Increased visual sensitivity and occipital activity in patients with hemianopia following vision rehabilitation

Hemianopia, loss of vision in half of the visual field, results from damage to the visual pathway posterior to the optic chiasm. Despite negative effects on quality of life, few rehabilitation options are currently available. Recently, several long-term training programs have been developed that show visual improvement within the blind field, although little is known of the underlying neural changes. Here, we have investigated functional and structural changes in the brain associated with visual rehabilitation. Seven human participants with occipital lobe damage enrolled in a visual training program to distinguish which of two intervals contained a drifting Gabor patch presented within the blind field. Participants performed;25 min of training each day for 3–6 months and undertook psychophysical tests and a magnetic resonance imaging scan before and after training. A control group undertook psychophysical tests before and after an equivalent period without training. Participants who were not at ceiling on baseline tests showed on average 9.6% improvement in Gabor detection, 8.3% in detection of moving dots, and 9.9% improvement in direction discrimination after training. Importantly, psychophysical improvement only correlated with improvement in Humphrey perimetry in the trained region of the visual field. Whole-brain analysis showed an increased neural response to moving stimuli in the blind visual field in motion area V5/hMT. Using a region-of-interest approach, training had a significant effect on the blood oxygenation level-dependent signal compared with baseline. Moreover, baseline V5/hMT activity was correlated to the amount of improvement in visual sensitivity using psychophysical and perimetry tests. This study, identifying a critical role for V5/hMT in boosting visual function, may allow us to determine which patients may benefit most from training and design adjunct interventions to increase training effects

Increased visual sensitivity and occipital activity in patients with hemianopia following vision rehabilitation

Acknowledgements We would like to thank the participants for giving up their time to engage with the research.Peer reviewedPublisher PD

Visual Field Reconstruction in Hemianopia Using fMRI Based Mapping Techniques

PURPOSE: A stroke that includes the primary visual cortex unilaterally leads to a loss of visual field (VF) representation in the hemifield contralateral to the damage. While behavioral procedures for measuring the VF, such as perimetry, may indicate that a patient cannot see in a particular area, detailed psychophysical testing often detects the ability to perform detection or discrimination of visual stimuli (“blindsight”). The aim of this study was to determine whether functional magnetic resonance imaging (fMRI) could be used to determine whether perimetrically blind regions of the VF were still represented in VF maps reconstructed on the basis of visually evoked neural activity. METHODS: Thirteen patients with hemianopia and nine control participants were scanned using 3T MRI while presented with visual stimulation. Two runs of a dynamic “wedge and ring” mapping stimulus, totaling approximately 10 min, were performed while participants fixated centrally. Two different analysis approaches were taken: the conventional population receptive field (pRF) analysis and micro-probing (MP). The latter is a variant of the former that makes fewer assumptions when modeling the visually evoked neural activity. Both methods were used to reconstruct the VF by projecting modeled activity back onto the VF. Following a normalization step, these “coverage maps” can be compared to the VF sensitivity plots obtained using perimetry. RESULTS: While both fMRI-based approaches revealed regions of neural activity within the perimetrically “blind” sections of the VF, the MP approach uncovered more voxels in the lesioned hemisphere in which a modest degree of visual sensitivity was retained. Furthermore, MP-based analysis indicated that both early (V1/V2) and extrastriate visual areas contributed equally to the retained sensitivity in both patients and controls. CONCLUSION: In hemianopic patients, fMRI-based approaches for reconstructing the VF can pick up activity in perimetrically blind regions of the VF. Such regions of the VF may be particularly amenable for rehabilitation to regain visual function. Compared to conventional pRF modeling, MP reveals more voxels with retained visual sensitivity, suggesting it is a more sensitive approach for VF reconstruction

The Need for Head Protection Protocols for Craniectomy Patients during Rest, Transfers and Turning

After craniectomy, patients are generally advised to wear a helmet when mobilising to protect the unshielded brain from damage. However, there exists limited guidance regarding head protection for patients at rest and when being transferred or turned. Here, we emphasise the need for such protocols and utilise evidence from several sources to affirm our viewpoint. A literature search was first performed using MEDLINE and EMBASE, looking for published material relating to head protection for patients post-craniectomy during rest, transfer or turning. No articles were identified using a wide-ranging search strategy. Next, we surveyed and interviewed staff and patients from our neurosurgical centre to ascertain how often their craniectomy site was exposed to external pressure and the precautions taken to prevent this. 59% of patients admitted resting in contact with the craniectomy site, in agreement with the observations of 67% of staff. In 63% of these patients, this occurred on a daily basis and for some, was associated with symptoms suggestive of raised intracranial pressure. 44% of staff did not use a method to prevent craniectomy site contact while 65% utilised no additional precautions during transfer or turning. 63% of patients received no information about avoiding craniectomy site contact upon discharge, and almost all surveyed wished for resting head protection if it were available. We argue that pragmatic guidelines are needed and that our results support this perspective. As such, we offer a simple, practical protocol which can be adopted and iteratively improved as further evidence becomes available in this area

Optic Tract Shrinkage Limits Visual Restoration After Occipital Stroke

BACKGROUND AND PURPOSE: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral visual hemifield, initiating a process of trans-synaptic retrograde degeneration. The present study examined functional implications of this process, asking if degeneration impacted the amount of visual recovery attainable from visual restoration training in chronic patients, and if restoration training impacted optic tract (OT) shrinkage. METHODS: Magnetic resonance imaging was used to measure OT volumes bilaterally in 36 patients with unilateral occipital stroke. From OT volumes, we computed laterality indices (LI), estimating the stroke-induced OT shrinkage in each case. A subset of these chronic patients (n=14, 13±6 months poststroke) underwent an average of nearly 1 year of daily visual restoration training, which repeatedly stimulated vision in their blind field. The amount of visual field recovery was quantified using Humphrey perimetry, and post training magnetic resonance imaging was used to assess the impact of training on OT shrinkage. RESULTS: OT LI was correlated with time since stroke: it was close to 0 (no measurable OT shrinkage) in subacute participants (6 months poststroke) exhibited LI >0, but with significant variability. Visual training did not systematically alter LI, but chronic patients with baseline LI≈0 (no OT shrinkage) exhibited greater visual field recovery than those with LI>0. CONCLUSIONS: Unilateral OT shrinkage becomes detectable with magnetic resonance imaging by ≈7 months poststroke, albeit with significant interindividual variability. Although visual restoration training did not alter the amount of degeneration already sustained, OT shrinkage appeared to serve as a biomarker of the potential for training-induced visual recovery in chronic cortically blind patients

Rehabilitating homonymous visual field deficits: white matter markers of recovery—stage 1 registered report

Damage to the primary visual cortex (V1) or its afferent white matter tracts results in loss of vision in the contralateral visual field that can present as homonymous visual field deficits. Recent evidence suggests that visual training in the blind field can partially reverse blindness at trained locations. However, the efficacy of visual training to improve vision is highly variable across subjects, and the reasons for this are poorly understood. It is likely that variance in residual functional or structural neural circuitry following the insult may underlie the variation among patients. Many patients with visual field deficits retain residual visual processing in their blind field, termed ‘blindsight’, despite a lack of awareness. Previous research indicates that an intact structural and functional connection between the dorsal lateral geniculate nucleus (dLGN) and the human extrastriate visual motion-processing area (hMT+) is necessary for blindsight to occur. We therefore predict that changes in this white matter pathway will underlie improvements in motion discrimination training. Twenty stroke survivors with unilateral, homonymous field defects from retro-geniculate brain lesions will complete 6 months of motion discrimination training at home. Visual training will involve performing two daily sessions of a motion discrimination task, at two non-overlapping locations in the blind field, at least 5 days per week. Motion discrimination and integration thresholds, Humphrey perimetry and structural and diffusion-weighted MRI will be collected pre- and post-training. Changes in fractional anisotropy will be analysed in two visual tracts: (i) between the ipsilesional dLGN and hMT+ and (ii) between the ipsilesional dLGN and V1. The (non-visual) tract between the ventral posterior lateral nucleus of the thalamus (VPL) and the primary somatosensory cortex (S1) will be analysed as a control. Tractographic changes will be compared to improvements in motion discrimination and Humphrey perimetry-derived metrics. We predict that (i) improved motion discrimination performance will be directly related to increased fractional anisotropy in the pathway between ipsilesional dLGN and hMT+ and (ii) improvements in Humphrey perimetry will be related to increased fractional anisotropy in the dLGN-V1 pathway. There should be no relationship between behavioural measures and changes in fractional anisotropy in the VPL-S1 pathway. This study has the potential to lead to greater understanding of the white matter microstructure of pathways underlying the behavioural outcomes resulting from visual training in retro-geniculate strokes. Understanding the neural mechanisms that underlie visual rehabilitation is fundamental to the development of more targeted and thus effective treatments for this underserved patient population

Rehabilitating homonymous visual field deficits: white matter markers of recovery—stage 2 registered report

Damage to the primary visual cortex or its afferent white matter tracts results in loss of vision in the contralateral visual field that can present as homonymous visual field deficits. Evidence suggests that visual training in the blind field can partially reverse blindness at trained locations. However, the efficacy of visual training is highly variable across participants, and the reasons for this are poorly understood. It is likely that variance in residual neural circuitry following the insult may underlie the variation among patients. Many stroke survivors with visual field deficits retain residual visual processing in their blind field despite a lack of awareness. Previous research indicates that intact structural and functional connections between the dorsal lateral geniculate nucleus and the human extrastriate visual motion-processing area hMT+ are necessary for blindsight to occur. We therefore hypothesized that changes in this white matter pathway may underlie improvements resulting from motion discrimination training. Eighteen stroke survivors with long-standing, unilateral, homonymous field defects from retro-geniculate brain lesions completed 6 months of visual training at home. This involved performing daily sessions of a motion discrimination task, at two non-overlapping locations in the blind field, at least 5 days per week. Motion discrimination and integration thresholds, Humphrey perimetry and structural and diffusion-weighted MRI were collected pre- and post-training. Changes in fractional anisotropy (FA) were analysed in visual tracts connecting the ipsilesional dorsal lateral geniculate nucleus and hMT+, and the ipsilesional dorsal lateral geniculate nucleus and primary visual cortex. The (non-visual) tract connecting the ventral posterior lateral nucleus of the thalamus and the primary somatosensory cortex was analysed as a control. Changes in white matter integrity were correlated with improvements in motion discrimination and Humphrey perimetry. We found that the magnitude of behavioural improvement was not directly related to changes in FA in the pathway between the dorsal lateral geniculate nucleus and hMT+ or dorsal lateral geniculate nucleus and primary visual cortex. Baseline FA in either tract also failed to predict improvements in training. However, an exploratory analysis showed a significant increase in FA in the distal part of the tract connecting the dorsal lateral geniculate nucleus and hMT+, suggesting that 6 months of visual training in chronic, retro-geniculate strokes may enhance white matter microstructural integrity of residual geniculo-extrastriate pathways

Improving sleep and learning in rehabilitation after stroke, part 2 (INSPIRES2): study protocol for a home-based randomised control trial of digital cognitive behavioural therapy (dCBT) for insomnia

Introduction Consolidation of motor skill learning, a key component of rehabilitation post-stroke, is known to be sleep dependent. However, disrupted sleep is highly prevalent after stroke and is often associated with poor motor recovery and quality of life. Previous research has shown that digital cognitive behavioural therapy (dCBT) for insomnia can be effective at improving sleep quality after stroke. Therefore, the aim of this trial is to evaluate the potential for sleep improvement using a dCBT programme, to improve rehabilitation outcomes after stroke. Methods and analysis We will conduct a parallel-arm randomised controlled trial of dCBT (Sleepio) versus treatment as usual among individuals following stroke affecting the upper limb. Up to 100 participants will be randomly allocated (2:1) into either the intervention (6–8 week dCBT) or control (continued treatment as usual) group. The primary outcome of the study will be change in insomnia symptoms pre to post intervention compared with treatment as usual. Secondary outcomes include improvement in overnight motor memory consolidation and sleep measures between intervention groups, correlations between changes in sleep behaviour and overnight motor memory consolidation in the dCBT group and changes in symptoms of depression and fatigue between the dCBT and control groups. Analysis of covariance models and correlations will be used to analyse data from the primary and secondary outcomes. Ethics and dissemination The study has received approval from the National Research Ethics Service (22/EM/0080), Health Research Authority (HRA) and Health and Care Research Wales (HCRW), IRAS ID: 306 291. The results of this trial will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate. Trial registration number NCT05511285

Improving sleep and learning in rehabilitation after stroke, part 2 (INSPIRES2): study protocol for a home-based randomised control trial of digital cognitive behavioural therapy (dCBT) for insomnia

INTRODUCTION: Consolidation of motor skill learning, a key component of rehabilitation post-stroke, is known to be sleep dependent. However, disrupted sleep is highly prevalent after stroke and is often associated with poor motor recovery and quality of life. Previous research has shown that digital cognitive behavioural therapy (dCBT) for insomnia can be effective at improving sleep quality after stroke. Therefore, the aim of this trial is to evaluate the potential for sleep improvement using a dCBT programme, to improve rehabilitation outcomes after stroke. METHODS AND ANALYSIS: We will conduct a parallel-arm randomised controlled trial of dCBT (Sleepio) versus treatment as usual among individuals following stroke affecting the upper limb. Up to 100 participants will be randomly allocated (2:1) into either the intervention (6–8 week dCBT) or control (continued treatment as usual) group. The primary outcome of the study will be change in insomnia symptoms pre to post intervention compared with treatment as usual. Secondary outcomes include improvement in overnight motor memory consolidation and sleep measures between intervention groups, correlations between changes in sleep behaviour and overnight motor memory consolidation in the dCBT group and changes in symptoms of depression and fatigue between the dCBT and control groups. Analysis of covariance models and correlations will be used to analyse data from the primary and secondary outcomes. ETHICS AND DISSEMINATION: The study has received approval from the National Research Ethics Service (22/EM/0080), Health Research Authority (HRA) and Health and Care Research Wales (HCRW), IRAS ID: 306 291. The results of this trial will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate. TRIAL REGISTRATION NUMBER: NCT05511285

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival