Product Presentation Metris 2009lbn

Product Presentation Instruments for Animal Behavioral Research

© Metris b.v. 2009

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Content ■

Company overview

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Products

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Importance of the energy parameter in Behavioral Pharmacology

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Company overview Goal Provide turnkey solutions / expertise in the area of automatic animal behavior analysis. Products LABORAS SonoTrack Third Party products

Markets Pharmaceutical industry Research institutes/CRO’s Universities/ Academic Hospitals

Activities Product Development, Marketing / Sales , Assembly and Product support.

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History ■ ■ ■ ■ ■ ■ ■ ■

5/1999 9/2001

Metris BV start Delivery of first LABORAS for Windows systems 2/2005 Introduction SONOTRACK (Ultrasound recording and analysis) 7/2005 Distributor SleepSign for Animals (EU) 8/2006 Introduction LABORAS 2.0 12/2008 Introduction SonoTrack USV Playback 1/2009 Introduction SonoTrack 2.0 Since 2001 ± 400 platforms are delivered and over 50 references on our website support the value of LABORAS as experienced by researchers

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Company Relations Distributors ■ ■ ■ ■ ■ ■

Neuroscience Inc. (Japan) Kuo Yang Scientific Corporation (Taiwan) Mirae Korea Inc. (South Korea) Medi Analytika Ltd. (India) AH Medical Supply (China) Radon Medical (Turkey)

Cooperations ■ ■ ■ ■

DataSciences – Telemetry (USA) Kissei (Japan) Porsolt (France) National Instruments (USA, NL, Armenia) 5

LABORAS What is LABORAS? LABORAS is a fully automatic system for continuous behavior recognition and tracking of small rodents (mice and rats) ■

LABORAS replaces, reduces and refines behavioral scoring by human observers ■

LABORAS sets a new standard in the area of behavioral observation instruments ■

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Evolution of automatic tracking & behavioral observation systems Low

0

1980 Infrared beam matrix (4x3)

1990 Infrared beam matrix (8x5)

2000

2010

resolution XY track

no. of behaviors

Infrared beam matrix (3D)

ANIMEX Video tracking (single point)

Video tracking (multi point)

LABORAS 1st. generation

high

>10

LABORAS 2.0

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LABORAS technique

(1/3)

Main components LABORAS ■ ■

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Measurement platform(s) Electronics (e.g. amplifiers & control & A/D conv.) LABORAS software for Windows 8

LABORAS technique (2/3) Measurement platform(s)

Electronics (@ platform)

Electronic Control Unit

PC + software Administration Amp. Ctr.

A/D conv.

ctr

& Tracking Results

ctr

Graphs

Tables

y

Track

x

0 10 0.25 9 0.50 4 0.75 3

t

x

8 8 6 10

y

Export ASCII e.g. MS-Excel SPSS

t

Behavior Behaviors

0 immob 5.25 eat 9.75 drink 15.5 groom

t

behav

SAS JMP

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LABORAS technique (3/3) Example of recognition of behavioral features Locomotion

Scratching

Fast up and down movement of the hind foot, rubbing the side of the body, neck and face. 10

Tracking measurement Tracking information provided by LABORAS     

 

High resolution XY position track Velocity data (average, max.) Distance traveled Position distribution (details like favorite spots) Circling / turning (Clockwise and counter-clockwise circle count, avg. circle size, avg. circling speed, avg. time in circle) Sociality Cage (preference to visit specific compartments in cage) Estimation of energy use (in development) 11

Detection of behaviors LABORAS distinguishes more than 16 different rat and mouse behaviours Normal behaviours       

Locomotion Immobility Rearing Climbing Eating Drinking Grooming

Special behaviours       

Scratching (mice) Seizures - tonic-clonic convulsions, barrel-rolls, Racine P4 and P5 (mice) Hind limb licking / Formalin test (rat) Purposeless chewing (rat) Wet dog shakes (rat) Headshakes (rat) Head twitches (rat) 12

LABORAS configurations Configuration variables ■ ■ ■

Up to to 8 measurement platforms connected to one computer Species: mice, rat or both Tracking and Behavior software modules: – Tracking – Normal behaviors – Special behaviors

■ ■ ■

Integration with Telemetry (Behavior & Psychology) Sociality Cage (special cage that enables sociability test) User interface specials – GLP – Independent start of the platforms 13

Examples of results

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Examples of results

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LABORAS Qualification (1/6) ■

Operational Validation: – Does LABORAS performs as advertised – Explained in the following sheets

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Pharmacological Validation – Does LABORAS assist me with my research – Metris role to assist – E.g. new experiments or new algorithms

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Certificates – GLP (Laboratory req.) , CE / FCC (electrical

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LABORAS Qualification (2/6)

Electronics

Platform

Camera 17

LABORAS Qualification (3/6)

Lab(t )cum − Obs (t )cum ≤ 1.5σ

obs

(t ) + 5% Obs (t )cum + 1% T + 4% Obs (T )cum

− Lab(t )cum = cumulative time LABORAS at t − Obs (t )cum = mean of cumulative time observers at t − Obs (T )cum = mean of cumulative time observers at T = Test duration

−t

= time

Grooming (Rat14) : 90% 800

700

Cumulat. time Grooming (s)

−T

600

500

LABORAS Alex Lee Mean Obs Boundary-

400

Boundary+

300

200

100

0 0

500

1000

1500

2000 Time (s)

2500

3000

3500

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LABORAS Qualification (4/6)

Immobility (Rat01): 90% 1800 1600

LABORAS

Cumulative time (s)

1400

Alex

1200

Tania Heleen

1000

Mean Obs. 800

Bound -10% Bound +10%

600 400 200 0 0

600

1200

1800

Time (s)

2400

3000

3600

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LABORAS Qualification (5/6)

Validation Results ● Correlation

with human observers (according to validation criterion) – – –

Locomotion, Climbing Immobility, Grooming Eating, Drinking, Rearing

– Special behaviors

> 95% > 90%

> 80% > 80-90%

● Since

2001 ± 400 platforms are delivered and over 50 references on our website support the value of LABORAS as experienced by researchers 20

LABORAS Qualification (6/6)

Development of new algorithms • •

Good animal behavior definition Proper definition of the experiment protocol - and use of the LABORAS experiment administration

• •

Choice of pharmacological relevant behaviors Good correlation with the real behavior (acceptation criterion) - Not always human observer reference

•

Results presentation

- Recording and Presentation of result data - Use of previous raw data/ result summaries

Enabling the full benefit of LABORAS

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Examples of performance

Normal Behaviou (rat)

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Examples of performance Wet Dog Shakes (rat)

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Examples of performance Head Twitches (rat)

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Examples of performance Circling (rat)

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Examples of performance Sociality Cage (mice)

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Applications LABORAS ■

LABORAS application areas are: (behavioral assessment in) – Drug Development – Phenotyping – Safety Pharmacology – Lab. animal science – Toxicology

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Typical customers are: – – –

Pharmaceutical Corp – CRO’s (Contract Research Org.) Academic institutes – Lab. animal suppliers Hospitals – Governmental Organizations 27

Applications LABORAS Monitoring of behavioral changes and effects in: ■

Drug Development Drug Discovery research – Efficacy studies of new compounds – Long term observation tests (e.g. circadian rhytm,eatdrink patterns) – Experimentally induced behaviors (e.g. grooming, drinking, movement patterns, hindlimb-licking / formalintest, scratching, WDS, Head Shakes)

■ ■ ■

Safety Pharmacology Toxicology Phenotyping research – High Capacity Phenotyping with transgenic mice 28

Applications LABORAS ■

Animal models based on behavioral assessment in home cage environment – Normal behaviors – Drug induced behaviors

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Pain studies – Automated Formalin Test

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Social Interaction – Preference studies (with stranger and familiar mouse – Sociality cage)

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Animal welfare studies – Cage enrichment studies – Behavioral effects of manipulation of animal 29

Applications LABORAS Examples of LABORAS applications in drug discovery TEST

RESULT

Behavioral phenotyping transgenic mice

Target discovery for future drug development

Primary observation test

Adverse drug effects

Open field test

E.g. sedative, stimulant, anxiolytic, anxiogenic properties

Pain test (formaline induced hindlimb licking)

Analgesic properties

Dermatology test (scratching)

Skin protective effects

Telemetry & Behavior

Integrated cardiovascular, CNS and behavioral data

Sociability Test

Analysis of social behavior (for amongst other Autism research)

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Applications LABORAS Examples of LABORAS applications in drug discovery TEST

RESULTS

Effect on Pharmacologically induced effects, such as • m-CPP hypolocomotion and hypophagia • 8-OH-DPAT hyperlocomotion • d-Amphetamine hyperactivity • Angiotensin II polydypsia • Orexin-A induced grooming • Excessive climbing • Turning/circling behavior • Wet Dog Shakes (WDS) • Head Shake & Head Twitch • Seizure

Pharmacological efficacy of (potential) leads Pharmacological antagonist efficacy, eg. anticonvulsant activity

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Applications LABORAS Examples of LABORAS applications in drug discovery NEAR FUTURE APPLICATIONS Antagonism of pharmacologically induced effects, such as • Dyskinesia • Startle response FUTURE APPLICATIONS Respiration

Adverse effects

Heart beat

Efficacy and safety issues

Sniffing, Digging, Jumping

Detailed Exploration/Anxiety measure

Energy spend

Metabolic effects

Disturbed feeding / drinking patterns (Eating / Drinking)

Hypo- or hyperphagia; Hypo- or polydipsia

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Overall benefits LABORAS General benefits for customer ●

Standard and objective method − Eliminates inter- and intra observer deviation − Does not require trained or experienced raters

● ● ●

●

Reduces time & costs (>75% reduction) Results are almost immediately available Many independent parameters can be measured with just one system (Tracking & behavior recognition combined in single system) Growth potential to determine several new behavioral and tracking parameters

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Overall benefits LABORAS Important benefits for experiment ● ● ● ● ●

Independent of light conditions Home cage environment and non-invasive method (stress minimized) Large scale observational experiments possible Long test periods possible More consistent results

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SONOTRACK

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What is SONOTRACK? ●

SONOTRACK records, visualizes and plays back Ultrasound Calls

●

SONOTRACK records the full spectrum from 15kHz up to 100kHz

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SONOTRACK records 4 independent ultrasound channels

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SONOTRACK can easily be adjusted to experimental environment and is easy to use 36

1

moth

porpoise

beluga whale

bat

mouse

rat

opossum

cat

gerbil

guineapig

bat

mouse

moth

beluga whale

rat

opossum

porpoise

cat

gerbil

guineapig

hedgehog

dog

ferret

rabbit

raccoon

cow

horse

sheep

10000

hedgehog

dog

ferret

rabbit

raccoon

cow

horse

sheep

chinchilla

1000

chinchilla

Log

Freq. range (Hz)

Ultrasonic Vocalizations Hearing range of Animals

1000000

100000

100

10

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What is SONOTRACK ●

SONOTRACK can be used for long term experiments

●

SONOTRACK recognizes and counts Ultrasonic Vocalizations in user definable frequency bands

●

SONOTRACK offers a new approach for characterization of animal behavior

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SONOTRACK Applications ●

SONOTRACK can be used to monitor animal welfare and interaction between animals based on the ultrasonic vocalizations of the animals

●

Typical research areas: – – – – – –

Pain Anxiety Stress Depression Social interaction Animal Welfare 39

SONOTRACK Applications ●

Playback of Ultrasounds to the animal (stimulus) - playing back parts or complete recordings - playing back specific (artificial) frequency patterns

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Examples of results

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Examples of results

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Examples of results

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Examples of Results

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Examples of results Ultrasound Vocalizations Marmoset Rats, Mother & Pup

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Example of results

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What is SleepSign? ■

Software for scoring of sleep stages

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Based on EMG and EEG signals

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Sleep stages can be scored in a manual mode as well as well as automatically

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Scores pre-assigned sleep stages (such as REM, WAKE, SWS) and up to 3 user defined vigilance stages 47

Special features ■

■

■

■

Works with wireless or wired EMG and EEG signals In depth analysis using Hypnograms and Trend Graphs Various analysis functions, incl. Stage Graphs, Vigilance State Parameter Display, FFT analysis Integrated with Video

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Application areas ■

Pharmaceutical Research

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Sleep Disorder Studies and Sleep pattern Analysis

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Integration of Systems Integration of systems such as LABORAS, Video, DSI Telemetry, SonoTrack & Sleepsign 

Less Experiments & Experimental lead time

 Less Resources (animals, researchers & money)  Integrated analysis of parameters from different domains collected from the same experiment - Behavioral data and Tracking data - Psychological data - Sounds - Sleep stages 50

Integration of Systems Example of integration in Laboras

LABORAS

With Sonotrack

With SleepSign 51

ENERGY & PHARMACOLOGY Behavior and external / internal conditions Environment - External condition

The study of animal behaviour, particularly from evolutionary and ecological viewpoints, has been one of the major growing points in biology over the last 15 years. Process in the Body – Internal condition 52

ENERGY & PHARMACOLOGY Basic structure BEHAVIOR = Function { Internal stimulus, external stimulus}

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ENERGY & PHARMACOLOGY Information filtering and Decision Behaviorr Decision

Animal Body Internal Stimuli

External Stimuli

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ENERGY & PHARMACOLOGY Animal behavior and environment Sensory system

1. inernoreceptor – convey information within organisms 2. Proprioreceptor- report information position of the body part 3. Externoreceptor- obtains information about the outside (environment and ecology) 4. Sometoreceptor – capture events on the body surface 5. Teloreceptor- monitor stimuli at a distance from the body

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ENERGY & PHARMACOLOGY Animal behavior and environment Structure

Types of information

1. Information 2. Motivation 3. Development 4. Decision

Genetics- evolution Competition and Risk Investigation information Recognition Analysis Data monitory Saving and summarise

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ENERGY & PHARMACOLOGY Information Process Store Information

Transform Information

Action Information

Cognition and brain

Filtering

Muscle Cells

Detection Information Sensory cells

Transmit Information Nerve cells Chemical messenger

Integration Information Nerve Cells

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ENERGY & PHARMACOLOGY Processing information in the animal body Sensory Cells

Nerve Cells

Chemical messengers

Behavior

Muscle Cells

Sensory Cells Pick up different changes in the environment Nerve Cells Transmit and integrate information Chemical messenger Transmit Chemical information (more leisurely time than nervous system) Muscle Cells Transform information from the nervous system into action

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ENERGY & PHARMACOLOGY Nervous System (CNS) Sensory Cells

Sensory Neuron

Motor Neuron

Interneuron

Effector

Advanced nervous system have five major components, linking stimulus perception and motor respond. Sensory Cells –acting sensory as sensory receptor Sensory Neuron-carrying impulses from the sense cells Motor neurons - carrying impulses into effector cells Interneuron- linking sensor neuron and motor neuron Effector- Effector organ 59

ENERGY & PHARMACOLOGY Animal behavior and environment BEHAVIOR= Function {Process in the Body, Body nervous system structure, nervous function, hormonal effects , biological clocks, perceptual mechanisms, Genes, internal/external stimulus filtering}

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ENERGY & PHARMACOLOGY External factor and environmental variables Temperature = function { temperature control Unit , CV } Airflow = function air-conditioning} Barometric pressure = function { place, time } Humidity = function { office level or place } Visual effect = function { walking researchers in the laboratory} Light = function { lights control unit} Sounds = function { sounds generating equipment, voices } Vibration = function { refrigerators, ventilators, PCs, specific equipment } Elektromagnetic waves = function{ transmitting equipment, magnets} Smell = function {specific gases, parfums, etc,}

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ENERGY & PHARMACOLOGY Rule of energy preservation of the body E = K + P = constant ■

(Formula of energetic balance)

Potential Energy of the Body

P = ∆U+ δ(ε − Tη + Pν) -∆U -Ε

is the change in biochemical energy is the internal energy

- Tη - Pv

is the entropy energy is the thermodynamic energy

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THE IMPORTANCE OF THE ENERGY PARAMETER IN BEHAVIORAL PHARMACOLOGY ■

Kinetical energy of body

∑ E k = Mv²/2

+

δmω ²R²/2

E (Locomotion) = Mv²/2 V = velocity, M = total mass of body E (Oscillation) = δm ω²R²/2 ω = radial frequency, R = radius of oscillation, δm = mass of oscillating body part 63

THE IMPORTANCE OF THE ENERGY PARAMETER IN BEHAVIORAL PHARMACOLOGY ■

Kinetical energy of body

E (Locomotion) is the kinetic energy resulting from: Locomotion, Walking, Rearing, Climbing

E (Oscillation) is the kinetic energy resulting from different repetitive movements: Scratching, Grooming , Chewing, Sniffing, Wet Dog Shakes, Head Shakes, Head Twitches, Tremors 64

Detection, recognition and registration of behavior Detection of behavioral features Locomotion

Scratching

Fast up and down movement of the hind foot, rubbing the side of the body, neck and face.

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LABORAS HS Signal

Analog

Digital

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H S Pa W w DS Li c Sc kin ra g tc hi n Se g iz G u re ro om in Ea g ti D ng rin ki ng C h Lo ew co i m ng m ot i R on ea Im ring m ob C il ity li m bi ng

H T

Energy

E (Oscillation) / E (Locomotion) spectrogram Energy spectrogram Energy

10 9 8 7 6 5 4 3 2 1 0

Behavior

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For Fast, Efficient & Quality Pre-clinical Research

Questions? More information mail: [email protected] Metris BV Kruisweg 825 2132 NG Hoofddorp Phone:+31 23 5623400 Fax: +31 23 5623425 www.metris.nl 68