated with disease at 1.5 years. The most frequent acquisition disease form in 72% of cases was by vertical transmission. We observed the presence of clinical neurological manifestations, imaging abnormalities, or electroencephalographic changes in 40 patients (31.5%), 25 of these (26.5%) showing encephalopathic problems characterized by progressive loss of motor function, cortical atrophy, and language delay. The imaging abnormalities found comprised cortical atrophy (cortical or central), basal ganglia calcification, and demyelinizing disorders. The EEG exhibited diffuse dysfunction in basal activity and low voltage, with epileptic activity, and only 4 patients had partial seizures. More than one half of patients had normal academic achievement. Conclusion. One of every 3 patients with HIV infection presents some neurological manifestations, which are observed from very early disease stages. This merits a formal neurological protocol for follow-up that would aid in detecting neurological manifestations in a more timely fashion, which can permit establishment of earlier treatments.