Vision-related quality of life after unilateral occipital stroke.

BACKGROUND/OBJECTIVES: Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision-related quality of life (VR-QoL) is impacted by time since stroke. SUBJECTS/METHODS: We conducted a retrospective meta-analysis of 95 occipital stroke patients (female/male = 26/69, 27-78 years old, 0.5-373.5 months poststroke) in whom VR-QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) and its 10-item neuro-ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24-2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR-QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis. RESULTS: Occipital stroke patients had significantly lower NEI-VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age. CONCLUSIONS: VR-QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR-QoL may change gradually over time, even without therapeutic intervention.

Training in Cortically Blinded Fields Appears to Confer Patient-Specific Benefit Against Retinal Thinning.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Limited restoration of contrast sensitivity with training after V1 damage in humans.

Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and motion direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute patients (<3 months post-V1-stroke) and 12 chronic patients (>6 months post-V1-stroke) were pre-tested, then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts as their performance improved. At baseline, more subacute than chronic participants could correctly discriminate the orientation of high-contrast Gabors in their blind field, but all failed to perform this task at lower contrasts, even when 10Hz flicker or motion direction were added. Training improved CS in a greater portion of subacute than chronic participants, but no-one attained normal CS, even when stimuli contained flicker or motion. We conclude that, unlike the near-complete training-induced restoration of high-contrast orientation and motion direction discrimination abilities, V1 damage in adulthood may severely limit the residual visual system's ability to regain normal CS. Our results support the notion that CS involves different neural substrates and computations than those required for orientation and direction discrimination in V1-damaged visual systems.Significance statement Stroke-induced V1 damage in adult humans induces a rapid and severe impairment of contrast sensitivity for orientation and motion direction discrimination in the affected hemifield, although discrimination of high-contrast stimuli can persist for several months. Adaptive training with Gabor patches of progressively lower contrasts improves contrast sensitivity for both orientation and motion discriminations in the blind-field of subacute (<3 months post-stroke) and chronic (>6 months post-stroke) participants; however, it fails to restore normal contrast sensitivity. Nonetheless, more subacute than chronic stroke participants benefit from such training, particularly when discriminating the orientation of static, non-flickering targets. Thus, contrast sensitivity appears critically dependent on processing within V1, with perceptual training displaying limited potential to fully restore it after V1 damage.

Poster Session: Evidence for preserved conscious orientation discrimination in perimetrically-blind fields early after V1-damage.

Cortically-blind (CB) patients with stroke damage to the primary visual cortex (V1) lose conscious vision but many exhibit blindsight - the ability to unconsciously detect or discriminate moving or flickering targets inside their blind-fields. However, the prevalence of conscious visual abilities in CB is less clear. Having developed a new method to assess vision inside perimetrically-defined blind fields, we found that >50% of subacute CB patients (<6 months post-stroke) can consciously discriminate global motion inside their blind field. Here, we asked if they can also discriminate orientation of static targets, which do not typically elicit blindsight. In 10 subacute patients, we mapped their intact and blind hemifields using static, non-flickering, 1cpd Gabors across a wide range of luminance contrasts. Blind-field locations were labeled "preserved" if performance was >72.5% correct. Considering overall performance, only 1 participant had preserved static orientation perception in the blind-field. However, this increased to 4 participants when only considering performance at high contrasts (>50%), all of whom reported awareness of stimuli. Thus, early after V1 damage, conscious percepts for oriented, high-contrast, static targets can remain inside CB fields, similar in incidence to global motion discriminations. We are now testing additional patients to assess if these abilities persist into the chronic period and to detail their underlying neural substrates.

Contrast sensitivity: a fundamental limit to vision restoration after V1 damage.

Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute (<3 months post-V1-stroke) and 12 chronic (>6 months post-V1-stroke) participants were pre-tested, then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts. At baseline, more subacute than chronic participants could correctly discriminate the orientation of high-contrast Gabors in their blind field, but all failed to perform this task at lower contrasts, even when 10Hz flicker or motion direction were added. Training improved CS in a greater portion of subacute than chronic participants, but no-one attained normal CS, even when stimuli contained flicker or motion. We conclude that, unlike the near-complete training-induced restoration of high-contrast orientation and direction discrimination, there is limited capacity for restoring CS after V1 damage in adulthood. Our results suggest that CS involves different neural substrates and computations than those required for orientation and direction discrimination in V1-damaged visual systems.

GABA and Glutamate in hMT+ Link to Individual Differences in Residual Visual Function After Occipital Stroke.

BACKGROUND: Damage to the primary visual cortex following an occipital stroke causes loss of conscious vision in the contralateral hemifield. Yet, some patients retain the ability to detect moving visual stimuli within their blind field. The present study asked whether such individual differences in blind field perception following loss of primary visual cortex could be explained by the concentration of neurotransmitters γ-aminobutyric acid (GABA) and glutamate or activity of the visual motion processing, human middle temporal complex (hMT+). METHODS: We used magnetic resonance imaging in 19 patients with chronic occipital stroke to measure the concentration of neurotransmitters GABA and glutamate (proton magnetic resonance spectroscopy) and functional activity in hMT+ (functional magnetic resonance imaging). We also tested each participant on a 2-interval forced choice detection task using high-contrast, moving Gabor patches. We then measured and assessed the strength of relationships between participants' residual vision in their blind field and in vivo neurotransmitter concentrations, as well as visually evoked functional magnetic resonance imaging activity in their hMT+. Levels of GABA and glutamate were also measured in a sensorimotor region, which served as a control. RESULTS: Magnetic resonance spectroscopy-derived GABA and glutamate concentrations in hMT+ (but not sensorimotor cortex) strongly predicted blind-field visual detection abilities. Performance was inversely related to levels of both inhibitory and excitatory neurotransmitters in hMT+ but, surprisingly, did not correlate with visually evoked blood oxygenation level-dependent signal change in this motion-sensitive region. CONCLUSIONS: Levels of GABA and glutamate in hMT+ appear to provide superior information about motion detection capabilities inside perimetrically defined blind fields compared to blood oxygenation level-dependent signal changes-in essence, serving as biomarkers for the quality of residual visual processing in the blind-field. Whether they also reflect a potential for successful rehabilitation of visual function remains to be determined.

Altered contractility, Ca2+ transients, and cell morphology seen in a patient-specific iPSC-CM model of Ebstein's anomaly with left ventricular noncompaction.

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the "structural constituent of muscle" pathway was suppressed, whereas the "ER lumen" pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation.NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein's anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling.

Training in cortically-blind fields confers patient-specific benefit against retinal thinning after occipital stroke.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of trans-synaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness, and asked if perceptual training in the intact or blind field impacts its progression. Methods: We performed a meta-analysis of optical coherence tomography (OCT) data in 48 participants with unilateral V1 stroke and homonymous visual defects, who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layers (GCL-IPL), and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ~6 months of daily motion discrimination training in the intact- or blind-field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results: Pre-training, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact-field exhibited increased LIGCL-IPL. Those trained in their blind-field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training, but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Perceptual restoration fails to recover unconscious processing for smooth eye movements after occipital stroke.

The visual pathways that guide actions do not necessarily mediate conscious perception. Patients with primary visual cortex (V1) damage lose conscious perception but often retain unconscious abilities (e.g. blindsight). Here, we asked if saccade accuracy and post-saccadic following responses (PFRs) that automatically track target motion upon saccade landing are retained when conscious perception is lost. We contrasted these behaviors in the blind and intact fields of 11 chronic V1-stroke patients, and in 8 visually intact controls. Saccade accuracy was relatively normal in all cases. Stroke patients also had normal PFR in their intact fields, but no PFR in their blind fields. Thus, V1 damage did not spare the unconscious visual processing necessary for automatic, post-saccadic smooth eye movements. Importantly, visual training that recovered motion perception in the blind field did not restore the PFR, suggesting a clear dissociation between pathways mediating perceptual restoration and automatic actions in the V1-damaged visual system.

Benefits of Endogenous Spatial Attention During Visual Double-Training in Cortically-Blinded Fields.

Recovery of visual discrimination thresholds inside cortically-blinded (CB) fields is most commonly attained at a single, trained location at a time, with iterative progress deeper into the blind field as performance improves over several months. As such, training is slow, inefficient, burdensome, and often frustrating for patients. Here, we investigated whether double-location training, coupled with a covert spatial-attention (SA) pre-cue, could improve the efficiency of training. Nine CB participants completed a randomized, training assignment with either a spatial attention or neutral pre-cue. All trained for a similar length of time on a fine direction discrimination task at two blind field locations simultaneously. Training stimuli and tasks for both cohorts were identical, save for the presence of a central pre-cue, to manipulate endogenous (voluntary) SA, or a Neutral pre-cue. Participants in the SA training cohort demonstrated marked improvements in direction discrimination thresholds, albeit not to normal/intact-field levels; participants in the Neutral training cohort remained impaired. Thus, double-training within cortically blind fields, when coupled with SA pre-cues can significantly improve direction discrimination thresholds at two locations simultaneously, offering a new method to improve performance and reduce the training burden for CB patients. Double-training without SA pre-cues revealed a hitherto unrecognized limitation of cortically-blind visual systems' ability to improve while processing two stimuli simultaneously. These data could potentially explain why exposure to the typically complex visual environments encountered in everyday life is insufficient to induce visual recovery in CB patients. It is hoped that these new insights will direct both research and therapeutic developments toward methods that can attain better, faster recovery of vision in CB fields.

Spared perilesional V1 activity underlies training-induced recovery of luminance detection sensitivity in cortically-blind patients.

Damage to the primary visual cortex (V1) causes homonymous visual-field loss long considered intractable. Multiple studies now show that perceptual training can restore visual functions in chronic cortically-induced blindness (CB). A popular hypothesis is that training can harness residual visual functions by recruiting intact extrageniculostriate pathways. Training may also induce plastic changes within spared regions of the damaged V1. Here, we link changes in luminance detection sensitivity with retinotopic fMRI activity before and after visual discrimination training in eleven patients with chronic, stroke-induced CB. We show that spared V1 activity representing perimetrically-blind locations prior to training predicts the amount of training-induced recovery of luminance detection sensitivity. Additionally, training results in an enlargement of population receptive fields in perilesional V1, which increases blind-field coverage and may support further recovery with subsequent training. These findings uncover fundamental changes in perilesional V1 cortex underlying training-induced restoration of conscious luminance detection sensitivity in CB.

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) while chronic 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.

Efficacy of Visual Retraining in the Hemianopic Field after Stroke: Results of a Randomized Clinical Trial.

PURPOSE: To evaluate the efficacy of motion discrimination training as a potential therapy for stroke-induced hemianopic visual field defects. DESIGN: Clinical trial. PARTICIPANTS: Forty-eight patients with stroke-induced homonymous hemianopia (HH) were randomized into 2 training arms: intervention and control. Patients were between 21 and 75 years of age and showed no ocular issues at presentation. METHODS: Patients were trained on a motion discrimination task previously evidenced to reduce visual field deficits, but not in a randomized clinical trial. Patients were randomized with equal allocation to receive training in either their sighted or deficit visual fields. Training was performed at home for 6 months, consisting of repeated visual discriminations at a single location for 20 to 30 minutes daily. Study staff and patients were masked to training type. Testing before and after training was identical, consisting of Humphrey visual fields (Carl Zeiss Meditech), macular integrity assessment perimetry, OCT, motion discrimination performance, and visual quality-of-life questionnaires. MAIN OUTCOME MEASURES: Primary outcome measures were changes in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer in both eyes. RESULTS: Mean PMDs improved over 6 months in deficit-trained patients (mean change in the right eye, 0.58 dB; 95% confidence interval, 0.07-1.08 dB; mean change in the left eye 0.84 dB; 95% confidence interval, 0.22-1.47 dB). No improvement was observed in sighted-trained patients (mean change in the right eye, 0.12 dB; 95% confidence interval, -0.38 to 0.62 dB; mean change in the left eye, 0.10 dB; 95% confidence interval, -0.52 to 0.72 dB). However, no significant differences were found between the alternative training methods (right eye, P = 0.19; left eye, P = 0.10). CONCLUSIONS: To date, no widely accepted therapy is available to treat HH. This study evaluated the efficacy of a promising potential treatment, visual perceptual training. We failed to find a difference between treatment training within the deficit field and control training within the sighted field when performed in a home environment.

Contractility of Induced Pluripotent Stem Cell-Cardiomyocytes With an MYH6 Head Domain Variant Associated With Hypoplastic Left Heart Syndrome.

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease; however, its etiology remains largely unknown. We previously demonstrated that genetic variants in the MYH6 gene are significantly associated with HLHS. Additionally, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from an HLHS-affected family trio (affected parent, unaffected parent, affected proband) carrying an MYH6-R443P head domain variant demonstrated dysmorphic sarcomere structure and increased compensatory MYH7 expression. Analysis of iPSC-CMs derived from the HLHS trio revealed that only beta myosin heavy chain expression was observed in CMs carrying the MYH6-R443P variant after differentiation day 15 (D15). Functional assessments performed between D20-D23 revealed that MYH6-R443P variant CMs contracted more slowly (40 ± 2 vs. 47 ± 2 contractions/min, P < 0.05), shortened less (5.6 ± 0.5 vs. 8.1 ± 0.7% of cell length, P < 0.05), and exhibited slower shortening rates (19.9 ± 1.7 vs. 28.1 ± 2.5 µm/s, P < 0.05) and relaxation rates (11.0 ± 0.9 vs. 19.7 ± 2.0 µm/s, P < 0.05). Treatment with isoproterenol had no effect on iPSC-CM mechanics. Using CRISPR/Cas9 gene editing technology, introduction of the R443P variant into the unaffected parent's iPSCs recapitulated the phenotype of the proband's iPSC-CMs, and conversely, correction of the R443P variant in the proband's iPSCs rescued the cardiomyogenic differentiation, sarcomere organization, slower contraction (P < 0.05) and decreased velocity phenotypes (P < 0.0001). This is the first report to identify that cardiac tissues from HLHS patients with MYH6 variants can exhibit sarcomere disorganization in atrial but not ventricular tissues. This new discovery was not unexpected, since MYH6 is expressed predominantly in the postnatal atria in humans. These findings demonstrate the feasibility of employing patient-derived iPSC-CMs, in combination with patient cardiac tissues, to gain mechanistic insight into how genetic variants can lead to HLHS. Results from this study suggest that decreased contractility of CMs due to sarcomere disorganization in the atria may effect hemodynamic changes preventing development of a normal left ventricle.

Effect of a Collaboration Between a Health Plan, Oncology Practice, and Comprehensive Genomic Profiling Company from the Payer Perspective.

BACKGROUND: Comprehensive genomic profiling (CGP) is a next-generation sequencing-based methodology that detects 4 classes of genomic alterations, as well as gene signature biomarkers such as microsatellite instability and tumor mutational burden. In the context of precision oncology, CGP can help to direct treatment to genomically matched therapies. OBJECTIVE: To describe the results of a 3-year observational analysis of patients undergoing testing with CGP assays (either FoundationOne or FoundationOne Heme) at a community oncology practice after a regional health plan implemented a medical policy that enabled coverage of CGP. METHODS: A retrospective analysis of medical records was completed at the oncology practice from November 2013 to January 2017; this date range was chosen to coincide with the regional health plan's medical policy implementation of CGP. The medical policy provided coverage of CGP for patients with advanced solid and hematologic cancers. A medical record review assessed all previous and current molecular test results, matched therapy or clinical trial enrollment, and clinical outcomes (clinical benefit or disease progression). The potential cost diversion, from payer to study sponsor, for patients who enrolled in clinical trials was explored. RESULTS: There were 96 patients in the community oncology practice who received CGP over the 3-year period, 86 of whom had clinically relevant genomic alterations. Of the 86, 15 patients were treated with genomically matched therapy, and 6 patients enrolled in clinical trials based on CGP results. In a subset of 32 patients who previously underwent conventional testing, most (84%) had clinically relevant genomic alterations detected by CGP that conventional testing did not identify, and a portion of these patients subsequently received treatment based on the CGP results. In the separate cost diversion analysis of 20 patients who enrolled in phase 1 clinical trials, an estimated $25,000 per-patient cost-benefit may have been accrued to the payer. CONCLUSIONS: This observational analysis characterized the use of CGP in a large community oncology practice among a group of patients insured by a regional health plan. Clinical trial enrollment was facilitated by CGP use in the community setting and may have contributed to cost diversion from the payer to study sponsors. DISCLOSURES: No separate study-related funding was provided by or to Priority Health, Foundation Medicine, and Cancer and Hematology Centers of West Michigan. Data analysis by Reitsma was conducted as part of an internship funded by Priority Health. Reitsma and Fox are employed by Priority Health. Anhorn, Vanden Borre, Cavanaugh, Chudnovsky, and Erlich are employed by Foundation Medicine.

Feature-based attention potentiates recovery of fine direction discrimination in cortically blind patients.

Training chronic, cortically-blind (CB) patients on a coarse [left-right] direction discrimination and integration (CDDI) task recovers performance on this task at trained, blind field locations. However, fine direction difference (FDD) thresholds remain elevated at these locations, limiting the usefulness of recovered vision in daily life. Here, we asked if this FDD impairment can be overcome by training CB subjects with endogenous, feature-based attention (FBA) cues. Ten CB subjects were recruited and trained on CDDI and FDD with an FBA cue or FDD with a neutral cue. After completion of each training protocol, FDD thresholds were re-measured with both neutral and FBA cues at trained, blind-field locations and at corresponding, intact-field locations. In intact portions of the visual field, FDD thresholds were lower when tested with FBA than neutral cues. Training subjects in the blind field on the CDDI task improved FDD performance to the point that a threshold could be measured, but these locations remained impaired relative to the intact field. FDD training with neutral cues resulted in better blind field FDD thresholds than CDDI training, but thresholds remained impaired relative to intact field levels, regardless of testing cue condition. Importantly, training FDD in the blind field with FBA lowered FDD thresholds relative to CDDI training, and allowed the blind field to reach thresholds similar to the intact field, even when FBA trained subjects were tested with a neutral rather than FBA cue. Finally, FDD training appeared to also recover normal integration thresholds at trained, blind-field locations, providing an interesting double dissociation with respect to CDDI training. In summary, mechanisms governing FBA appear to function normally in both intact and impaired regions of the visual field following V1 damage. Our results mark the first time that FDD thresholds in CB fields have been seen to reach intact field levels of performance. Moreover, FBA can be leveraged during visual training to recover normal, fine direction discrimination and integration performance at trained, blind-field locations, potentiating visual recovery of more complex and precise aspects of motion perception in cortically-blinded fields.

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery.

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness.

OBJECTIVE: To assess if visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement. METHODS: 24-2 and 10-2 Humphrey visual fields were analyzed for 17 chronic cortically blind stroke patients prior to and following visual discrimination training, as well as in 5 untrained, cortically blind controls. Trained patients practiced direction discrimination, orientation discrimination, or both, at nonoverlapping, blind field locations. All pretraining and posttraining discrimination performance and Humphrey fields were collected with online eye tracking, ensuring gaze-contingent stimulus presentation. RESULTS: Trained patients recovered ∼108 degrees2 of vision on average, while untrained patients spontaneously improved over an area of ∼16 degrees2. Improvement was not affected by patient age, time since lesion, size of initial deficit, or training type, but was proportional to the amount of training performed. Untrained patients counterbalanced their improvements with worsening of sensitivity over ∼9 degrees2 of their visual field. Worsening was minimal in trained patients. Finally, although discrimination performance improved at all trained locations, changes in Humphrey sensitivity occurred both within trained regions and beyond, extending over a larger area along the blind field border. CONCLUSIONS: In adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field. Our findings underscore a critical need for future studies to measure the effects of vision restoration approaches on perimetry in larger cohorts of patients.

Visual recovery in cortical blindness is limited by high internal noise.

Damage to the primary visual cortex typically causes cortical blindness (CB) in the hemifield contralateral to the damaged hemisphere. Recent evidence indicates that visual training can partially reverse CB at trained locations. Whereas training induces near-complete recovery of coarse direction and orientation discriminations, deficits in fine motion processing remain. Here, we systematically disentangle components of the perceptual inefficiencies present in CB fields before and after coarse direction discrimination training. In seven human CB subjects, we measured threshold versus noise functions before and after coarse direction discrimination training in the blind field and at corresponding intact field locations. Threshold versus noise functions were analyzed within the framework of the linear amplifier model and the perceptual template model. Linear amplifier model analysis identified internal noise as a key factor differentiating motion processing across the tested areas, with visual training reducing internal noise in the blind field. Differences in internal noise also explained residual perceptual deficits at retrained locations. These findings were confirmed with perceptual template model analysis, which further revealed that the major residual deficits between retrained and intact field locations could be explained by differences in internal additive noise. There were no significant differences in multiplicative noise or the ability to process external noise. Together, these results highlight the critical role of altered internal noise processing in mediating training-induced visual recovery in CB fields, and may explain residual perceptual deficits relative to intact regions of the visual field.