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1.  Visual cortex organization in a macaque monkey with macular degeneration 
The European journal of neuroscience  2013;38(10):10.1111/ejn.12349.
The visual field is retinotopically represented in early visual areas. It has been suggested that when adult primary visual cortex (V1) is deprived of normal retinal input it is capable of large-scale reorganization, with neurons inside the lesion projection zone (LPZ) being visually driven by inputs from intact retinal regions. Early functional magnetic resonance imaging (fMRI) studies in humans with macular degeneration (MD) report > 1 cm spread of activity inside the LPZ border, whereas recent results report no shift of the LPZ border. Here, we used fMRI population receptive field measurements to study, for the first time, the visual cortex organization of one macaque monkey with MD and to compare it with normal controls. Our results showed that the border of the V1 LPZ remained stable, suggesting that the deafferented area V1 zone of the MD animal has limited capacity for reorganization. Interestingly the pRF size of non-deafferented V1 voxels increased slightly (∼20% on average), although this effect appears weaker than that in previous single-unit recording reports. Area V2 also showed limited reorganization. Remarkably, area V5/MT of the MD animal showed extensive activation compared to controls stimulated over the part of the visual field that was spared in the MD animal. Furthermore, population receptive field size distributions differed markedly in area V5/MT of the MD animal. Taken together, these results suggest that V5/MT has a higher potential for reorganization after MD than earlier visual cortex.
PMCID: PMC3834013  PMID: 24033706
Plasticity; Reorganization; fMRI; V1; MT
2.  Spectral Domain Optical Coherence Tomography in Mouse Models of Retinal Degeneration 
Spectral domain optical coherence tomography (SD-OCT) allows cross-sectional visualization of retinal structures in vivo. Here, we report the efficacy of a commercially available SD-OCT device to study mouse models of retinal degeneration.
C57BL/6 and BALB/c wild type mice and three different mouse models of hereditary retinal degeneration (Rho-/-, rd1, RPE65-/-) were investigated using confocal scanning laser ophthalmoscopy (cSLO) for en face visualization and SD-OCT for cross-sectional imaging of retinal structures. Histology was performed to correlate structural findings in SD-OCT with light microscopic data.
In C57BL/6 and BALB/c mice, cSLO and SD-OCT imaging provided structural details of frequently used control animals (central retinal thickness, CRTC57BL/6 = 237±2μm and CRTBALB/c = 211±10μm). RPE65-/- mice at 11 months of age showed a significant reduction of retinal thickness (CRTRPE65 = 193±2μm) with thinning of the outer nuclear layer. Rho-/- mice at P28 demonstrated degenerative changes mainly in the outer retinal layers (CRTRho = 193±2μm). Examining rd1 animals before and after the onset of retinal degeneration allowed to monitor disease progression (CRTrd1 P11 = 246±4μm, CRTrd1 P28 = 143±4μm). Correlation of CRT assessed by histology and SD-OCT was high (r2 = 0.897).
We demonstrated cross sectional visualization of retinal structures in wild type mice and mouse models for retinal degeneration in vivo using a commercially available SD-OCT device. This method will help to reduce numbers of animals needed per study by allowing longitudinal study designs and facilitate characterization of disease dynamics and evaluation of putative therapeutic effects following experimental interventions.
PMCID: PMC2800101  PMID: 19661229
optical coherence tomography; retinal degeneration; imaging; mouse models
4.  Pupillary Light Reaction during High Altitude Exposure 
PLoS ONE  2014;9(2):e87889.
This study aimed to quantify the pupillary light reaction during high altitude exposure using the state of the art Compact Integrated Pupillograph (CIP) and to investigate a potential correlation of altered pupil reaction with severity of acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study.
Parameters of pupil dynamics (initial diameter, amplitude, relative amplitude, latency, constriction velocity) were quantified in 14 healthy volunteers at baseline (341 m) and high altitude (4559 m) over several days using the CIP. Scores of AMS, peripheral oxygen saturation and heart rate were assessed for respective correlations with pupil dynamics. For statistical analysis JMP was used and data are shown in terms of intra-individual normalized values (value during exposure/value at baseline) and the 95% confidence interval for each time point.
During high altitude exposure the initial diameter size was significantly reduced (p<0.05). In contrast, the amplitude, the relative amplitude and the contraction velocity of the light reaction were significantly increased (p<0.05) on all days measured at high altitude. The latency did not show any significant differences at high altitude compared to baseline recordings. Changes in pupil parameters did not correlate with scores of AMS.
Key parameters of the pupillary light reaction are significantly altered at high altitude. We hypothesize that high altitude hypoxia itself as well as known side effects of high altitude exposure such as fatigue or exhaustion after ascent may account for an altered pupillogram. Interestingly, none of these changes are related to AMS.
PMCID: PMC3913681  PMID: 24503770
5.  Missing correlation of retinal vessel diameter with high-altitude headache 
The most common altitude-related symptom, high-altitude headache (HAH), has recently been suggested to originate from restricted cerebral venous drainage in the presence of increased inflow caused by hypoxia. In support of this novel hypothesis, retinal venous distension was shown to correlate with the degree of HAH. We quantified for the first time retinal vessel diameter changes at 4559 m using infrared fundus images obtained from a state of the art Spectralis™ HRA+OCT with a semiautomatic VesselMap 1® software. High-altitude exposure resulted in altered arterial and venous diameter changes at high altitude, however, independent of headache burden.
PMCID: PMC4207505  PMID: 25356382
6.  Successful Subretinal Delivery and Monitoring of MicroBeads in Mice 
PLoS ONE  2013;8(1):e55173.
To monitor viability of implanted genetically engineered and microencapsulated human stem cells (MicroBeads) in the mouse eye, and to study the impact of the beads and/or xenogenic cells on retinal integrity.
Methodology/Principal Findings
MicroBeads were implanted into the subretinal space of SV126 wild type mice using an ab externo approach. Viability of microencapsulated cells was monitored by noninvasive retinal imaging (Spectralis™ HRA+OCT). Retinal integrity was also assessed with retinal imaging and upon the end of the study by light and electron microscopy. The implanted GFP-marked cells encapsulated in subretinal MicroBeads remained viable over a period of up to 4 months. Retinal integrity and viability appeared unaltered apart from the focal damage due to the surgical implantation, GFAP upregulation, and opsin mistargeting in the immediate surrounding tissue.
The accessibility for routine surgery and its immune privileged state make the eye an ideal target for release system implants for therapeutic substances, including neurotrophic and anti-angiogenic compounds or protein based biosimilars. Microencapsulated human stem cells (MicroBeads) promise to overcome limitations inherent with single factor release systems, as they are able to produce physiologic combinations of bioactive compounds.
PMCID: PMC3557268  PMID: 23383096
7.  Correction: Effects of Combined Ketamine/Xylazine Anesthesia on Light Induced Retinal Degeneration in Rats 
PLoS ONE  2012;7(8):10.1371/annotation/d52a610e-6a56-4158-90bf-45e37f053567.
PMCID: PMC3414543
8.  Structural and Functional Changes of the Human Macula during Acute Exposure to High Altitude 
PLoS ONE  2012;7(4):e36155.
This study aimed to quantify structural and functional changes at the macula during acute exposure to high altitude and to assess their structure/function relationship. This work is related to the Tuebingen High Altitude Ophthalmology (THAO) study.
Methodology/Principal Findings
Spectral domain optical coherence tomography and microperimetry were used to quantify changes of central retinal structure and function in 14 healthy subjects during acute exposure to high altitude (4559 m). High-resolution volume scans and fundus-controlled microperimetry of the posterior pole were performed in addition to best-corrected visual acuity (BCVA) measurements and assessment of acute mountain sickness. Analysis of measurements at altitude vs. baseline revealed increased total retinal thickness (TRT) in all four outer ETDRS grid subfields during acute altitude exposure (TRTouter = 2.80±1.00 μm; mean change±95%CI). This change was inverted towards the inner four subfields (TRTinner = −1.89±0.97 μm) with significant reduction of TRT in the fovea (TRTfoveal = −6.62±0.90 μm) at altitude. BCVA revealed no significant difference compared to baseline (0.06±0.08 logMAR). Microperimetry showed stable mean sensitivity in all but the foveal subfield (MSfoveal = −1.12±0.68 dB). At baseline recordings before and >2 weeks after high altitude exposure, all subjects showed equal levels with no sign of persisting structural or functional sequels.
During acute exposure to high altitude central retinal thickness is subject to minor, yet statistically significant changes. These alterations describe a function of eccentricity with an increase in regions with relatively higher retinal nerve fiber content and vascular arcades. However, these changes did not correlate with measures of central retinal function or acute mountain sickness. For the first time a quantitative approach has been used to assess these changes during acute, non-acclimatized high altitude exposure.
PMCID: PMC3340355  PMID: 22558365
9.  Effects of Combined Ketamine/Xylazine Anesthesia on Light Induced Retinal Degeneration in Rats 
PLoS ONE  2012;7(4):e35687.
To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats.
Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls.
Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p<0.01) and significant reduction one week (p<0.01) after light damage. In contrast, ketamine-xylazine pre-treated animals showed no significant alteration of total retinal or ONL thickness at either time point (p>0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03) were observed in non-treated vs. ketamine-xylazine treated animals.
Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage.
PMCID: PMC3338443  PMID: 22558200
10.  Quantification of Optic Disc Edema during Exposure to High Altitude Shows No Correlation to Acute Mountain Sickness 
PLoS ONE  2011;6(11):e27022.
The study aimed to quantify changes of the optic nerve head (ONH) during exposure to high altitude and to assess a correlation with acute mountain sickness (AMS). This work is related to the Tuebingen High Altitude Ophthalmology (THAO) study.
Methodology/Principal Findings
A confocal scanning laser ophthalmoscope (cSLO, Heidelberg Retina Tomograph, HRT3®) was used to quantify changes at the ONH in 18 healthy participants before, during and after rapid ascent to high altitude (4559 m). Slitlamp biomicroscopy was used for clinical optic disc evaluation; AMS was assessed with Lake Louise (LL) and AMS-cerebral (AMS-c) scores; oxygen saturation (SpO2) and heart rate (HR) were monitored. These parameters were used to correlate with changes at the ONH. After the first night spent at high altitude, incidence of AMS was 55% and presence of clinical optic disc edema (ODE) 79%. Key stereometric parameters of the HRT3® used to describe ODE (mean retinal nerve fiber layer [RNFL] thickness, RNFL cross sectional area, optic disc rim volume and maximum contour elevation) changed significantly at high altitude compared to baseline (p<0.05) and were consistent with clinically described ODE. All changes were reversible in all participants after descent. There was no significant correlation between parameters of ODE and AMS, SpO2 or HR.
Exposure to high altitude leads to reversible ODE in the majority of healthy subjects. However, these changes did not correlate with AMS or basic physiologic parameters such as SpO2 and HR. For the first time, a quantitative approach has been used to assess these changes during acute, non-acclimatized high altitude exposure. In conclusion, ODE presents a reaction of the body to high altitude exposure unrelated to AMS.
PMCID: PMC3206056  PMID: 22069483
11.  Noninvasive, In Vivo Assessment of Mouse Retinal Structure Using Optical Coherence Tomography 
PLoS ONE  2009;4(10):e7507.
Optical coherence tomography (OCT) is a novel method of retinal in vivo imaging. In this study, we assessed the potential of OCT to yield histology-analogue sections in mouse models of retinal degeneration.
Methodology/Principal Findings
We achieved to adapt a commercial 3rd generation OCT system to obtain and quantify high-resolution morphological sections of the mouse retina which so far required in vitro histology. OCT and histology were compared in models with developmental defects, light damage, and inherited retinal degenerations. In conditional knockout mice deficient in retinal retinoblastoma protein Rb, the gradient of Cre expression from center to periphery, leading to a gradual reduction of retinal thickness, was clearly visible and well topographically quantifiable. In Nrl knockout mice, the layer involvement in the formation of rosette-like structures was similarly clear as in histology. OCT examination of focal light damage, well demarcated by the autofluorescence pattern, revealed a practically complete loss of photoreceptors with preservation of inner retinal layers, but also more subtle changes like edema formation. In Crb1 knockout mice (a model for Leber's congenital amaurosis), retinal vessels slipping through the outer nuclear layer towards the retinal pigment epithelium (RPE) due to the lack of adhesion in the subapical region of the photoreceptor inner segments could be well identified.
We found that with the OCT we were able to detect and analyze a wide range of mouse retinal pathology, and the results compared well to histological sections. In addition, the technique allows to follow individual animals over time, thereby reducing the numbers of study animals needed, and to assess dynamic processes like edema formation. The results clearly indicate that OCT has the potential to revolutionize the future design of respective short- and long-term studies, as well as the preclinical assessment of therapeutic strategies.
PMCID: PMC2759518  PMID: 19838301

Results 1-11 (11)