Hans A. Braun

Fachbereich 20 der Philipps Universität Marburg

Institut für Physiologie und Pathophysiologie

Arbeitsgruppe Neurodynamik

Computer Simulation als Alternative in Lehre und Forschung

Fachforum „Ansätze und Methoden zum E-Learning in der Biologie“Fachbereich Biologie und HRZ der Philipps-Universität Marburg

8. September 2010

Body of ResearchComputer Models of Neuronal Encoding and Synchronization

oscillations, chaos and noise: complex neuronal dynamics with simplified Hodgkin-Huxley type equations in excellent agreement with the experimental data.

Systemic Models of Manic-Depressive Disorders, Sleep and HPA-axis

combining systemic models of mood disorders and associated disturbances of sleep and cortisol release with neuron-based approaches (www.biosim-network.eu)

The Marburg Neurodynamics Group: Body of Research

Stimulus Encoding in Thermo- and Electrosensitive Skin Receptors

experiments beyond the laboratory rat also describing, for example, the exquisite sensitivity of sharks, boa constrictor and vampire bats.

Integrative Functions of Hypothalamic Neurons

how neuronal information processing takes advantage of nonlinear signal integration and impulse pattern modulation.

EXPERIMENTS MODELS

Data Analysis and Nonlinear System Theory

the impact of nonlinear dynamics with “cooperative” noise effects in comparison of experimental data and computer simulations.

Computer Laboratories for Teaching (www.clabs.de)

Virtual computer laboratories for a better understandung of dynamical biological functions.

www.uni-marburg.de/physiology/braun

Computer Simulationsat the Marburg Neurodynamics Group

We are

… developing computer simulations for teaching

… teaching how to develop computer simulations

… using computer simulation in research

Marburg Neurodynamics Group: Computer Simulation for

Teaching

Virtual Computer Laboratory for Action Potential Recordings from Afferent Skin Nerves to examine Sensory Encoding in Mechano- and Thermoreceptors.

the cLabs-series

the Virtual-Physiology series

A series of 5 computer programs:

SimNerv, SimMuscle, SimPatch, SimVessel, Sim Heart

Virtual realizations of classical "animal labs” for experimentation almost like in the real world.

Distributet by Thieme Publ. (Stuttgart/NewYork)

cLabs-SkinSenses

cLabs-Neuroninteractive computer animations and simulations for an intuitive understanding of neuronal dynamics.

Teaching Programs

Textboks , per se, are static media, and therefore can only have limited impact in demonstrating dynamical interrelations.

Interactive computer animations and simulations

can essentially improve the understanding of dynamic functions,especially when the user

- can directly follow the time dependencies of the dynamic processses

- can change the physiological control parameters and immediately can see the effects on the systems behavior

Background Living organisms are highly complex dynamical systems; understanding them can be a very demanding undertaking.

The programs are not primarily made for teaching factual knowledge but to practise how to make use of knowledge and thereby to improve the understanding of biological functions and their interrelations.

Factual Knowledge Understanding Know How (Excercises)

The Virtual Physiology and cLabs-programs are equally well suited for universities andbiology classes at high schools or for private studies.

the CONCEPT: learning by doing

DEMOs

typical examples from the Virtual Physiology series:

SimHeart / SimMuscle

cLabs-Neuronbasic neurophysiology single-channel lab

current-voltage-clamp lab

Physiologie Praktikum SSMarburg: Medizin, Zahnmedizin und Humanbiologie

1. Computersimulation SimNerv und cLabs-NeuronIsolierter Froschnerv: extrazelluläre Aktionspotentiale, Schwellen, Reizparameter, diphasische undmonophasische Aktionspotentiale, Refraktärzeit, Leitungsgeschwindigkeit

2. NervNervenreizung am Menschen, Ableitung von Elektromyogrammen, Bestimmung der Nervenleitungsgeschwindigkeitund deren Temperaturabhängigkeit

3. Schmerz (Somatosensorik)Neurogene Entzündung und Lokalanästhetika: Histamin mit Pricknadel, Oberflächenschmerz: Schmerzmessung mitAlgometer, Tiefen- und Kälteschmerz, ischämischer Muskelschmerz

4. AugeVisusbestimmungen, Akkommodationsbreite, Gesichtsfeld (Perimeter), Farbensehen (Anomaloskop),Schwellenempfindlichkeit bei Dunkeladaptation (Adapto-meter)

5. OhrUntersuchung von Tönen und Klängen mit Oszilloskop und Mikrofon, Prüfung der Hörvermögens (Versuche nachWeber und Rinne, Schwellenaudiometrie für Luft- und Knochenleitung), Richtungshören, Frequenzabhängigkeit desHörens, Demonstration der Altersschwerhörigkeit mit Hilfe eines elektronischen Tiefpaßfilters

6. ZNS / ReflexeReflexe am Menschen, Bestimmung von Reflexzeiten, vestibulärer und optokinetischer Nystagmus,Elektronystagmographie, EEG unter verschiedenen Versuchsuchsbedingungen

Virtual Physiology und cLabs Programme im Einsatz:

Physiologie Praktikum WS7. Computersimulation Skelett-Muskel

Isolierter Froschmuskel: Kraft- und Verkürzungsmessungen, Ruhe-Dehnungskurve, Abhängigkeit der Einzelzuckungvon Vordehnung und Reizstärke, Einzelzuckungen versus tetanische Kontraktionen, Ermüdung

8. Computersimulation Herz (Pharmakologie)Isoliertes, perfundiertes Herz nach Langendorff: Wirkungen von Pharmaka auf die kontraktionskraft (Adrenalin,Acetylcholin, Alpha- und Betablocker, Atropin, Herzglykoside, Ca-Antagonisten), Konzentrations-Wirkungs-Kurven

9. Herz (EKG)Standard-EKG am Menschen (12 Ableitungen), Auswertungen am Computerbildschirm, Vektor-EKG in der Frontalebene mitCarotispulsmessung, Modellversuch zum EKG

10. KreislaufBlutströmungsgeschwindigkeit (Ultraschall-Doppler-Prinzip), Blutdruckmessungen nach Riva-Rocci (Lage der Manschette zumHerzen, Orthostase, Schellongversuch), kontinuierliche Blutdruckmessung mit arterieller Tonometrie (Valsalva-Manöver)

11. AtmungMessungen mit dem Pneumotachygraphen (statische und dynamische Parameter), Atemwegswiderstand, Atemregulation beikontinuierlicher Rückatmung (Messung von Kohlendioxid in der Atemluft)

12. LeistungVersuche am Fahrradergometer, Messungen von kardiovaskulären und respiratorischen Parametern, Laktatkonzentration imBlut und Blutgase

13. NiereTrinkversuch nach Volhard (Wasser, Kochsalzlösung, ADH-Applikation): Bestimmung von Volumen, Dichte, Osmolarität, Na-und K-Konzentration, Messung der Kreatinin-Clearance

14. BlutBSG, Hämatokrit, Erythrozyten- und Leukozytenzahl, MCV, Gerinnungszeit, Kreuzprobe, Blutgruppen- undRhesusfaktorbestimmung

frommedical students’ evaluation(Marburg 1999)

Evaluation of whether or not the students consider virtual experiments as useful alternatives to real experiments.

The question was answered prior to the SimNerv experiment referring to multimedia programs in general (red bars) and once again following the use of SimNerv specifically referring to this program (blue bars).

05

1015202530354045

1 2 3 4 5 6

rating scale

frequ

ency

(per

cent

of t

otal

)

Students answers prior toSimNerv

Students answers after theuse of SimNerv

p = 3,48 x 10-10

24.08.2009 12cLAB

The Virtual Physiology and cLabs programs are used in several hundred University Institutes and Schools all over the world.

More than 100 000 students should have been educated with these programs

The Actual Task

– The Problem• 'Virtual Physiology' is programmed in C and C++

and had been closely fitted to Pentium- and Motorola-Processors.

• It is not possible to compile or easily transform 'Virtual Physiology' into Rich-Internet-Applications.

• It is not possible to integrate the present 'Virtual Physiology' in webbased teaching- and training curricula.

– The Opportunity• We get more and more requests for Updates.• The role of Internet-based courses and blendend

learning has significantly increased.• Especially in the Third World the Internet is an

opportunity to supply students with teaching- and learning-material.

• Webbased communities play a growing role in collaborative learning and training.

• 'Virtual Physiology' is a proven and reliable teaching tool with about 25.000 implementations in over 10 countries all over the world.

24.08.2009 cLAB 13

Dear Mr Braun,I am a teacher of physiology of the Padova University (Italy), Faculty of Veterinary Medicine.My colleagues and me used for long time your interactive CD roms and we think that they are really useful.We actually cannot use these CDroms as our computers (Windows XP) do not support more them.Please let me know if more updated versions of these CDroms are available.Thank you very much and best wishesDaniela__Dr.ssa Daniela BertottoDipartimento di Scienze Sperimentali VeterinarieUniversità di Padova

• Need for 'Virtual Physiology' Updates

Approach – the new cLabs Concept

• transform 'Virtual Physiology' into Rich-Internet-Applications

– cLAB is a concept to completely redesign the four major applications from 'Virtual Physiology'.

– cLAB will be programmed in Flex, Adobes new platform to create Rich-Internet-Applications (via Flash) and classical Desktop-Applications (via AIR or ZINC).

– Additionally, versions for iOS, called icLab, will be programmed in Objective-C (XCode).

– The four all-new applications will be based on the proven and reliable simulation algorithms from Dr. Hans Braun.

– The new applications will be ready for the integration in a SCORM-compatible Learning Management System (LMS) such as “Moodle”.

24.08.2009 cLAB 14

Future Applications• cLAB will be ready for the upcoming teaching and learning platforms

– Touch-based devices like the iPad give the students a more intensive laboratory experience than a normal PC

– Interactive wall charts like SmartBoard allow teachers to interact with simulated animal experiments on the wall of a lecture room

24.08.2009 cLAB 15

TeamThe editors and developers of Virtual Physiology Series

are also responsible for the cLABs project with updates and extensions of the Virtual Physiology programs

24.08.2009 cLAB 16

Prof. Dr. med. Karl VoigtPhysicianUniversity of MarburgPhysiological InstituteDirector35037 Marburg

Dr. Hans BraunEngineer and Physiologist

University of MarburgPhysiological Institute

Head Neurodynamics Lab35037 Marburg

Dr. Martin HirschPhysiologist

CEO eyePlorer GmbH35037 Marburg

… who else would be interested to contribute?

please contact:braun@staff.uni-marburg.de

computer mouse

Braun HA:

Virtual versus real laboratories in life-science education: Concepts and experiences.

from: The Biological Physicist

The Real and Virtual Laboratory: A Conversation with Dr. Hans Braun

Early in the 1990s, student protest against animal use led the University ofMarburg, Germany, to stop using experimental preparations in its practicalphysiology course. For course director Hans A. Braun, this led to a search foralternatives. How could the high standard of physiology instruction bemaintained without experimentation?

Braun, who has been an APS Fellow since 1998 (cited for “the discovery ofnoise-mediated neuronal oscillators and for elucidating their nonlineardynamical properties”), soon realized that a virtual laboratory was the answer.In collaboration with his then students Martin Hirsch and Martin Huber, Braundeveloped an interactive program called “MacFrog”. The program was winningawards almost from its inception. In 1994 the software won theGerman/Austrian Software Award for the Best Teaching Software in Biologyand Medicine, the Award for the Best Multimedia Application and also theMacWorld Editors Award for Trendsetting Multimedia Software.

Encouraged by this positive response, and by the support of Karlheinz Voigt,Director of the Institute of Physiology, Braun, Huber and Hirsch (who now runsa software company called interActiveSystems, www.brainmedia.de) expandedMacFrog into the first part of a software package called Virtual Physiology.Coverage of the program, “SimNerv”, in the local media led to support fromApple Computers, and then from the Hessian State Ministry of Science andArts (HMWK). Later, the group was awarded a grant from the GermanMinistry of Education and Science (BMBF), in combination with a grant fromThieme Publishers. This support allowed them to take SimNerv into its finalform for public distribution, and to develop three more programs, SimMuscle,SimVessel and SimHeart.

The programs in the Virtual Physiology series, available in both English andGerman, reproduce exactly the experiments which had been done with realanimal preparations in integrated physiology/pharmacology courses for medicalstudents at Marburg. Today, the programs are in regular use in practicalphysiology courses in Marburg, used by nearly 300 students each semester.

The Newsletter of the Division of Biological Physics of the American Physical SocietyVol.1 No.1 June 2001 p 5-7

http://www.aps.org/DBP/newsletter/jun01.pdf

The programs offer an exquisitely detailed “in silico” laboratory forthe student. In SimMuscle and SimNerve, video sequencesdemonstrate dissection of the frog and preparation of the isolatednerves and muscles, respectively. The student can then manipulate theexperimental setup onscreen in order to “collect data” and reproduceclassic experiments.

SimVessel combines physiological and pharmacological experimentswhich are done on isolated strips of the smooth muscle from vessels(aorta) and the stomach (antrum) of the rat. SimHeart presents anislotated preparation of the rat heart in the classical Langendorff set-up. The programs include a “chemistry lab” where students prepare thepharmacological substances in appropriate dilutions for theexperiments in the onscreen physiology/pharmacology lab.

Like all the Virtual Physiology Software, SimMuscle offers a realisticlaboratory setting for the student to explore.

Marburg Neurodynamics Group: Computer Simulation in

Research

BioSim WP10 D30

26 academic, 10 industrial and 4 regulatory partnersIn collaboration with EUPHEPS

Computer Simulations for Drug Development-----------------------------------------------------------------

EU-Network of Excellence, Nov. 2004 – March 2010

We propose … the development of professional, physiologically-based models that can help the pharmaceutical industry develop safe and effective drugs at significantly lower costs.

Genomics and biotechnology for health

Research:

BioSim WP10 D30

Computer Simulations for Drug Development----------------------------------------------------------------

www.biosim-network.net

Genomics and biotechnology for health

Activity Areas:

1. Regulatory issues, ethics, dialogue with the publicHanne Gürtler, Copenhaven (Denmark) & Marival Bermejo, Valencia (Spain)

2. DiabetesPatrik Rorsman, Lund (UK)

3. Hypertension and cardiovascular diseasesDenis Noble, Oxford (UK)

4. Mental disorders and neuronal systems => Major Depression and SleepHans Braun, Marburg (Germany)

5. CancerFrancis Levi, Paris (France)

6. Methodological issuesJürgen Kurths, Potsdam (Germany)

BioSim WP10 D30

Workpackage WP10:Mental Disorders and Sleep-Wake Cycles

Computer models will be developed on the basis of experimental andclinical data

(i) to identify the neuronal and systemic parameters that are responsiblefor the patients vulnerability and for the disease progression and

(ii) to find effective targets for the application of drugs and their goal-directed development.

Contributors to WP10: Mental Disorders and Sleep-Wake Cycles

University of Marburg

participant No 6 (HB):Hans Braun, Karheinz Voigt, Horst Schneider, Svetlana Postnova (BioSim), Bastian Wollweber, Marcus Belke, Christian Finke, Institute of Physiology, MarburgElectrophysiological Experiments (rat hypothalamic brain slices). Computer models of neurons and neuronal networks. Systemic models of sleep, neuroendocrine functions (HPA-Axis) and mental disorders

Martin Huber, Uli Hemmeter, Jürgen Chr. Krieg, Dept. of Psychiatry, MarburgContributions to the modelling studies, clinical data from depressive patients

Thomas Penzel, Sleep Laboratory, Inner Medicine, MarburgData from sleep disorders, Sleep models, Clinical trials (sleep, hormones and mental diorders)

Industrial Partners:

participant No 32 (HM): Harald Murck, Amarin Neuroscience Lim., Stirling, UK (SME)Clincal trials: effects of unsaturated fatty acid EPA on hormones, sleep and depression.

participant No 33 (MCH): Martin Chr. Hirsch, interActiveSystems, Berlin/Marburg, D (SME): Development of associative information management tools

WP1. Ethics and dialogue with the public

… A sound bioethical performance is increasingly important for thepharmaceutical industry to maintain its license, and this conditionwill be an obvious motivator for the adoption of alternative methods,such as biosimulation

The emphasis on implementation of the Three Rs(Reduction, Replacement and Refinement alternatives)

As an effective tool in drug development, biosimulation can contribute to the implementation of the Three Rs alternatives both in animal and human research.

Computer simulations shall be used for the design of more specific, goal directed experimental and clinical studies.

This can significantly reduce the number of animal experiments and avoid unnecessary suffering of patients - at simultaneously decreasing costs.

ad 6.3 Spreading of excellence activities

Education

The complexity of living systems combined with thetraditional lack of advanced mathematics in the medical andpharmaceutical educations and with insufficient biologicalinsight from the part of engineers, physicists, and computerscientists represent one of the most obvious obstacles to thegrowth of the field of biosimulation.

BIOSIM & cLabs(from the BioSim project description)

Some of the BioSim participants also have expertise in the development of teaching software. For example, Hans Braun,together with other members of the Marburg Group (participant No. 6) and with Martin Hirsch (participant No. 33) from interActiveSystems, is developer and co-editor of the “Virtual Physiology” (Thieme Publ., Heidelberg/New York) and the “cLabs” series (Biomedical Techn. Inc., Heidelberg/Marburg).

….. This can help to attract students to numerical simulations and to overcome the repeatedly mentioned lack of modellers in the medical and pharmaceutical sciences.

seminar... and what we are doing in Marburg to improve the situation:

a new seminar with practical excercises at the Physiological Insitute with unexpected good acceptance by the medical students.

Von der Nervenzellmembran zur psychiatrischen Erkrankung – Computersimulation physiologischer, biochemischer und medizinischer Probleme -

From the nerve-cell membrane to psychiatric disorders – Computer simulations of physiological, biochemical and medical processes -

Vorklinisches Wahlfach für Studierende der HumanmedizinKlinisches Wahlfach für die Wahlfach-Schwerpunkte 2 (Nervensystem)

und 18 (Klinische Neurobiologie

Dr. Dr. K. Mandrek*, Dr. H.A. Braun*, Dr. G. Käuser**Institut für Normale und Pathologische Physiologie(*), Dekanat (**)

… the traditional lack of advanced mathematics in the medical and pharmaceutical educations …

Max-Planck-Institut für Physik Komplexer Systeme

(MPIPKS), Dresden, Germany

Hans A. BraunPhilipps-UniversityMarburg, Germany

Erik MosekildeTechnical University of

DenmarkLyngby, Denmark

Frank MossUniversity of Missouri

St. Louis, USA

Organisation:Mandy Lochar/Renate Seidel

MPIPKSDresden, Germany

http://mpimpks-dresden.mpg.de/~medsim07

International Seminar and Workshop

From Complex Systems Theory To Clinical NeurologyJune 4 – 8, 2007, Dresden (Germany)

Scientific Coordinators

Einsatzgebiete der Computer Simulation:

Computer-Simulationen können immer dann von Vorteil sein, wenn ein System derart kompliziert und komplex wird, dass es in seinem Verhalten nicht mehr unmittelbar überschaubar ist.

Dazu braucht es nicht viel. Es hat sich gezeigt, dass das menschliche Vorstellungsvermögen sehr schnell an seine Grenzen kommt - insbesondere wenn nichtlineare und zeitverzögerte Wechselwirkungen und Rückkopplungen im Spiel sind.

Gerade dies aber sind charakteristische Merkmale biologischer Systeme.

Es kann daher nicht überraschen, wenn es häufig zu Fehlinterpretation experimenteller und klinischer Daten und auch zu Fehleinschätzungen bezüglich der Wirkung und Nebenwirkung von Medikamenten kommt.

Potentieller Nutzen der Computer Simulation:

Überprüfung von Hypothesen - Zwang zur Konkretisierung/FokussierungDurch die Notwendigkeit einer exakten mathematischen Formulierung werden unweigerlich vorhandenen Unschärfen von Hypothesen und Wissenslücken aufgedeckt.Computersimulationen in den Lebenswissenschaften sind immer Vereinfachungen der Realität, notwendigerweise - und meist auch so gewollt. Es geht schließlich darum, aus der Vielzahl von Prozessen die funktionell relevanten Komponenten zu erfassen.

Erkenntnisgewinn – heuristische Aspekte der ModellentwicklungWenn ein nach physiologischen Annahmen erstelltes Modell die Daten nicht reproduzieren kann, sollte dies nicht als Fehlschlag gewertet werten, Es gibt vielmehr Anlass, die Grundannahmen zu überdenken. Häufig ergeben sich schon aus den Modelldaten Hinweise darauf, wie die Hypothesen zu revidieren wären.

Erfassung von Wechselwirkungen – experimentell nur punktuell machbarEin biologisches System ist vielfältigen Einflüssen unterworfen mit meist nicht-linearen Wechselwirkungen, die experimentell praktisch nicht mehr erfassbar sind, sich aber mit Computersimulationen durchspielen lassen. Diese geben Hinweise auf kritische Konstellationen, was sich dann durch gezielte Experimente überprüfen läßt.

Beispiele aus eigenen Arbeiten:

Die Entwicklung eines Modell der KältetransduktionErsatz einer allgemein anerkannten aber offensichtlich falschen Hypothesen

Analyse des KälterrezeptormodellsAufdeckung zuvor unbekannter Gesetzmäßigkeiten der Impulsauslösung

Eine im Experiment überhaupt nicht mögliche Modell-Studiezur Diskrepanz experimenteller Daten von Somata und sensorischen Afferenzen

Neuronale Wechselwirkungen im Hypothalamusmit bislang in Konkurrenz stehenden Modellansätzen

Ein Modell der HPA (Stress) – Achsewelches trotz Implementierung allseits akzeptierter Hypothesen die experimentellen Daten in bestimmten Fällen nicht reproduzieren kann.

Ein Modell der Schlaf-Wach-Regulationwelches konkrete Ansätze bietet zur weiteren, gezielten Abklärung in experimentellen und klinischen Studien

Ein Modell zum Zeitverlauf manisch-depressiver Störungenformal - aber mit neuen Einblicken in die Ursachen von Vulnerabilität und Progression.

Major Actual CooperationsChristian Finke & Ulrike FeudelDepartment for Theoretical Physics and Complex Systems, University of Oldenburg synchronization effects and sensitivity changes in coupled neurons.(common DFG project)Werner Bonath & Marcel BeulerDepartment for Microelectronics, Univ of Applied Sciences, Giessenneuron and network models as analogue-circuits on microchips (VHDL-AMS technology). Svetlana Postnova, Peter Robinson & Ron GrunsteinBrain Dynamics Group and Woolcock Institute for Medical Research, Sydney, Australiasleep and mental disordersRaúl Toral & Emilio HernandezUniversity of Balearic Island, Mediterranean Institute of Advanced Studies, SpainImpact of neuronal heterogeneity on network dynamicsHans Liljenström & Peter Århem (Agora for Biosystems, Sigtuna, Sweden)Dept. of Biometry and Informatics, SLU, UppsalaNobel Institute for Neurophysiology, Karolinska, Stockholm integrative approaches: from ion channels to neurons and networksFrank Moss, Sonya Bahar & Epaminondas RosaCenter for Neurodynamics at the University of Missouri, St. Louis, USADepartment of Physics, Illinois State University, Normal/Bloomington, USAmechanisms of neuronal synchronization during epileptic seizures, synaptic transmission

Erik Mosekilde & Olga SosnovtsevaTechnical University of Denmark, Department of Physics, DenmarkPanum Medical School, Copenhagen, Denmarkimpulse patterns in neurons and pancreatic ß-cellsDmitry E. Postnov & Oxana Semaychkina-GlushkovskayaInstitute of Nonlinear Dynamics and Biology Department, Saratov, Russiaimpact of glial cells and external potassium on neuronal coupling,

one example