Unilateral removal of the posterior insula or of area SII: inconsistent effects on tactile, visual and auditory performance in the monkey

1

Behavioural Brain Research, 26 (1987) 1-17 Elsevier BBR00722

Research Papers

Unilateral removal of the posterior insula or of area SII" inconsistent effects on tactile, visual and auditory performance in the monkey W. HOrster and G. Ettlinger The University of Bielefeld, Bielefeld (F.R.G.) (Received 27 February 1987) (Revised version received 15 June 1987) (Accepted 22 June 1987)

Key words." Insula; SII; Tactile discrimination; Visual discrimination; Auditory discrimination; Monkey

Unilateral removals of the posterior insula or of the second somatic sensory projection area (SII) were made in respectively 8 and 6 monkeys. These animals were divided into a 'contralateral' group of 7 with removals from the hemisphere opposite to the preferred hand; and an 'ipsilateral' group of 7 animals with removals from the hemisphere on the same side as the preferred hand. In addition, 6 unoperated monkeys were trained comparably. Both the contralateral and ipsilateral animals were impaired in comparison with unoperated animals at threshold discriminations of graded roughness and/or sizes when using the hand opposite the removals. Animals with contralateral ablations were impaired in comparison with those having ipsilateral ablations only in a few of many instances: with the hand ipsilateral to the removals at re-learning a tactile discrimination and at learning an auditory discrimination; with the hand opposite to the removals when it was initially used on visual or auditory tasks that had already been mastered with the other hand. It is suggested that in addition to SII the insula is also organized asymmetrically in relation to hand preference in the monkey, but the insula of the predominant hemisphere may be involved as much in non-tactual as tactual performances, for example in tasks involving successive discrimination and when a familiar task has to be performed initially with the other hand. INTRODUCTION

amygdaloid complex and indirectly to the hippoc a m p u s 9,24,30.

Subsequent to the primary sensory projection area (SI), somatosensory inflow is next processed by two systems in parallel: in the superior and inferior lobules of the posterior parietal cortex (PPC) 33, as well as in the second somatosensory projection area (SII) of the parietal operculum 7. Thereafter both systems converge onto the posterior insula 28 and access to the limbic system is afforded by connections from the insula to the

The two parallel systems differ considerably. The extent of PPC is relatively vast in comparison to that of SII; it comprises many subdivisions that are distinguishable on cytoarchitectonic criteria and/or by their anatomical connections 33, whereas SII has not so far proved thus subdivisible7; large regions within PPC are devoid of known somatotopic representation, whereas SII is topographically organized in its entirety39; and the

Correspondence: G. Ettlinger, The University of Bielefeld, 4800 Bielefeld 1, F.R.G. 0166-4328/87/$03.50 (© 1987 Elsevier Science Publishers B.V. (Biomedical Division)

thalamic connectivities of PPC and SII differ 3,5,8,21,42. Despite these striking morphological and physiological differences between PPC and SII, selective cortical removals have in general failed to reveal distinctive somatosensory functions during tactile discrimination performance (TDP). Certainly removals of PPC may be followed not merely by impaired TDP (e.g. ref. 36), but also by non-tactual disorders, for example by inaccurate visual reaching ~7 and/or by a wider spatial disorientation 35. However, such non-tactual disorders (e.g. refs. 1, 25) have been explicitly considered as functionally unrelated to the impaired TDP associated with removals of PPC; and the impaired TDP associated with removals of SII was not f o u n d z°'11'37'38 to differ in important respects. Indeed, yet another similarity between PPC and SII was reported by Garcha et al. 12" unilateral removals of either PPC or of SII from the hemisphere contralateral to the preferred hand gave rise to more substantial impairment of TDP than did comparable removals from the hemisphere ipsilateral to the preferred hand. A contrary view has recently been expressed by Murray and Mishkin3~: TDP was impaired on a larger number of tasks and also more severely by removals of SII than of area 5, leading to the suggestion that SII, but not area 5 (or presumably any other sector of PPC), is critically involved in TDP. This conclusion can, however, be questioned. First, the SII removals '... extended posteriorly about 3 mm beyond the caudal end of the insula...'. However, the p a p e r s 7"39 cited by Murray and Mishkin as stating the boundaries of SII are not in agreement on this point, the former writing: 'The digits, hand and arm are represented... in the region immediately in front of the posterior pole of the insula'. Thus, the SII removals of Murray and Mishkin may have included an anterolateral portion of area 7b which is a sector of the PPC, and possibly also portions or all of area Ri. (The SII leg area does lie more posteriorly; the more detailed recent study of Friedman et al. 9 again confirms that the hand region within SII lies anterior to the posterior end of the insula, see his Figs. 5 and 8B). Second, it has been shown 2v that removals of a single sub-

sector of PPC are not usually as effective in producing impairment of TDP as are removals of several or all sectors of PPC in combination. It seems that in monkeys with partial removals of PPC the sectors that remain intact can take over the functions of those that are ablated. In the monkeys of Murray and Mishkin with removals of area 5, inflow of the hand region of SI could still have reached area 7 and the remainder of the PPC via the intraparietal sulcus 4°. Third, area 5 is known to be primarily (but not exclusively) related to the lower limb of the opposite side 4°, whereas SII is known to contain large representations of the hand and digits 7"9. A different outcome might have been obtained by Murray and Mishkin if their monkeys had been trained to discriminate with the feet; or, given that the hands were used to discriminate, if additional (or other) regions of PPC had been removed. If then the two anatomically parallel somatosensory systems in PPC and SII cannot (as yet) be distinguished with certainty by behavioural criteria, but both converge onto the posterior insula, a comparison between the behavioural consequences of removing SII and the posterior insula might reveal differences: quantitative differences, because removing the site of convergence might impair TDP more profoundly than removing only one of the two sources of its inflow; qualitative differences, because the site of convergence could be regarded as a 'higher order' system. Moreover, so far only a brief report exists 32 of the changes in TDP consequent upon removals of the insula. In designing the present study account was also to be taken of the increasing number of recent reports indicating cerebral asymmetry in the monkey: either in respect of the preferred hand ~s'41 or favouring the left hemisphere (e.g. refs. 13, 16, 18, 20, 34). There is also one recent claim of anatomical asymmetry in the monkey6. Accordingly, not only were removals of SII to be compared with removals of the posterior insula; but additionally, each lesion group was to be subdivided into animals with unilateral removals from the hemisphere contralateral to the preferred hand and from the hemisphere ipsilateral to the preferred hand. This design could at the same time provide a comparison between differing

lesion sites as well as a replication, and extension to the insula, of the finding of Garcha et al. 12 that contralateral, but not ipsilateral, removals of SII impair TDP in both hands. (The procedures of Garcha et al.12 were exactly replicated because their findings were so unexpected: e.g. that even when the monkey uses the postoperatively preferred hand (now ipsilateral to the removal) a removal contralateral to the originally preferred hand gives rise to impairment.) Moreover, by including non-tactual tests while maintaining a 'successive' test procedure as in touch (where the two simultaneously present objects are, in reality, palpated successively), a third question was to be asked: are the findings of Garcha et al. 12 (which indicated an asymmetry related to hand-preference) contingent upon the tactual or upon the successive aspects of TDP tasks ? Therefore, after exactly replicating the 9 training stages of Garcha et al. ~2 - all concerned exclusively with TDP some of the animals were trained additionally on visual and auditory successive discrimination tasks. If the tactual factor is critical, animals impaired on TDP would not be impaired on nontactual successive tasks; but if the successive aspects of the TDP tasks are critical, animals impaired on TDP would be equally impaired on non-tactual successive tasks. MATERIALS A N D M E T H O D S

Subjects Twenty immature rhesus monkeys, M. mulatta, trained in two groups of 12 and 8, were allocated to 4 operated and one unoperated group on the basis of matched preoperativ e learning scores on the first task: 4 monkeys (Inc-1 to Inc-4) were to have the insula contralateral to the preferred hand removed; 4 (Ini- 1 to Ini-4) the insula ipsilateral to that hand; 3 (SIIc-1 to SIIc-3) the SII contralateral to that hand; 3 (SIIi-1 to SIIi-3) the SII ipsilateral to that hand; and 6 (Unop-1 to Unop-6) were to remain uffoperated. However, in matching the groups, account was also to be taken (if possible) of (1) strength of hand preferences; (2)direction of hand preferences (cf. ref. 19); (3)gender (cf. ref. 16); (4)weight (cf. ref. 16); and (5) prior experience. Unexpectedly, 8 of the 20 monkeys proved to have inconsistent

hand preferences (i.e. the same hand was chosen on less than 9 0 ~ of trims during criterion on the task given preoperatively); 5 of these 8 monkeys were allocated to the unoperated group, the remainder as Inc-1, Ini-1 and Ini-3 to the insular group (the hand used on a simple majority of trials was counted as the 'preferred hand'). Four of the remaining 12 monkeys (Inc-2, SIIc-2, SIIc-3 and SIIi-2) were left-handed and 8 (Inc-3, Inc-4, Ini-2, Ini-4, SIIc-1, SIIi-1, SIIi-3 and Unop-4) righthanded. Nine monkeys (Inc-4, Ini-1, Ini-4, SIIc-3, SIIi-3, Unop-3 to Unop-6) were female, the remaining 11 male. The weights of animals at the time of surgery are given in Table III. Four monkeys (Inc-2, SIIi-1; SIIi-2 and Unop-1)had previously participated in a short investigation on 'pointing as communication '2, and 3 (Inc-3, SIIc-2 and Ini-3) in a longer investigation of'map reading' (Immelmann and Ettlinger, unpublished observations). This prior training was held to be irrelevant to TDP.

Operations The removal of the insula was intended to involve the granular region (Ig of Mesulam and Mufson 23, as well as the posterior portion of the dysgranular insula lying ventrally to Ig (posterior part of Idg of Mesulam and MufsonZ3). Initially, access was obtained by turning a large bone-flap, opening the dura widely, but leaving the temporal muscle largely intact. When it was found that the temporal muscle, lying ventrally in the exposure, obstructed a ventrodorsal line of sight, a small bone defect was made beneath the divided temporal muscle (which was subsequently repaired) in animals Inc-2, Inc-4, and Ini-2 to Ini-4. Care was taken to avoid damage to the parietal operculum; and the insula was located by ablating medially along the lower bank of the lateral fissure. The removal of SII was intended to involve only the cortex designated as such by Friedman et al. 7. Access was invariably obtained by turning a bone-flap. Left-sided removals were made in 5 animals (Inc-3, Inc-4, Ini-1, SIIc-1 and SIIi-2), and rightsided removals in the remaining 9 operated animals. Contra- and ipsi-lateral removals were interleaved to avoid any effects related to improvement of surgical skill.

Histology The procedures for all animals except Inc-4, Ini-4, SIic-3 and SIIi-3 remained the same as previously described 38, except that blocks of the fixed brain were embedded in paralTm and sections were cut at 10 #m, every 50th being stained with Cresyl blue. Fig. 1 shows crosssections through the ablation in one unselected animal of each lesion group (i.e. Inc-2, Ini-2, SIic-2 and SIIi-2). Tables I and II show a summary of the main histological findings: a quantitative estimate of the extent of insular/SII cortex remaining intact at successive levels 0.5 mm apart

Inc-2

SIic-2

behind the central sulcus; the deep structures which were unintentionally damaged; and the thalamic nuclei in which gliosis (frequently accompanied by cell loss) was most often found. The damage to SII in the insular animals was in general slight; its location variable; and in no animal more than a small proportion of the ablation in the SII animals. The 4 operated animals Inc-4, Ini-4, SIic-3 and SIIi-3 participated in a subsequent experiment involving the injection of 2-deoxyglucose (2-DG). Figs. 2 and 3 show serial reversal prints of the lesions in Ini-4 and SIIi-3. (Similar series, but for Inc-4 and SIic-3,

Ini-2

SlIi-2 Fig. h group left of SIIi-2

Representative cross-sections through the areas of removal in 4 representative animals. One animal from each lesion was selected by its number and not by the extent of its removal. Areas of removal are indicated by cross-hatching. The each representation refers to the left side of the brain. All sections were taken at 3.0 mm apart, but in the case of animal the lower section was taken from a different block. Areas missing but not cross-hatched relate to the absence of tissue close to block junctions.

-

-

-

2

3

6 4 4 0 3 3

Ini-1

3

2

Animals Inc-I

Level." 8

? ? 4 4

-

? ? 0 0 3 3

lO

2 3 1 4

-

? 2 0 0 2 2

12

0

0 0 0 2 2

0 2 2 3 4

0 0 2 0 0 0

16

0

0 2 0 0 0 0

14

0 0 0 *

0

0 0

0 0 *

18

0 0 *

*

1 0

*

*

20

0 0 *

*

*

*

*

22

* * *

*

*

*

*

24

Amount of cortex remaining intact at given levels behind rostral end of insula

20

27

28

21

20

23

Level at which lesion ends

+ +

+

+ +

++

+

< +

SH

+ +

+ +

+

+++

Cls

Damage to

+

+

++

+

Put

++

+++

+++

Int. cap

++

+++

+++

+++

+++

+++

TA/TB/TC

+

++

+

++

VPL

Gliosis in

++

+++

+++

+

VP1

++

++

+

+++

Pul

++

+++

+++

+++

+++

+++

GM

Levels are successive histological sections, separated by 500 #m, starting from the rostral end o f the insula. Thus level 8 is 4 m m , level 10 is 5 ram, posterior to the rostral end o f the insula. The values in the body of the table under the successive levels represent m m o f insular cortex remaining intact in the uper portion (above lateralis) or lower portion (below lateralis), given respectively in the upper/lower line for each animal. - signifies that no (or virtually no) cortex has been removed. ? signifies that an estimate can not be m a d e on account o f tissue missing at block junctions. * signifies that the given level is posterior to the caudal end o f the insula. + , + + and + + + respectively signify slight, m o d e r a t e and severe damage/gliosis. Cls, claustrum; Put, p u t a m e n ; Int. cap, internal capsule; TA/TB/TC, cortex on lower b a n k o f lateralis; VPL, nucleus ventralis posterior lateralis; VPI, nucleus ventralis posterior inferior; Pul, pulvinar; G M , nucleus geniculatus medialis. D a m a g e to SII excludes damage to that portion o f SII forming part o f the insula.

Summary of histological findings in animals with insular ablations

TABLE I

2*

0 2

Animals SIlc-I 2

SIIi-I 2

Level." 2

0 1

2 0

4

0 0

1 0

6

0 0

0 1

8

0 0

0 3

10

Amount of cortex remaining intact at given levels behind rostral tip of central sulcus

19 19

14 14

Level at which lesion ends

15 12

9 10

Level at which insula ends

++

Ins

++

Cls

+

++

Put

Damage to . . . . . . . . .

+++ +++

Int. cap

+

TA/TB/TC

+++

VPL

Gliosis in

÷

+

+++

VPI

++

VL

÷

÷

++

Pul

Levels have the same meaning as for Table 1, except that they start from the most rostral part of the central sulcus. The values in the table under the successive levels represent mm of SII cortex remaining intact, starting from the junction of the insula with the uper inner face and extending laterally. Only in the level marked * was there cortex remaining in the lateral portion of the upper face. Ins, insula; VL, nucleus ventralis lateralis. All other symbols and abbreviations as for Table 1.

Summary of histological findings in animals with ablations of SI1

TABLE I[

Ini-4

+++i¸ ,

i~

1022

994

966

938

910

882

85~

826

798

Fig. 2. Serial reversal prints (every second section, separated by 980/~m) of the autoradiographs at the level of the insular ablation in animal Ini-4. The left and right hemispheres were individually sectioned; the sections were mounted on glass slides; the slides were aligned for correspondence of structures in the two hemispheres; and then exposed to film. The left hemisphere is shown on the left; the dark regions indicate stronger labelling with 2-DG.

-t

~Q

(.I"1 C~

r~

m

0

QD

C]O C~ C~

Q~ ~0

r~

~0 (31 r~

0

(.O

r

! (.~

,mmm8

IlmO

are to be found in Figs. 1 and 2 of HOrster et al., in preparation.) Their lesions are to be detailed in that publication, but can meanwhile be regarded as comparable to (and in 3 animals as more complete than) those listed in Tables I and II. The exception is animal Inc-4, where the lower third of the insula remained intact at levels 8-14 from the rostral end. Only minimal damage was done to SII in animals Inc-4 and Ini-4; but minor damage to the superior temporal sulcus in animal Inc-4 (slight at levels 20-24; posteriorly more extensive). In SIIi-3 there was posteriorly a slit-like lesion, extending over 6 levels into the internal capsule. In summary, the posterior two-thirds of the insular cortex was successfully removed in all animals except Ini-3 (and possibly Ini-1), albeit with some very minor and variable damage to SII; the SII removals were adequate in all animals, but tended to extend behind SII; there were no systematic differences between contra- and ipsilateral removals.

Training procedures These have remained the same as for previous reports. In brief, training was carried out in a WGTA for peanut reward, 40 trials being given daily, 5 days per week. In the case of TDP, training was given in the dark, comparisons being monitored on an I.R. video system. Tasks These have been divided into 5 main groups: I. TDP, given exactly as described in Garcha et al. 12 to all 20 monkeys: they were first trained with their preferred hand (cylinder/sphere, convex/concave, pillar/diabolo, block/spikes), and then with their non-preferred hand (block/spikes, T/L, cone/pyramid) - see also Tables III and IV for a list of the tasks; II. visual successive discrimination performance (VSDP), modified slightly from Hamilton and Vermeire ~5 - the modifications are detailed with the Results - and given to 19monkeys; III. visual separation between cue and response (Landmark), given to 11 monkeys exactly as described in Mishkin et al. 26, except that the animals were first trained, and then tested 14 days later for retention, with the non-preferred hand restricted; IV. auditory successive discrimination performance (ASDP),

modelled closely on VSDP (e.g. again symmetrically rewarded Go/No-GO) with a 1-kHz tone as rewarded stimulus, white-noise of equal intensity (viz. 79 dB) as the unrewarded stimulus, both emitted from a centrally located overhead speaker and given to 11 monkeys; and V. balancing performance, given to only 4 operated and 4 unoperated animals (see Results for further details). Tasks 1-IV were given to both hands tested individually.

RESULTS The Mann-Whitney U-test has been used throughout for statistical comparisons between groups. The one-tailed P values are reported when P = < 0.05 ; but caution is advised since no correction has been made for multiple comparisons. In the case of TDP the present 6 unoperated monkeys did not differ statistically from the 5 unoperated macaques of Garcha et al. 12. Since one of us (G.E.) has participated in both studies, the two groups of unoperated animals were combined to constitute a control group of 11 animals; but the results from only 3 additional unoperated animals were available on tasks of graded roughness/size discrimination. (Only the newly described operated animals, totalling 14, were included in the statistical tests.)

I. TDP The performance scores are to be found in Tables III and IV. In interpreting these (and also subsequent) scores, allowance should be made for the difficulties in balancing groups (already discussed under Subjects), and in particular for the necessity of allocating 3 animals without consistent hand preferences to the groups with insular removals. Five out of 7 monkeys changed their preferred hand after removals contralateral to it; but animal Inc-4 (with a large removal of the insula) and animal SIic-2 (despite a near-total removal of SII and some damage to the internal capsule) failed to change, as did also all of the animals with ipsilateral removals. Animal SIic-2 died from causes unrelated to surgery after it had completed most of its tactile training.

10 TABLE IlI

Performance on 6 tactile tasks, the first given pre- and postoperatively, the other 5 given postoperatively Figures are the number of trials required to reach standard levels of performance. * indicates the animals that changed their preferred hand after operation. + indicates the animals that did not show a strong hand preference before operation. F indicates that the animals failed to reach the standard level in the stated number of trials. E indicates the number of errors made when the learning score is zero. In the case of the one task, Block/spikes, values are shown only for the non-preferred hand (but the animal had previously been trained first without restriction of any hand, and then with restriction of the non-preferred hand, on this task). Preop., peroperatively; postop., postoperatively.

Preferred hand

Non-preferred hand

Preop. Postop.

Animals

Weight (kg)

Cylinder/sphere Concave~convex Pillar/diabolo

Block/spikes

Shapes T/L

lnc-1 Inc-2 Inc-3 Inc-4

1.7 5.4 4.9 2.5

110 + 200 340 100

SIIc-1 SIic-2 SIic-3

2.7 3.6 2.1

lni-1 Ini-2 Ini-3 Ini-4

Cone/pyramid

20* 0/3E* 190" 50

80* 90* 20* 220

30* 220* 200* 250

110 20 0/4E 0/0E

200 620 1060 520

130 60 320 50

250 220 130

70* 60 0/4E*

120' 70 70*

130' 430 260*

190 0/1E 90

880 270 1000F

460 221) 750

3.6 3.0 3.6 3.1

80 + 250 320 + 180

0/2E 0/7E 0/1E 30

50 60 30 90

150 290 200 400

10 0/4E 60 0/5E

1000F 1140F 160 560

320 330 I100F 520

SIIi-1 SIIi-2 SIIi-3

2.4 4.4 2.1

270 160 170

0/2E 0/0E 0/1E

90 70 40

160 140 170

10 0/5E 10

780. 560 420

170 260 710

Unop-1 Unop-2 Unop-3 Unop-4 Unop-5 Unop-6

2.5 2.4 2.2 2.3 2.1 2.3

280 + 60 + 120 + 220 200 + 150 +

0/1E 0/5E 0/2E 0/4E 0/1E 0/3E

80 20 50 100 40 50

90 120 100 250 80 320

0/1E 0/0E 0/0E 0/2E 0/2E 0/0E

450 390 410 300 200 340

60 50 90 260 40 330

Comparison of contralateral vs ipsilateral removals In only a single comparison was the combined contralateral group of 7 animals significantly inferior to the combined ipsilateral group of 7 animals: at re-learning after surgery the discrimination between cylinder and sphere first learned before surgery (P = 0.006). The most severe impairment at this stage was shown by 2 animals (Inc-3 and SIIc-1) using the hand ipsilateral to the removals (i.e. the postoperatively preferred hand, which was not the one preoperatively preferred); less severely impaired were the 2 animals, Inc-4 and SIic-2, still using the contralateral hand (since

their hand preference did not change); least severely affected were 3 animals, Inc-1, Inc-2 and SIic-3, using the ipsilateral hand. At this stage the entire contralateral group was also significantly impaired (P = <0.02) in comparison with the unoperated group; and the contralateral SII group in comparison with the ipsilateral SII group (P = 0.05). Subsequently, only a weak trend in the same direction was obtained when learning with the preferred hand to discriminate concave/convex. This trend was absent thereafter, and even reversed on the last learning task (cone/pyramid), now with enforced usage of the non-preferred

TABLE IV

Performance on 3 tactile tasks given only before (Roughnesses), before and after (Sizes) or only after (C/D) visual training; and on the successive auditory task Figures in the case of Graded Roughnesses and Sizes are terminal thresholds indicating grades of carborundum papers discriminable from 320 or diameters (in mm) of cylinders discriminable from 1.27; in the case of the last 3 columns are the number of trials required to reach standard levels of performance. E has the same significance as in the previous table. - indicates that this animal gave no results. The headings P.h. and Np.h. indicate use respectively of the preferred or non-preferred hand.

Before visual training

After visual training

Animals

Graded roughness P.h. Np.h.

Graded sizes P.h. Np.h.

Graded sizes Shapes C/3 Np.h. P.h.

Auditory successive P.h. Np.h.

Inc-I Inc-2 Inc-3 Inc-4

135 230 90 110

90 200 55 110

1.36 1.33 1.43 1.46

1.40 1.36 1.63 -

30 80 30 -

1360 2130 2310 -

4O 5O 7O

SIIc-1 SIIc-2 SIIc-3

230 250 110

90 110 70

1.33 . 1.38

50

1610

120

-

-

Ini-1 Ini-2 Ini-3 Ini-4

260 165 135 125

90 80 55 90

SIIi- 1 SIIi-2 SIIi-3

200 230 150

Unop-1 Unop-2 Unop-3 Unop-4 Unop-5 Unop-6

135 230 165 150 165 165

1.46 1.38 1.69 1.40 1.40 1.36

1.40 . -

1.40 1.36 1.36 " 1,36

1.36 1.40 1.69 1.38

1.34 1.40 1.69 -

150 280 50 -

1070 1110 1270 -

20 10 10

90 100 125

1.36 1.33 1.36

1.46 1.33 1.36

1.46 1.33 -

70 I0 -

990 5t0 -

90 50

135 200 150 135 165 185

1.38 1.36 1.38 1.36 1.34 1.40

1.33 1.38 1.33 1.33 1.33 1.34

1.33 1.36 -

60 100 -

1600 1090 _

.

h a n d ; i n d e e d at c o n e / p y r a m i d t h e 7 i p s i l a t e r a l a n i m a l s w e r e s i g n i f i c a n t l y ( P = 0.02) s l o w e r t h a n the control group, whereas the 7 contralateral a n i m a l s w e r e not. T h e c o n t r a - a n d i p s i l a t e r a l g r o u p s d i d n o t differ in t h e i r t e r m i n a l t h r e s h o l d s at r o u g h n e s s o r at size d i s c r i m i n a t i o n ; b u t b o t h the c o n t r a l a t e r a l ( P = 0.006 a n d P = < 0 . 0 0 1 ) and also the ipsilateral group (P = <0.001 and P = 0.006) g a v e significantly h i g h e r t h r e s h o l d s r e s p e c t i v l y o n t h e r o u g h n e s s a n d size t a s k s t h a n did the unoperated control animals when using their n o n - p r e f e r r e d h a n d . ( T h r e s h o l d s w e r e a l s o significantly elevated for the individual lesion g r o u p s , viz. i n s u l a r / S I I a b l a t i o n s , w i t h t h e n o n preferred hand; but no group differed from control a n i m a l s w i t h t h e p r e f e r r e d h a n d . )

.

.

m

10 0/2E B

Comparison o f left vs right removals In no comparison did the combined group of 5 a n i m a l s w i t h t h e l e f t - s i d e d r e m o v a l s differ significantly from the combined group of 9 animals w i t h r i g h t - s i d e d r e m o v a l s . H o w e v e r , at l e a r n i n g to d i s c r i m i n a t e b e t w e e n T / L , t h e 3 a n i m a l s w i t h left-sided insular removals (P = <0.02) and the c o m b i n e d left g r o u p ( P = < 0.002) r e q u i r e d m o r e trials t h a n d i d t h e u n o p e r a t e d c o n t r o l s ; a n d at c o n e / p y r a m i d t h e c o m b i n e d r i g h t - s i d e d g r o u p req u i r e d m o r e trials t h a n t h e c o n t r o l s ( P = < 0.05). T h e left- a n d r i g h t - s i d e d g r o u p s d i d n o t differ in t h e i r t e r m i n a l t h r e s h o l d s at r o u g h n e s s o r at size d i s c r i m i n a t i o n . ( A g a i n , b o t h g r o u p s d i f f e r e d sign i f i c a n t l y f r o m t h e c o n t r o l a n i m a l s at b o t h t a s k s with their non-preferred hand, but not with the preferred hand.)

12

H. VSDP The procedures of Hamilton and Vermeire ~5 were modified: training was in a W G T A ; stimuli were mounted on cardboard plaques (6 × 6 cm) presented one at a time on a central food-well in a wooden board; the monkey was allowed 6 s to displace the rewarded stimulus, or was rewarded (by hand) if it failed to displace the negative stimulus within 6 s; the hand not currently being trained was always restricted with a weighted bail; training was to 72 correct responses in 80 consecutive trials (72/80) for the 4 tasks listed in Table V (but animals were adapted to the en-

forced usage of a particular hand by pretraining with a weighted bail attached to the other hand to 45/50 on the task just learned with the other hand; in the case of the very first task they were adapted by pretraining on cylinder/sphere). All 6 unoperated animals were still available for comparison, but one insular animal was excluded (see legend to Table V).

Comparison of contralateral vs ipsilateral removals No consistent differences between groups were obtained (see 4 left-hand columns of Table V). However, when animals were first adapted to use of the non-preferred hand by training on

TABLE V Performance on 4 successive visual discrimination tasks and on the task with spatial separation between cue and response Figures and symbol E as in previous tables; symbols P.h. and N.p.h. as in Table IV. Animal SIic-2 is not included as it gave no results on these tasks. Animal Inc-1 has been included in the table but not in any statistical evaluation of the data for visual successive (Go/No-go), since it was inadvertently trained on the Green/yellow and Plus/square tasks with the Np.h. and on the Red/blue and Curves/star tasks with the P.h. Visual successive (Go~No-go)

Landmark Spatial separation 0 cm

Animals

Green/yellow P.h.

Red/blue Np.h.

Plus~square P.h.

Inc-1 Inc-2 Inc-3 Inc-4

420 150 110 140

160 50 90 140

80 30 30 50

SIIc-1 SIic-3

170 110

30 60

Ini- 1 Ini-2 Ini-3 lni-4

70 110 80 80

SIIi-1 SIIi-2 SIIi-3 Unop-1 Unop-2 Unop-3 Unop-4 Unop-5 Unop-6

Curves/star Np.h.

5 cm

0 cm

5 cm

Preferred hand

Non-preferred hand

70 40 50 70

80 160 30 .

.

20 30 30 .

50 40

70 60

320 .

.

60 60 100 120

40 110 10 50

70 90 50 110

240 120 330 .

110 350 80

60 30 130

90 30 30

80 40 60

460 350 .

350 100 90 80 60 190

50 0/8E 110 130 50 70

150 50 40 40 30 130

80 40 80 70 70 90

450 490 . . . .

200 1220 1430 . 90

0/3E .

90

.

180 120 140

.

0/3E 0/3E 0/3E .

120 190

.

0/IE 0/3E .

120 90

. . . .

0/2E 0/2E . . . .

520 120 980 . 430 520 . 440 920 . . . .

120 230 190

13 green/yellow (just learned with the preferred hand), the 5 contralateral animals required significantly more trials (P = 0.012) than the 7 ipsilateral monkeys and the 3 contralateral insular animals more trials (P = 0.028) than the 4 ipsilateral insular animals (scores are not tabulated as this was an adaptation task).

Comparison of left vs right removals In no comparison did the combined group of 5 animals with left-sided removals differ significantly from the combined group of 7 animals with right-sided removals.

III. Landmark The procedures of Mishkin et al. 26 w e r e exactly followed except that: the hand not currently being used was always restricted with the weighted ball; animals were allowed 14 days rest after meeting the criterion at 5 cm separation with a particular hand and then retrained (to 90/100) with the same hand. These retention scores were uniformly low and are not tabulated. Only Unop-1 and Unop-2 were available for comparison.

Comparison of contralateral vs ipsilateral removals No consistent differences between groups were obtained (see 4 right-hand columns of Table V). However, when animals were first adapted to use the non-preferred hand by training on 0 cm (previously learned with the preferred hand), the 3 animals with contralateral removals of the insula required significantly more trials (P = 0.05) than the 3 with ipsilateral removals of the insula. Combining the results on VSDP and Landmark, the contralateral animals were found to be impaired only when usage of the non-preferred hand was initially enforced; thereafter the animals performed well with this hand, and no differences were obtained with the preferred hand. Comparison of left vs right removals Again no differences between left-sided removals (n = 4) and right-sided removals (n = 5) were obtained.

Additional tasks (TDP) After the visual training shown in Table V, the animals were re-tested for TDP (see columns 5 and 6 of Table IV). On graded sizes with the nonpreferred hand, the contralateral and ipsilateral groups still differed in their terminal thresholds from unoperated animals ( P - 0.029 and P = 0.044), but not from each other; no differences were obtained on a new task (C/D) trained to 72/80 with the preferred hand. IV. ASDP Except that training with either hand was to 90/100, the procedures remained as for VSDP; the scores are in Table IV. The contralateral group was impaired relative to the ipsilateral group (P = 0.008), and animals with contrallateral insular removals relative to those with ipsilateral insular removals (P = 0.05), during acquisition with the preferred hand. The latter comparison was again significant (P = 0.05) during re-training with the non-preferred hand. No differences between left- and right-sided removals were obtained.

V. Balancing Animals were tested for their ability to move between two points 150 cm apart along a rope; and retain their balance when positioned on a narrow support which was rotated. Only animals Inc-4, Ini-4, SIic-3 and SIIi-3 (as well as certain unoperated animals) were tested. No abnormalities were observed.

VI. Summary of results The large majority of training procedures yielded no significant differences between groups. Exceptions were of 3 kinds: (1)irrespective of whether the insula or area SII was removed, and irrespective of whether the removal was contra- or ipsilateral to the preoperatively preferred hand, performance with the hand contralateral to a unilateral removal was significantly impaired at roughness and at size thresholds in operated animals in comparison with unoperated animals,

14 and in the case of sizes this defect persisted over 1 year; (2) the entire group with removals contralateral to the preoperatively preferred hand was significantly impaired in comparison with the ipsilateral group when using the postoperatively preferred hand (generally ipsilateral to the removal) to (a)relearn a tactile discrimination, and (b) learn an auditory discrimination; and (3)the entire contralateral group, and the contralateral insular group, were significantly impaired in comparison with the respective ipsilateral groups when using the postoperatively non-preferred hand (contralateral to the removal) during the training procedures given as adaptation to a new task, whether it was (a) VSDP, (b) Landmark, or (c) ASDP. In no comparison were ipsilateral animals significantly impaired with respect to contralateral animals; or those with left-sided ablations in comparison with those with right-sided removals; or did those having SII ablations differ significantly from those with insular ablations. DISCUSSION

Histological findings The study of Friedman et al. 9 appeared only after all the insular ablations had been made. Although exclusively an anatomical study, it suggests that only anterior Ig (as well as posterior Id) is relevant for TDP (see pp. 332, 345 ofref. 9), whereas our ablations were guided by earlier work 23. The findings of Tables I and II, taken together with the additional autoradiographical data for Inc-4 and Ini-4, indicate that the removals did extend more posteriorly than might have been necessary (i.e. to include the most posterior portion of the insula). Perhaps more important, however, is that the relevant cortex was totally removed most probably in all animals except Ini-3 (and possibly Ini-1). Moreover, in no animal with an insular ablation was there severe damage to SII. Although small areas of damage extended for 2-3.5 mm behind the posterior end of the insula, all SII removals were generally as intended. In particular, in this study there were only 3 SII monkeys with damage to the internal capsule (extending only over 3 mm in SIIc-2 and SIIi-3). The

insula (other than the dorsal 2 mm which is part of SII) was damaged only in SIIc-1. The subsequent Discussion will focus on the role of the insula and of SII. However, the authors are aware that other structures have been damaged (unilaterally): the claustrum in many animals; the lower bank of the lateral fissure in most insular animals; and other structures (Ri, lower 7b, etc). The possible contribution to the behavioural changes of such (unilateral) damage is not known.

Beha vioural findings Comparison between present results and those of ref 12. The present results on TDP differ from the earlier ones in that: the performance of the present contralateral animals with their postoperatively preferred hand - in 5 monkeys the hand ipsilateral to the removal - was only transiently impaired, but more severely and for longer in the previous study; the performance of the present ipsilateral animals with their postoperatively non-preferred hand - in most monkeys the hand contralateral to the removal was (exept on block/spikes) more severely impaired than in the previous study; there was also greater variability within groups in this than in the previous study. Cerebralasymmetries. Hamilton ~4has reviewed the considerable evidence in support of some degree of cerebral asymmetry in the monkey. That such asymmetry can be demonstrated is no longer in doubt. Unresolved, however, remain questions as to: (1) the role of sensemodality; (2) the nature of tasks that are/are not asymmetrically organized (cf. ref. 14); (3) the role of gender and of age at the time of testing (cf. ref. 16); (4)the brain structure(s) that mediate(s) the behavioural asymmetries (cf. ref. 12); and (5)whether it is the hemispheres contra-/ipsilateral to the preferred hand that differ (cf. refs 12, 15) and/or the left/right hemispheres (cf. refs. 13, 16). The present findings may provide some tentative answers. First, at least in the case of structures or systems responsive to more than a single modality, the modality of the sensory inflow may be less important than the nature of the task (since the contralateral group was impaired in respect to

15 the ipsilateral group on only one tactile task but also at ASDP). Second, the contralateral animals may have been selectively impaired with the preferred hand on account of the successive requirements which provided a common feature on both tactile and auditory tasks (although it then is not clear why these animals were impaired on only one tactile and on no visual successive task). In any case the suggestion of Burton 4 that sensory deficits can account for all the T D P defects seems untenable; the present monkeys were impaired at learning a shape discrimination with the preferred hand, but were not impaired on either sensory task with this hand. Third, the contralateral insular animals were selectively impaired when initially required to shift from use of the postoperatively preferred to the non-preferred hand on two visual and one auditory task (but not on block/spikes in TDP) - even when the task requirements remained unaltered after unimpaired learning with the preferred hand. This suggests that the insula of the predominant hemisphere is involved in the response organization of both hands, an impairment arising only in the contralateral insular group when the second hand was to take over from the first in new situations. Fourth, the asymmetrical organization of insular cortex may differ (quantitatively and/or qualitatively) from that of SII (since in certain comparisons the contra-/ipsilateral insular groups differed, whereas the contra-/ipsilateral SII animals did not differ). Lastly, earlier reports that in the monkey cerebral asymmetry in T D P can be associated with the preferential usage of one hand, are supported, although only to a limited degree. It is recognized that many paradoxes remain. For instance, by exact analogy to Hamilton's 14 results in vision, certain findings in T D P - from this and the earlier study of Garcha et al.12 _ implicate hand preference instead of left/right differences as the important factor underlying cerebral asymmetry in the monkey; and yet at the same time other findings in T D P - from H0rster and Ettlinger 19 suggest that left/right differences also exist. So far we do not know when the one or other kind of organization is important. Again, although heavy commissural connections to SII have been carefully documented =, yet, in un-

-

published 2-DG studies, HOrster et al. observed one monkey (of 19) with consistently stronger labelling of the ipsilateral hemisphere after performance of a graded roughness threshold task with its preferred hand. The insular cortex. Since in many of our animals the 'in sular' removals were confined - as intended to the posterior insula, the present observations apply, strictly, only to this subdivision. In respect to T D P the findings differ markedly from those briefly described in the abstract of Murray et al. 32. Our animals having unilateral removals were not impaired, as were their animals having bilateral removals, at learning unfamiliar tactile tasks (e.g. those of Table III, or the initial discriminations between the most different roughness/size pairs). This discrepancy could merely reflect differences between unilateral and bilateral insular removals. However, our (unilateral) animals were impaired, in contrast to their (bilateral) animals, at roughness/size thresholds when tested with the hand contralateral to the unilateral removals. It then seems unlikely that unilateral removals give rise to less impairment at new learning but to more impairment at thresholds than do bilateral removals. A resolution of the discrepant results will have to wait upon more information becoming available from Murray et al. No clear-cut differences emerged by comparing lesion groups from within the present study (or from a comparison with those animals of Garcha etal. 12 having removals exclusively of SII) between the effects upon T D P of removing respectively the insula or SII. Thus, for example, animals USII-5 o f G a r c h a et al. and Inc-3 of this study are similar in that both were severely impaired at roughness and size thresholds in both hands following unilateral removals of SII or of the insula. The impaired terminal threshold values with the non-preferred hand in the majority of the present insular group overlap widely with those of the present and previous SII groups, but a weak trend exists in the direction of more severe impairment in insular than in SII-ablated animals. In no group was there a trend towards impairment with the preferred hand on either sensory task (whereas Garcha etal. ~2 had obtained a significant defect on sizes with this hand after contralateral -

16

removals of SII). Therefore, it has not been possible to establish within TDP a hierarchical organization, for instance of the kind: 'insula involved in learning/memory; SII in the detection of small somatosensory differences', as might be expected from the convergence of both SII and PPC onto the insula (see Introduction). However, animals with contralateral insular but not those with contralateral SII removals were impaired on one visual task (see Results). Taken with the additional but still controversial evidence 24"29 that non-somatosensory systems (visual/auditory) also may project (partly via the thalamus) into the insula but not into SII, the insula is perhaps a site of polysensory confluence instead of a region of higher-order somatosensory processing. (This evidence has, however, been questioned by Friedman et al. 9 who believe that any auditory input to the insula '... is largely, if not entirely, segregated (in the posteroventral sector) from the somatic portions of the insula' (p. 343), and who did not report a visual input.) If the insula can indeed be regarded as functionally polysensory, then PPC and SII would be converging onto the insula as sources of fully processed somatosensory inflow into a polysensory system conveying information onwards to the amygdala and hippocampus. At the level of the insula (at least in the case of the predominant hemisphere), this system would be involved in sequential performance and response organization, irrespective of the modality of the sensory inflow. (It remains possible, although unlikely, that the visual deficits in the insular animals are related to damage to the claustrum, and the auditory deficits to damage to the lower bank of the lateral fissure.)

ACKNOWLEDGEMENTS

We thank the D F G who supported this work and W.H. under Grants Et 10/3-1 and Et 10/9-1 ; Mrs. G. Immelmann for performing some of the training; Prof R. Schnabel for processing the 10 brains examined histologically; and Dr. A.D. Milner as also an anonymous referee for helpful criticism of earlier versions of this paper.

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