Understanding Charles Bonnet syndrome: mechanisms and intervention

Ph. D. Thesis.Background: Charles Bonnet Syndrome (CBS) is defined by the occurrence of vivid, recurring visual hallucinations (VH) secondary to visual impairment in the absence of psychiatric illness or cognitive impairment. Previous research has proposed that deafferentation, due to loss of sensory input from the eyes, leads to spontaneous hyperexcitability in the visual cortex resulting in VH. Approximately one-third of people with CBS report distress and disruption to daily functioning as a consequence of VH, however there are currently no effective treatments and a lack of research into the aetiology of VH has hindered their development. Aims: 1) To investigate the role of visual cortical activity in the production of VH in CBS, compared to non-hallucinating controls, to better understand why VH occur in some patients but not others. 2) To investigate whether inhibitory non-invasive transcranial direct current stimulation (tDCS) could be used to remediate VH by reducing cortical excitability in CBS. Methods: Study 1: A comparison study consisting of people with CBS (n=19) and nonhallucinating sight-matched controls (n=18) was performed utilising transcranial magnetic stimulation, functional magnetic resonance imaging, and magnetic resonance spectroscopy to compare differences in visual cortical activity between groups. Study 2: Informed by a pilot study in continuous CBS hallucinators, sixteen members of the CBS group received 4- consecutive days of active and sham inhibitory tDCS over the primary visual cortex, comparing visual cortical activity and VH ratings before and after stimulation between active and sham weeks. Results: Study 1: Comparable visual cortical excitability was observed in both groups, although greater excitability was associated with more severe VH in the CBS group. Functional activation of the visual cortex was observed to be lower in the CBS group than controls during an eye movement task, with greater functional activation associated with lower visual cortical excitability. Study 2: Active cathodal tDCS of the primary visual cortex resulted in a significant decrease to VH frequency and intrusiveness compared to sham stimulation. No significant changes to cortical activity were observed following stimulation. Conclusions: This thesis constitutes the largest neurophysiological comparison and treatment study performed in CBS to date. These data support the role of changes to visual cortical activity in the production of VH following sight loss, providing a basis for further study. Furthermore, tDCS was observed to present a potential effective new treatment option for CBS, however further study is needed to understand underlying mechanisms.The Macular Society, Esme’s Umbrella, Fight for Sight, the National Eye Research Centre, and the Thomas Pocklington Trus

Transcranial direct current stimulation in the treatment of visual hallucinations in Charles Bonnet syndrome: A randomized placebo-controlled crossover trial.

Objective To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet Syndrome (CBS). Design Randomized, double-masked(blind), placebo-controlled crossover trial. Participants Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. Intervention All participants received four consecutive days of active and placebo cathodal stimulation (current density: 0.29mA/cm2) to the visual cortex (Oz) over two defined treatment weeks, separated by a four-week wash-out period. Main Outcome Measures Ratings of visual hallucination frequency and duration following active and placebo stimulation, accounting for treatment order, using a 2x2 repeated measures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. Results When compared to placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-to-large effect size. Impact measures of visual hallucinations improved in both placebo and active conditions suggesting support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants with no significant adverse effects reported, including no deterioration in pre-existing visual impairment. Conclusions Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability prior to stimulation. tDCS may offer a feasible, novel intervention option for CBS with no significant side effects, warranting larger scale clinical trials to further characterize its efficacy

Investigation of structural brain changes in Charles Bonnet Syndrome

Background and objectives In Charles Bonnet Syndrome (CBS), visual hallucinations (VH) are experienced by people with sight loss due to eye disease or lesional damage to early visual pathways. The aim of this cross-sectional study was to investigate structural brain changes using magnetic resonance imaging (MRI) in CBS. Methods Sixteen CBS patients, 17 with eye disease but no VH, and 19 normally sighted people took part. Participants were imaged on a 3T scanner, with 1 mm resolution T1 weighted structural imaging, and diffusion tensor imaging with 64 diffusion directions. Results The three groups were well matched for age, sex and cognitive scores (MMSE). The two eye disease groups were matched on visual acuity. Compared to the sighted controls, we found reduced grey matter in the occipital cortex in both eye disease groups. We also found reductions of fractional anisotropy and increased diffusivity in widespread areas, including occipital tracts, the corpus callosum, and the anterior thalamic radiation. We did not find any significant differences between the eye disease participants with VH versus without VH, but did observe a negative association between hippocampal volume and VH severity in the CBS group. Discussion Our findings suggest that although there are cortical and subcortical effects associated with sight loss, structural changes do not explain the occurrence of VHs. CBS may relate instead to connectivity or excitability changes in brain networks linked to vision

Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion

Vitamin-D-binding protein (DBP) or group-specific component of serum (GC-globulin) carries vitamin D metabolites from the circulation to target tissues. DBP is highly localized to the liver and pancreatic α cells. Although DBP serum levels, gene polymorphisms, and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α cell morphology, α cell function, and glucagon secretion. Deletion of DBP leads to smaller and hyperplastic α cells, altered Na+ channel conductance, impaired α cell activation by low glucose, and reduced rates of glucagon secretion both in vivo and in vitro. Mechanistically, this involves reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects are also seen in β cell and δ cell function. Immunostaining of human pancreata reveals generalized loss of DBP expression as a feature of late-onset and long-standing, but not early-onset, type 1 diabetes. Thus, DBP regulates α cell phenotype, with implications for diabetes pathogenesis.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.D.J.H. was supported by MRC ( MR/N00275X/1 and MR/S025618/1 ) and Diabetes UK ( 17/0005681 ) project grants. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). L.J.B.B. was supported by a Sir Henry Wellcome Postdoctoral Fellowship ( Wellcome Trust ; 201325/Z/16/Z ) and a Junior Research Fellowship from Trinity College, Oxford . P.E.M. was funded by a foundation grant from the Canadian Institutes of Health Research (grant 148451 ). G.G.L. was supported by a Wellcome Trust Senior Research Fellowship ( 104612/Z/14/Z ). N.G.M. and S.J.R. were supported by Diabetes UK ( 15/0005156 and 16/0005480 ), MRC ( MR/P010695/1 ), and JDRF ( 2-SRA-2018-474-S-B ) project grants. We thank Dr. Deirdre Kavanagh and COMPARE for microscopy assistance. Human pancreas sections were provided by the Alberta Diabetes Institute IsletCore at the University of Alberta in Edmonton, with the assistance of the Human Organ Procurement and Exchange (HOPE) program, Trillium Gift of Life Network (TGLN), and other Canadian organ procurement organizations.published version, accepted version, submitted versio

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 (COVID-19) including two novel mRNA-based vaccines. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S), receptor binding domain (RBD) binding titers. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant