Funktionelle Anwendungen der optischen Kohärenztomografie

Funktionelle Anwendungen der Optischen Kohärenztomografie (OCT) in der Ophthalmologie bilden einen Forschungsschwerpunkt der AG Hüttmann. Am Institut selbst und den mit der AG Hüttmann kooperierenden Firmen Heidelberg Engineering GmbH, Thorlabs GmbH und Optomedical Technologies GmbH, welche OCT-Technologien unseres Institutes kommerzialisiert haben, wird modernste OCT-Technologie entwickelt, die eine sehr schnelle tomographische Bildgebung der menschlichen Retina ermöglicht.

Für eine funktionelle Bildgebung werden kleinste Veränderungen des Brechungsindex oder Bewegungen im Nanometerbereich visualisiert. Realisiert wird dies durch eine phasensensitive Auswertung der Messdaten, bei der nicht nur die Intensitäten, sondern auch die Phasen der komplexen OCT-Daten ausgewertet werden.

Visualisierung der Photokoagulation

Ein Anwendungsbeispiel der funktionellen OCT ist die Beobachtung der während der Photokoagulation stattfindenden Prozesse. Insbesondere die thermische Ausdehnung des Gewebes und die anschließend stattfindende Denaturierung lassen sich mit wenigen Millisekunden Zeitauflösung genau verfolgen. Dies ermöglicht einen einzigartigen Zugang zum Verständnis der Photokoagulation und wird möglicherweise zu einer Optimierung oder sogar Echtzeit-Steuerung der Behandlung beitragen.

Tomografische Darstellung der thermischen Ausdehnung einer Retina während der Photokoagulation.
En-face-Projektion der thermischen Ausdehnung einer Retina während der Photokoagulation.

Analyse der Pulsation von retinalen Gefäßen

Durch Einsatz der extrem schnellen Holoskopie, die von der AG Hüttmann in Kooperation mit der Thorlabs GmbH entwickelt wurde, lassen sich ganze 3D-Volumen der Retina phasenstarr aufzeichnen. Dies ermöglicht beispielsweise eine Visualisierung der Bewegung von retinalen Blutgefäßen und dem umliegenden Gewebe beim Auftreffen der durch den Herzschlag ausgelösten Pulswelle. Durch eine Messung der Pulswellengeschwindigkeit können biomechanische Parameter des Gefäßnetzwerks nicht-invasiv bestimmt werden.

Pulsation von zwei Gefäßen in der menschlichen Retina. Man erkennt, wie die Pulswelle zuerst die Arterie (rechts) und anschließend die Vene (links) durchläuft. Dabei nimmt die Dicke der Retina lokal um 1 bis 2 Mikrometer zu; das ist eine Änderung um weniger als 1 Prozent. Obwohl die Effekte so klein sind, können wir sie mit hoher Genauigkeit messen.

Messung der Reaktion von Photorezeptoren auf Licht

Aber auch noch wesentlich kleinere Veränderungen lassen sich mit Hilfe der phasensensitiven Holoskopie detektieren. Im Jahr 2015 ist es uns weltweit zum allerersten Mal gelungen, den Sehprozess in der Retina eines lebenden Menschen räumlich aufgelöst sichtbar zu machen. In der klassischen OCT verhindern Abbildungsfehler des Auges, dass einzelne Photorezeptoren dargestellt werden können. Durch eine numerische Aberrationskorrektur können in unseren Aufnahmen die Abbildungsfehler des Auges jedoch nachträglich kompensiert werden, so dass einzelne Photorezeptoren auflösbar werden. Kombiniert mit einer phasensensitiven Auswertung der komplexen OCT-Daten ermöglicht dies, die Reaktion einzelner Photorezeptoren auf einfallendes Licht direkt zu visualisieren

Reaktion der Photorezeptoren in einer menschlichen Retina auf zwei unterschiedliche Muster, die in das Auge eines Probanden projiziert wurden.

Publikationen

2018

  • Hendrik Spahr and Clara Pfäffle and Peter Koch and Helge Sudkamp and Gereon Hüttmann and Dierck Hillmann: Interferometric detection of 3D motion using computational subapertures in optical coherence tomography. Opt. Express, no. 26, pp. 18803-18816, OSA, Jul, 2018
    BibTeX Link Link
    @article{Spahr:18,
    author = {Hendrik Spahr, Clara Pfäffle, Peter Koch, Helge Sudkamp, Gereon Hüttmann und Dierck Hillmann},
    journal = {Opt. Express},
    keywords = {Funktion, Fullfield},
    number = {15},
    pages = {18803--18816},
    publisher = {OSA},
    title = {Interferometric detection of 3D motion using computational subapertures in optical coherence tomography},
    volume = {26},
    month = {Jul},
    year = {2018},
    url = {http://www.opticsexpress.org/abstract.cfm?URI=oe-26-15-18803},
    doi = {10.1364/OE.26.018803},
    abstract = {Doppler optical coherence tomography (OCT) quantifies axial motion with high precision, whereas lateral motion cannot be detected by a mere evaluation of phase changes. This problem was solved by the introduction of three-beam Doppler OCT, which, however, entails a high experimental effort. Here, we present the numerical analogue to this experimental approach. Phase-stable complex-valued OCT datasets, recorded with full-field swept-source OCT, are filtered in the Fourier domain to limit imaging to different computational subapertures. These are used to calculate all three components of the motion vector with interferometric precision. As known from conventional Doppler OCT for axial motion only, the achievable accuracy exceeds the actual imaging resolution by orders of magnitude in all three dimensions. The feasibility of this method is first demonstrated by quantifying micro-rotation of a scattering sample. Subsequently, a potential application is explored by recording the 3D motion vector field of tissue during laser photocoagulation in ex-vivo porcine retina.},
    }
    
    

2016

  • Huttmann, Gereon and Moltmann, Moritz and Spahr, Hendrik and Tode, Jan and de Roeck, Anna and Theisen-Kunde, Dirk and Birngruber, Reginald and Koinzer, Stefan and Brinkmann, Ralf: Retinal lesion formation during photocoagulation investigated by high-speed 1060 nm Doppler-OCT: first clinical results. Investigative Ophthalmology & Visual Science, no. 57, pp. 5852-5852, 2016
    BibTeX Link
    @article{Hüttmann2016,
       author = {Huttmann, Gereon and Moltmann, Moritz and Spahr, Hendrik and Tode, Jan and de Roeck, Anna and Theisen-Kunde, Dirk and Birngruber, Reginald and Koinzer, Stefan and Brinkmann, Ralf},
       title = {Retinal lesion formation during photocoagulation investigated by high-speed 1060 nm Doppler-OCT: first clinical results},
       journal = {Investigative Ophthalmology & Visual Science},
       volume = {57},
       number = {12},
       pages = {5852-5852},
       abstract = {Abstract Purpose : The molecular processes during heating with a photocoagulation laser, particularly in sub-visible or mere thermal stimulation treatment, have only partly been understood, and different theories exist that try to explain its clinical efficacy. Optical coherence tomography (OCT) was successfully used to grade lesions with high accuracy 1 hour after the treatments and beyond. During the irradiation, changes in tissue scattering and, by use of the Doppler signal, tissue motion caused by thermal expansion and coagulation-induced tissue contraction were shown to correlate ex-vivo and in rabbits with the strength of photocoagulation lesions. Aim of this study was to validate feasibility and reproducibility of these results in humans. Methods : In an ongoing study more than 100 lesions of three patients have been imaged with a slitlamp-based OCT (1060 nm, 90,000 A-scans/s) with varying irradiance during laser exposure. Durations of the exposure were 50 ms and 200 ms; spot size was 300 µm. Eye movements and heart beat were corrected by cross-correlation of the images. Increased tissue scattering and movement of the neuronal retina due to thermal expansion were determined from the image sequences with 3 ms temporal resolution. Results : In the first treatments with this prototype device, we received acceptable image quality in 1/3 of the lesions. Changes in the neuronal retina were successful visualized during and after the laser irradiation, demonstrating the feasibility of a real-time assessment of initial effects of photocoagulation in humans. Lesion visibility in standard, reflection-based OCT was much weaker during treatment compared to 1 hour afterwards. Increased tissue scattering was observed in stronger lesions already during the laser irradiation. At reduced irradiance, scattering increase was only observed after the end of irradiation. However, tissue motion towards the vitreous was still observed in these cases. Conclusions : In conclusion, high-speed OCT recording during photocoagulation measures initial tissue changes during photocoagulation in humans. It may enhance our understanding of the tissue dynamics right after laser irradiation. It may provide useful information for a real-time dosage control as well. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.},
       ISSN = {1552-5783},
       url = {http://dx.doi.org/},
       year = {2016},
       type = {Journal Article}
    }
    
  • Hillmann, Dierck and Spahr, Hendrik and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon: In vivo optical imaging of physiological responses to photostimulation in human photoreceptors. PNAS Early Edition, pp. 1-6, 2016
    BibTeX Link
    @article{Hillmann2016,
       author = {Hillmann, Dierck and Spahr, Hendrik and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon},
       title = {In vivo optical imaging of physiological responses to photostimulation in human photoreceptors},
       journal = {PNAS Early Edition},
       pages = {1-6},
       abstract = {Noninvasive functional imaging of molecular and cellular processes of vision may have immense impact on research and clinical diagnostics. Although suitable intrinsic optical signals (IOSs) have been observed ex vivo and in immobilized animals in vivo, detecting IOSs of photoreceptor activity in living humans was cumbersome and time consuming. Here, we observed clear spatially and temporally resolved changes in the optical path length of the photoreceptor outer segment as a response to an optical stimulus in the living human eye. To witness these changes, we evaluated phase data obtained with a parallelized and computationally aberration-corrected optical coherence tomography system. The noninvasive detection of optical path length changes shows neuronal photoreceptor activity of single cones in living human retina, and therefore, it may provide diagnostic options in ophthalmology and neurology and could provide insights into visual phototransduction in humans.},
       url = {http://www.pnas.org/content/early/2016/10/10/1606428113.abstract},
       year = {2016},
       type = {Journal Article}
    }
    
  • Spahr, H. and Hillmann, D. and Hain, C. and Pfäffle, C. and Sudkamp, H. and Franke, G. and Koch, P. and Hüttmann, G.: Darstellung von Blutfluss und Pulsation in retinalen Gefäßen mit Full-Field-Swept-Source-OCT. Klin Monatsbl Augenheilkd, no. 233, pp. 1324-1330, 2016
    BibTeX Link
    @article{Spahr2016,
       author = {Spahr, H. and Hillmann, D. and Hain, C. and Pfäffle, C. and Sudkamp, H. and Franke, G. and Koch, P. and Hüttmann, G.},
       title = {Darstellung von Blutfluss und Pulsation in retinalen Gefäßen mit Full-Field-Swept-Source-OCT},
       journal = {Klin Monatsbl Augenheilkd},
       volume = {233},
       number = {12},
       pages = {1324-1330},
       ISSN = {0023-2165},
       DOI = {10.1055/s-0042-120279},
       year = {2016},
       type = {Journal Article}
    }
    

2015

  • Huttmann, Gereon and Koinzer, Stefan Otto Johannes and Müller, Heike and Ellerkamp, Iris and Baade, Alex and Moltmann, Moritz and Theisen-Kunde, Dirk and Lange, Birgit and Brinkmann, Ralf and Birngruber, Reginald: Predicting ophthalmoscopic visibility of retinal photocoagulation lesions byhigh-speedOCT: an animal studyinrabbits. Investigative Ophthalmology & Visual Science, no. 56, pp. 5980-5980, 2015
    BibTeX
    @article{Hüttmann2015,
       author = {Huttmann, Gereon and Koinzer, Stefan Otto Johannes and Müller, Heike and Ellerkamp, Iris and Baade, Alex and Moltmann, Moritz and Theisen-Kunde, Dirk and Lange, Birgit and Brinkmann, Ralf and Birngruber, Reginald},
       title = {Predicting ophthalmoscopic visibility of retinal photocoagulation lesions byhigh-speedOCT: an animal studyinrabbits},
       journal = {Investigative Ophthalmology & Visual Science},
       volume = {56},
       number = {7},
       pages = {5980-5980},
       ISSN = {1552-5783},
       year = {2015},
       type = {Journal Article}
    }
    
  • Spahr, Hendrik and Hillmann, Dierck and Hain, Carola and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon: Imaging pulse wave propagation in human retinal vessels using full-field swept-source optical coherence tomography. Optics Letters, no. 40, pp. 4771-4774, 2015
    BibTeX Link Link
    @article{Spahr2015,
       author = {Spahr, Hendrik and Hillmann, Dierck and Hain, Carola and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon},
       title = {Imaging pulse wave propagation in human retinal vessels using full-field swept-source optical coherence tomography},
       journal = {Optics Letters},
       volume = {40},
       number = {20},
       pages = {4771-4774},
       abstract = {We demonstrate a new noninvasive method to assess biomechanical properties of the retinal vascular system. Phase-sensitive full-field swept-source optical coherence tomography (PhS-FF-SS-OCT) is used to investigate retinal vascular dynamics at unprecedented temporal resolution. The motion of retinal tissue that is induced by expansion of the vessels therein is measured with an accuracy of about 10 nm. The pulse shapes of arterial and venous pulsations, their temporal delays, as well as the frequency-dependent pulse propagation through the capillary bed, are determined. For the first time, imaging speed and motion sensitivity are sufficient for a direct measurement of pulse waves propagating with more than 600 mm/s in retinal vessels of a healthy young subject.},
       keywords = {Optical coherence tomography
    Ophthalmology
    Time-resolved imaging
    Functional monitoring and imaging},
       DOI = {10.1364/OL.40.004771},
       url = {http://ol.osa.org/abstract.cfm?URI=ol-40-20-4771},
       year = {2015},
       type = {Journal Article}
    }
    
  • Spahr, Hendrik and Hain, Carola and Sudkamp, Helge and Franke, Gesa and Hillmann, Dierck and Huttmann, Gereon: Functional Microangiography of in vivo human retina by Full-Field OCT. Investigative Ophthalmology & Visual Science, no. 56, pp. 5974-5974, 2015
    BibTeX Link
    @article{Spahr2015,
       author = {Spahr, Hendrik and Hain, Carola and Sudkamp, Helge and Franke, Gesa and Hillmann, Dierck and Huttmann, Gereon},
       title = {Functional Microangiography of in vivo human retina by Full-Field OCT},
       journal = {Investigative Ophthalmology & Visual Science},
       volume = {56},
       number = {7},
       pages = {5974-5974},
       abstract = { PurposeOCT based functional microangiography of the retina requires high speed acquisition of a large number of volumetric datasets. Imaging speed of conventional scanning OCT devices is limited by the applicable radiant power and the mechanics used to scan the focused beam over the desired field of view. Full-Field Swept-Source OCT (FF-SS-OCT) resolves both issues, using an areal illumination, which dramatically increases the allowed amount of radiation, and an ultrafast camera for a highly parallelized acquisition.  MethodsThe retina of healthy volunteers was illuminated with wavelengths between 816 and 867 nm by the extended beam of a tunable laser (Broadsweeper, Superlum). Retinal irradiance was below the maximum permissable exposure (MPE). Light backscattered from the retina was imaged onto an ultrafast CMOS camera (SA-Z, Photron), where it interfered with an extended reference beam. From a series of interference images at different wavelengths, volumetric OCT images of the retina were reconstructed.  ResultsWe demonstrate in vivo retinal imaging at 9.9 billion voxels per second (40 million A-scans/s with 256 axial pixels). Sacrificing depth resolution by reducing the number of axial pixels, the A-scan rate was increased to more than 1 billion A-scans per second. FF-SS-OCT allowed imaging of all important retinal structures with good quality at unprecedented imaging speed (see fig. 1). Fast volumetric imaging at up to 3000 volumes/s was used to visualize small capillaries and to analyze the pulsation of retinal arteries and veins (see fig. 2). Imaging time for an area of 4 mm x 2 mm (896 x 368 A-scans) was only 316 µs. The high volume rate and the inherent phase stability enabled quantitative measurement of the change of retinal thickness due to blood pulsation with approx. 10 nm precision. A delay of the venous pulsation with respect to the arteries was observed (approx. 11 ms). The amplitudes of higher frequency components of the venous pulsation were considerably attenuated.  ConclusionsFF-SS-OCT provides fast volumetric imaging of the retina with good image quality. The capillary network can be analyzed with high spatial and temporal resolution. Analysis of retinal pulsation may provide information on pathological changes of vessels and capillaries. Angiographic OCT acquired with the FF-SS-OCT setup. Functional angiography showing the pulsation of retinal artery and vein.},
       ISSN = {1552-5783},
       url = {http://dx.doi.org/},
       year = {2015},
       type = {Journal Article}
    }
    

2012

  • Mueller, H. H. and Ptaszynski, L. and Schlott, K. and Debbeler, C. and Bever, M. and Koinzer, S. and Birngruber, R. and Brinkmann, R. and Huettmann, G.: Imaging thermal expansion and retinal tissue changes during photocoagulation by high speed OCT. Biomedical Optics Express, no. 3, pp. 1025-1046, 2012
    BibTeX Link
    @article{Müller2012,
       author = {Mueller, H. H. and Ptaszynski, L. and Schlott, K. and Debbeler, C. and Bever, M. and Koinzer, S. and Birngruber, R. and Brinkmann, R. and Huettmann, G.},
       title = {Imaging thermal expansion and retinal tissue changes during photocoagulation by high speed OCT},
       journal = {Biomedical Optics Express},
       volume = {3},
       number = {5},
       pages = {1025-1046},
       note = {935RH
    Times Cited:8
    Cited References Count:37},
       abstract = {Visualizing retinal photocoagulation by real-time OCT measurements may considerably improve the understanding of thermally induced tissue changes and might enable a better reproducibility of the ocular laser treatment. High speed Doppler OCT with 860 frames per second imaged tissue changes in the fundus of enucleated porcine eyes during laser irradiation. Tissue motion, measured by Doppler OCT with nanometer resolution, was correlated with the temperature increase, which was measured non-invasively by optoacoustics. In enucleated eyes, the increase of the OCT signal near the retinal pigment epithelium (RPE) corresponded well to the macroscopically visible whitening of the tissue. At low irradiance, Doppler OCT revealed additionally a reversible thermal expansion of the retina. At higher irradiance additional movement due to irreversible tissue changes was observed. Measurements of the tissue expansion were also possible in vivo in a rabbit with submicrometer resolution when global tissue motion was compensated. Doppler OCT may be used for spatially resolved measurements of retinal temperature increases and thermally induced tissue changes. It can play an important role in understanding the mechanisms of photocoagulation and, eventually, lead to new strategies for retinal laser treatments. (c) 2012 Optical Society of America},
       keywords = {optical coherence tomography
    laser photocoagulation
    vein occlusion
    management
    diseases
    fundus
    blood},
       ISSN = {2156-7085},
       url = {<Go to ISI>://WOS:000303537400018},
       year = {2012},
       type = {Journal Article}
    }
    

  • Spahr, Hendrik and Hillmann, Dierck and Hain, Carola and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon: Imaging vascular dynamics in human retina using full-field swept-source optical coherence tomography (Conference Presentation). no. 9697, pp. 96970E-96970E-1,
    BibTeX Link
    @inproceedings{Spahr2016,
       author = {Spahr, Hendrik and Hillmann, Dierck and Hain, Carola and Pfäffle, Clara and Sudkamp, Helge and Franke, Gesa and Hüttmann, Gereon},
       title = {Imaging vascular dynamics in human retina using full-field swept-source optical coherence tomography (Conference Presentation)},
       volume = {9697},
       pages = {96970E-96970E-1},
       note = {10.1117/12.2214303},
       abstract = {We demonstrate a new non-invasive method to assess the functional condition of the retinal vascular system. Phase-sensitive full-field swept-source optical coherence tomography (PhS-FF-SS-OCT) is used to investigate retinal vascular dynamics at unprecedented temporal resolution. Motion of retinal tissue, that is induced by expansion of the vessels therein, is measured with an accuracy of about 10 nm. The pulse shape of arterial and venous pulsation, their temporal delay as well as the frequency dependent pulse propagation through the capillary bed are determined. For the first time, imaging speed and motion sensitivity are sufficient for a direct measurement of pulse waves propagating with more than 600 mm/s in retinal vessels of a healthy young subject.},
       url = {http://dx.doi.org/10.1117/12.2214303},
       type = {Conference Proceedings}
    }
    
  • Muller, Heike H. and Ptaszynski, Lars and Schlott, Kerstin and Bonin, Tim and Bever, Marco and Koinzer, Stefan and Birngruber, Reginald and Brinkmann, Ralf and Huttmann, Gereon: Imaging of temperature distribution and retinal tissue changes during photocoagulation by high speed OCT. no. 7889, pp. 78890E, SPIE,
    BibTeX
    @inproceedings{Müller2011,
       author = {Muller, Heike H. and Ptaszynski, Lars and Schlott, Kerstin and Bonin, Tim and Bever, Marco and Koinzer, Stefan and Birngruber, Reginald and Brinkmann, Ralf and Huttmann, Gereon},
       title = {Imaging of temperature distribution and retinal tissue changes during photocoagulation by high speed OCT},
       editor = {James, G. Fujimoto and Joseph, A. Izatt and Valery, V. Tuchin},
       publisher = {SPIE},
       volume = {7889},
       pages = {78890E},
    
    }
  • Spahr, Hendrik and Rudolph, Linda and Muller, Heike and Birngruber, Reginald and Huttmann, Gereon: Imaging of photothermal tissue expansion via phase sensitive optical coherence tomography. no. 8213, pp. 82131S, SPIE,
    BibTeX
    @inproceedings{Spahr2012,
       author = {Spahr, Hendrik and Rudolph, Linda and Muller, Heike and Birngruber, Reginald and Huttmann, Gereon},
       title = {Imaging of photothermal tissue expansion via phase sensitive optical coherence tomography},
       editor = {Joseph, A. Izatt and James, G. Fujimoto and Valery, V. Tuchin},
       publisher = {SPIE},
       volume = {8213},
       pages = {82131S},
    
    }
  • Hagen-Eggert, M. and Hillmann, D. and Koch, P. and Huttmann, G.: Diffusion-sensitive Fourier-domain optical coherence tomography. no. 7889, pp. 78892B, SPIE,
    BibTeX
    @inproceedings{Hagen-Eggert2011,
       author = {Hagen-Eggert, M. and Hillmann, D. and Koch, P. and Huttmann, G.},
       title = {Diffusion-sensitive Fourier-domain optical coherence tomography},
       editor = {James, G. Fujimoto and Joseph, A. Izatt and Valery, V. Tuchin},
       publisher = {SPIE},
       volume = {7889},
       pages = {78892B},
    
    }