assessment of functional recovery of manual dexterity in ...brinkman box without vision 23 cm 13.3...

Assessment of functional recovery of manual dexterity in non-human primates following a motor cortex lesion using the Brinkman box task

Anne-Dominique Gindrat; Cindy Leuthard; Mélanie Kaeser; Alexander F. Wyss and Eric M. Rouiller

Unit of Physiology, Department of Medicine, Faculty of Sciences and Fribourg Center for Cognition, University of Fribourg, Fribourg, Switzerland

Hypothesis

After a lesion in M1, the sensorimotor system will be affected in parallel with the motor control itself. The resulting impairments can be highlighted with another test derived from the Brinkman board task: the Brinkman box task without vision, which was specically designed to assess the role of sensory inputs in a precision grip task performed in the absence of visual feedback before and after a lesion of the hand representation of M1.

Introduction

Motor areas and somatosensory areas are densely interconnected and participate together to the motor control, forming the functional sensorimotor system. The primary somatosensory cortex (S1) sends corticospinal projections and somatosensory inputs to the primary motor cortex (M1), contributing to the control of voluntary movements, such as the precision grip. Moreover, the somatosensory system plays a key role in active motor exploration by palpation in the absence of visual feedback.

A behavioural task was initially developed by Brinkman and Kuypers (1973) to test the precision grip ability in non-human primates and is currently used in an improved version -the modied Brinkman board task- in our laboratory. The animal has to retrieve banana pellets contained in 25 vertically and 25 horizontally oriented wells distributed on a rectangular board.

Material and methods

[email protected] Supported by Swiss National Science Foundation grants 31-61857.00, 310000-110005, 31003A-132465, 3100A0-103924, the Novartis Foundation, the National Centre of Competence in Research (NCCR) on ‘‘Neural plasticity and repair’’ and the Christopher Reeves Foundation (Springfield, NJ).

The Brinkman box task consists of a square board containing 10 v e r t i c a l l y a n d 1 0 horizontally oriented wells, each lled with a banana pellet.

Brinkman box task

sliding top

closed

Brinkman box without vision

23 cm

13.3 cm

13.4 cm

sliding top

opened

digital camera

lighting system

Brinkman box with vision

frontal opening

11.6 cm

11.8 cm

1.5 cm0.75 cm

frontal opening

This board is located in a box whose top can be opened or closed. The task can conse-quently be performed unimanually with or with-out visual feedback. Without vision, the task is more challenging, relying mostly on tactile inputs from the ngers and on spatial memory.

As a rst approach, pre- and post-lesion mean plateaux were visually dened for each analysed parameter (need to use more systematic criteria in the near future) and are displayed in a lighter colour than the corresponding data. The percentage of recovery is dened for appropriate parameters as (mean post-lesion plateau/mean pre-lesion plateau)*100 when a higher plateau value means a better performance and as 1/(mean post-lesion plateau/mean pre-lesion plateau)*100 when a lower plateau value represents a better performance. Pre- and post-lesion plateaux were statistically compared with t-test (t), Mann-Whitney test (M), z-test (z) or Chi-square test (C), as the case may be. The corresponding p-value or ns (non-signicant, P>0.05) is indicated.The performance ratio (Pizzimenti et al., 2007) is dened for appropriate parameters as mean plateau/SD when a higher plateau value implies a better performance and as (1/mean plateau)/SD when a lower plateau value suggests a better performance. This measure takes into account the variability of the data and, thus, a more stable performance is indicated by a higher performance ratio. Partially or completely missing values at a given date are represented by .o

Results

Brinkman box data without vision obtained from the contralesional hand were analysed frame by frame (25 frames/sec) with the software Kinovea. The following parameters were measured:

Data analysis

Time course of successfull pellet retrievals

Motion of the wrist

Precision grip finger

Well contact finger

EV

EN

TS

AN

ALY

SE

D

PA

RA

ME

TE

RS

Well orientation

Time

Pellet contact time (n=5)

Well contact time (n=5)

Interval between contacts with 2 successive wells (n=5)

Detection time for first well

Interval between contacts with 2 successive pellets (n=5)

Time for first precision grip

Hand entrance in the box

First finger contact with the

well

PELLET 1

Precision grip finger in the

well

Precision grip out of the well

First finger contact with

the well

Precision grip finger in the

well

PELLET 2

Precision grip out of the well

0

PELLET 2

Time to successfully retrieve the first 6 pellets//

% of effective contacts with each finger (# pellets retrieved / #

contacts with pellets)

30 sec End of the task

% of pellets successfully retrieved

Types of errors

SENSORIMOTOR DEFICIT

Precision grip and hand back to the

mouth without pellet

Pellet jumped out of the well

Missed pelletPellet retrieved with non-tested

hand

LACK OF MOTIVATION

Ÿ Different behaviours and strategies were observed among the tested monkeys to retrieve the pellets before and after the lesion. Therefore, the relevant parameters vary among the animals.

Ÿ After the cortical lesion, the time course of recovery in a given monkey is different according to the analysed parameters. For example in Mk-JA, whereas the pre-lesionpreferentially used orientations of the wrist and nger for the precision grip are quickly regained after the lesion, the animal can no more successfully retrieve the rst 6 pellets as fast as before the lesion.

Ÿ As expected, the level of recovery for the Brinkman box task without vision is usually lower than the one for the modied Brinkman board task, given that the former is more difcult to perform than the latter (e.g. Mk-RO and Mk-VA).

Ÿ Using a detailed analysis, it appears that this task is relevant to test the exploratory ability and tactile sense in a lesional context. It highlights the importance of the somatosensory feedback without visual control.

Prospects

Ÿ Inclusion of additional animals in each treatment group

Ÿ Computation of a composite performance score (Pizzimenti et al., 2007) taking into account the different parameters studied as an global indicator of the ability of the monkeys to perform the task

Ÿ Study of the reorganisation of the sensorimotor system following a M1 lesion with somatosensory evoked potentials

ReferencesBashir, S., Kaeser, M., Wyss, A., Hamadjida, A., Liu, Y., Bloch, J., Brunet, J.F., Belhaj-Saif, A., Rouiller, E.M., 2012. Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys. Brain Struct.Funct. 217, 63-79.Brinkman, J., Kuypers, H.G., 1973. Cerebral control of contralateral and ipsilateral arm, hand and nger movements in the split-brain rhesus monkey. Brain 96, 653-674.Hamadjida, A., Wyss, A.F., Mir, A., Schwab, M.E., Belhaj-Saif, A., Rouiller, E.M., 2012. Inuence of anti-Nogo-A antibody treatment on the reorganization of callosal connectivity of the premotor cortical areas following unilateral lesion of primary motor cortex (M1) in adult macaque monkeys. Exp.Brain Res. 223, 321-340.Kaeser, M., Wyss, A.F., Bashir, S., Hamadjida, A., Liu, Y., Bloch, J., Brunet, J.F., Belhaj-Saif, A., Rouiller, E.M., 2010. Effects of unilateral motor cortex lesion on ipsilesional hand's reach and grasp performance in monkeys: relationship with recovery in the contralesional hand. J Neurophysiol 103, 1630-1645.Kaeser, M., Brunet, J.F., Wyss, A., Belhaj-Saif, A., Liu, Y., Hamadjida, A., Rouiller, E.M., Bloch, J., 2011. Autologous adult cortical cell transplantation enhances functional recovery following unilateral lesion of motor cortex in primates: a pilot study. Neurosurgery 68, 1405-1416.Pizzimenti, M.A., Darling, W.G., Rotella, D.L., McNeal, D.W., Herrick, J.L., Ge, J., Stilwell-Morecraft, K.S., Morecraft, R.J., 2007. Measurement of reaching kinematics and prehensile dexterity in nonhuman primates. J Neurophysiol. 98, 1015-1029.

Experiments were conducted on four adult Macaca fascicularis. When the monkeys reached a behavioural p lateau in manual dexterity tests, they were subjected to a permanent cortical lesion, performed unilaterally in the hand representation of M1 by infusion of ibotenic acid. One animal was a control subject (Mk-RO), one was treated with anti-Nogo-A antibody (Mk-VA)(Hamadjida et al., 2012; Kaeser et al., 2010) and two received an adult neural progenitor cell therapy (Mk-JO and Mk-JA)(Kaeser et al., 2011).

Monkeys

10 mmMk-RO Mk-VA

10 mmMk-JA

10 mmMk-JO

10 mm

Mk-RO§ Mk-VA Mk-JO Mk-JA*

Treatment None Anti-Nogo-A antibody Cell therapy Cell therapy

Age at time of lesion (rounded to 0.5 year) 4 5.5 3.5 4

Weight at time of lesion (kg) 3.2 4.9 3.4 4.3

Volume of ibotenic acid injected (ml) 18 15.5 15 38

Number of ICMS sites injected with ibotenic acid 12 11 10 38

Total volume of lesion (mm³) in the gray matter

(motor cortex + post-central gyrus)14 20 33.6 22.2

Volume of lesion in post-central gyrus (mm³) 0 5.8 3.8 2.5

Volume of lesion spread to subcorticall white

matter (mm³)0 0 23.6 38.4

§ Mk-RO was subjected to three successive cortical lesions because the rst two did not produce the expected impairment on the contralesional manual dexterity assessed with the modied Brinkman

rdboard task. Day 0 was dened as the time of the 3 lesion.* Mk-JA was treated post-operatively with an anti-epileptic drug, producing a neuroprotective effect

against the cortical lesion performed with excitotoxic drug (ibotenic acid). This resulted in a small volume of lesion in relation to the volume of ibotenic acid injected.

Location and extent of the permanent unilateral lesion of the M1 hand representation on lateral view of the brain. The lesion territory (in red) is derived from the lesioned zone of cerebral cortex (gray matter) visible on consecutive frontal histological sections. Spread of the lesion to the subcortical white matter below the gray matter is not represented here.

Mk-JO

0

1

2

3

4

5

-100 -50 0 50 100 150

# o

f ev

en

ts

Precision grip back to the mouth without pellet

0

10

20

30

40

-100 -50 0 50 100 150

sco

re in

30

se

c

Modified Brinkman board

pre- and post-lesion days

horizontal wellsver�cal wells total cell reimplanta�on

17.76

6.18

19.24

60%, P≤0.001 (M)

182%, P≤0.001 (M)

33%, P≤0.001 (M)

0

2

4

6

8

10

-100 -50 0 50 100 150

�m

e (

sec)

Pellet contact �mes

3.77

1.04

49%, P≤0.001 (M)

0

5

10

15

20

-100 -50 0 50 100 150

�m

e (

sec)

0.48 0.10

45%, P≤0.001 (M)

Intervals between contacts with 2 successive pellets

not measured

0

20

40

60

80

100

-100 -50 0 50 100 150

�m

e (

sec)

Time to successfully retrieve the first 6 pellets

0.022

0.006

48%, P≤0.001 (M)

0

20

40

60

80

100

-100 -50 0 50 100 150

%

Effec�ve contacts in the first 30 sec

6.165.02

92%, ns (t)

D3D1 D2 D4 D5

0

20

40

60

80

100

-100 -50 0 50 100 150

%

Orienta�on of the visited wells

horizontal wellsver�cal wells

ns (z)

0

20

40

60

80

100

-100 -50 0 50 100 150

%

Mo�ons of the wrist

- - -neutral posi�onradial devia�on ulnar devia�on

P=0.003 (C)

100

%

0

20

40

60

80

-100 -50 0 50 100 150

Fingers detec�ng the wells

D3D1 D2 D4 D5

P=0.006 (M)

0

20

40

60

80

100

-100 -50 0 50 100 150

%

Pellets successfully retrieved

19.6011.50

95%, ns (z)

not observed

Mk-JA

0

1

2

3

4

-150 -100 -50 0 50 100 150 200 250 300

# o

f ev

en

ts


0

10

20

30

40

-150 -100 -50 0 50 100 150 200 250 300

sco

re in

30

se

c



horizontal wellsver�cal wells total cell reimplanta�on

13.19

10.77

21.61

104%, ns (M)

75%, P≤0.001 (M) 139%, P≤0.001 (M)

0

4

8

12

16

-150 -100 -50 0 50 100 150 200 250 300

�m

e (

sec)

Well contact �mes

1.94

0.53

59%, P≤0.001 (M)

0

10

20

30

40

50

-150 -100 -50 0 50 100 150 200 250 300

�m

e (

sec)

0.770.27

67%, P=0.002 (M)

Intervals between contacts with 2 successive pellets

not measured

0

10

20

30

40

50

60

70

-150 -100 -50 0 50 100 150 200 250 300

�m

e (

sec)


0.013

0.008

63%, P≤0.001 (t)

0

20

40

60

80

100

-150 -100 -50 0 50 100 150 200 250 300

%


3.14

5.23100%, ns (M)

D3D1 D2 D4 D5

0

20

40

60

80

100

-150 -100 -50 0 50 100 150 200 250 300

%



ns (z) ns (z)

ns (z)

%

0

20

40

60

80

100

-150 -100 -50 0 50 100 150 200 250 300


- - - neutral posi�onradial devia�on ulnar devia�on

ns (C)

0

20

40

60

80

100

-150 -100 -50 0 50 100 150 200 250 300

%


15.69 10.56

96%, ns (z)

not observed

%

Fingers used for the precision grips

0

20

40

60

80

100

-150 -100 -50 0 50 100 150 200 250 300

D3D1 D2 D4 D5

ns (M)

Mk-RO

not observed

0

2

4

6

8

-200 -150 -100 -50 0 50 100

�m

e (

sec)


2.98 1.76

84%, ns (M)

0

10

20

30

40

50

60

-200 -150 -100 -50 0 50 100

�m

e (

sec)

1.40

68%, P=0.01 (M)

0.35

Intervals between contacts with 2 successive wells

0

2

4

6

-200 -150 -100 -50 0 50 100

�m

e (

sec)

Detec�on �me of the first pellet

16.054.23

65%, ns (M)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

�m

e (

sec)


0.040.01

78%, P=0.01 (t)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

%


2.52

6.79

113%, ns (M)

D3D1 D2 D4 D5

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

%



ns (z)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

%


neutral posi�onradial devia�on ulnar devia�on

P=0.018 (C)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

%


D3D1 D2 D4 D5

ns (M)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100

%


20.20

97%, ns (z)

19.12

not observed

0

10

20

30

40

-200 -150 -100 -50 0 50 100

sco

re in

30

se

c



horizontal wellsver�cal wells total

100%, ns (t)

8.20

12.53

Mk-VA

0

2

4

6

8

10

-200 -150 -100 -50 0 50 100 150 200

# o

f ev

en

ts


0

10

20

30

40

-200 -150 -100 -50 0 50 100 150 200

sco

re in

30

se

c



horizontal wellsver�cal wells total

10.276.39 6.97

52%, P≤0.001 (M)

88%, P=0.03 (M)

169%, P≤0.001 (M)

0

1

2

3

4

5

-200 -100 0 100 200

�m

e (

sec)


4.24

58%, P≤0.001 (M)

1.71

0

10

20

30

40

50

60

70

80

90

-200 -100 0 100 200

�m

e (

sec)

1.42 0.02

29%, P≤0.001 (M)

Intervals between contacts with 2 successive wells

0

5

10

15

20

25

-200 -100 0 100 200

�m

e (

sec)

Detec�on �me of the first well

14%, P=0.003 (M)

23.00

0.24

0

20

40

60

80

100

-200 -100 0 100 200

�m

e (

sec)


0.048

0.002

35%, P≤0.001 (M)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100 150 200

%


15.25

3.49

65%, P≤0.001 (M)

D3D1 D2 D4 D5

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100 150 200

%


- - -neutral posi�onradial devia�on ulnar devia�on

ns (C)

0

20

40

60

80

100

-200 -100 0 100 200

%


D3D1 D2 D4 D5

ns (M)

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100 150 200

%


92%, P≤0.001 (z)

21.048.95

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100 150 200

%

Pellets retrieved with the non-tested hand

0.314

3%, P≤0.001 (z)

0.001

0

20

40

60

80

100

-200 -150 -100 -50 0 50 100 150 200

%



P=0.026 (z)

assessment of functional recovery of manual dexterity in ...brinkman box without vision 23 cm 13.3...

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