Topographical memory impairments after unilateral lesions of the anterior thalamus and contralateral inferotemporal cortex

Neuropsychologia 42 (2004) 1178–1191

Topographical memory impairments after unilateral lesions of the anterior thalamus and contralateral inferotemporal cortex R. M. Ridley, H. F. Baker∗ , D. A. Mills, M. E. Green, R. M. Cummings Department of Experimental Psychology, Downing Street, Cambridge CB2 3EB, UK Received 13 August 2003; received in revised form 23 December 2003; accepted 4 February 2004

Abstract Monkeys with crossed unilateral excitotoxic lesions of the anterior thalamus and unilateral inferotemporal cortex ablation were severely impaired at learning two tasks which required the integration of information about the appearance of objects and their positions in space. The lesioned monkeys were also impaired at learning a spatial task and a task which required the integration of information about the appearance of objects and the background on which the objects were situated. Monkeys with only one of the unilateral lesions were not impaired and previous work has shown that monkeys with bilateral lesions of the anterior thalamus were not impaired on these tasks. These results indicate that the whole of the inferotemporal cortex-anterior thalamic circuit, which passes via the hippocampus, fornix, mamillary bodies and mamillothalamic tract, is essential for the topographical analysis of information about specific objects in different positions in space. Together with previous work, the results show that a unilateral lesion may affect cognition in the presence of other brain damage when an equivalent bilateral lesion alone does not. The tasks required the slow acquisition of information into long term memory and therefore assessed semantic knowledge although other research has shown impairment on topographical processing within working or episodic memory following lesions of the hippocampal-diencephalic circuit. It is argued that the hippocampal-diencephalic circuit does not have a role in a specific form of memory such as episodic memory but rather is involved in topographical analysis of the environment in perception and across all types of declarative memory. © 2004 Elsevier Ltd. All rights reserved. Keywords: Spatial learning; Marmoset monkey; Hippocampus

1. Introduction The anterior thalamic nucleus (AT) is a target area of the output of the medial temporal lobe memory circuit which includes the hippocampus, fornix, mamillary bodies and the mamillary thalamic tract (Aggleton, Desimone, & Mishkin, 1986). Kopelman (1995) has argued that the memory impairments seen in Korsakoff’s syndrome and other diencephalic amnesias are a consequence of damage to the AT rather than other thalamic areas such as the mediodorsal thalamic nucleus (MD). Harding, Halliday, Caine, and Kril (2000) found that damage in the AT was consistently associated with memory impairments whereas damage in the mamillary bodies and the MD was found in Wernicke’s encephalopathy with and without amnesia. ∗ Corresponding author. Present address: Innes Building, School of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK. Tel.: +44-1223-339-015; fax: +44-1223-339-014. E-mail address: [email protected] (H.F. Baker).

0028-3932/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2004.02.005

There have, however, been relatively few neuropathological reports of damage confined to the AT (e.g. Daum & Ackerman, 1994; Hankey & Stewart-Wynne, 1988) so it is difficult to determine the contribution which this nucleus makes to memory function from the study of patients with circumscribed lesions. Imaging studies have not elucidated the function of this area in humans although 2-deoxyglucose methods have indicated that the AT and other thalamic areas are involved when macaques are performing working memory tasks (Friedman, Janas, & Goldman-Rakic, 1990). Maguire, Frackowiak, and Frith (1997) and Maguire et al. (1998) used functional imaging to demonstrate a role for the hippocampus in recollecting information from both very long term memory and more recent memory about the spatial layout of the environment. This form of topographical memory, together with some non-spatial memory functions (Maguire & Frith, 2003), may be important components of the memory for events of everyday life in which the hippocampus has been specifically implicated. The rest of the

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hippocampal-diencephalic circuit may also be involved in memory for spatial layout. Macaques find it easier to discriminate between pairs of virtual ‘objects’ on a computer screen when each pair of ‘objects’ is placed in a fixed position against a unique, patterned background (the object-in-place task) rather than against a plain background which does not vary between pairs of objects (the concurrent discrimination or reward association task) (Gaffan, 1994). Macaques with fornix transection (Gaffan, 1994), or heat lesions of the mamillary bodies (Parker & Gaffan, 1997b) or the AT (Parker & Gaffan, 1997a) are impaired on the object-in-place task although it is not clear whether this is because performance on this task requires a form of memory specific for the recollection of the events of previous trials (episodic memory) as proposed by the authors of those papers, or a form of allocentric spatial (topographical) representation throughout declarative (working, episodic and semantic) memory. We have previously found that bilateral excitotoxic lesions of the combined AT and MD produce an impairment in marmoset monkeys which is confined to performance of the visuospatial task (Ridley, Maclean, Young, & Baker, 2002). In this task, the monkey has to choose the object on the left when one pair of identical objects is presented, and the object on the right when a different pair of identical objects is presented (see Fig. 1). Macaques with fornix transection (Gaffan et al., 1984) are also impaired on a task which is almost identical to the visuospatial task. These tasks have certain formal similarities to the object-in-place task since correct choice of an object is dependent on the position of the object on the test-tray. It differs from the object-in-place task in that the visuospatial task is a difficult task which requires many trials of acquisition, and which may therefore, depend on semantic memory, whereas the object-in-place task requires very few trials per pair of objects and may tax a form of memory within the episodic domain. Nonetheless the visuospatial task also resembles the object-in-place task in that performance is also impaired by lesions of the hippocampal-diencephalic circuit, specifically fornix transection (Ridley, Thornley, Baker, & Fine, 1991) or excitotoxic hippocampal lesions (Ridley, Timothy, Maclean, & Baker, 1995). In view of this finding it was surprising that marmosets with bilateral lesions confined to the AT were not impaired on this or other memory tasks (Ridley et al., 2002) since, as described above, the AT is the target of the mamillothalamic tract, and therefore, of the rest of the hippocampal-diencephalic circuit. In an attempt to investigate further the role of the AT in topographical memory, we have performed an excitotoxic lesion of AT in one hemisphere and an inferotemporal cortex (IT) ablation in the other hemisphere in marmoset monkeys. We have compared performance on tasks dependent on topographical memory and tasks which require various aspects of non-topographical memory. Our reasoning was that the IT ablation would interrupt the ventral stream carrying visual perceptual information into the hippocampal-diencephalic

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Fig. 1. Diagram illustrating the learning tasks with two types of trial per task. The rectangle is the test-tray. The black blobs are the food-wells (numbered 1–4 in the four hole test-tray, see text) which can be covered with the appropriate objects labelled A to F. + and − indicate where reward is hidden. All test-trays were white except in the background spatial task where the trays are patterned and labelled W or X. For each task, the two test-tray layouts shown were presented to the monkey in pseudorandom order. Thus, in the simple object discrimination task reward was always to be found under object A which could appear over the left or right food-well. In the spatial task, four sub-tasks, each using two test-tray layouts presented pseudorandomly, were given consecutively. In each sub-task, the reward was to be found in the positions shown. In the visuospatial task, the left/right position of the reward depended on whether objects D and D or E and E were presented. In the background spatial task, the left/right position of the reward depended on whether background W or X was presented.

memory circuits in one hemisphere and that lesioning the AT in the other hemisphere would, therefore, expose an impairment on tasks which were dependent on interactions between IT and AT.

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2. Materials and methods

Schwerdtfeger (1980). AT lesions were made by injecting 1.0 ␮l NMDA into three sites unilaterally, at co-ordinates AP 0.73 cm, L 0.11 cm, V 1.13 cm; AP 0.68 cm, L 0.11 cm, V 1.18 cm; AP 0.63 cm, L 0.15 cm, V 1.23 cm. Each injection was made over at least 2–3 min and the needle was left in place for at least a further 1 min before it was repositioned for the next injection. The injection resulted in tachycardia and hyperventilation, but this was usually of only a few minutes duration and was controlled by making the injections slowly. Following surgery the monkeys were injected subcutaneously with 1 mg/kg flunixin meglumine analgesia (Finadyne, Schering-Plough, Mildenhall, UK) and transferred to an incubator in a quiet, dim environment. The monkeys were returned to their home cages on the morning following surgery and resumed cognitive testing one week later.

2.1. Monkeys and surgery Twelve marmoset monkeys (Callithrix jacchus) were used. All monkeys were laboratory-bred, weighed 300–450 g, and were young adults (32 ± 2.8 S.E.M. months old) at the start of the experiments. Each monkey was housed with a cage-mate of similar age. Where mixed-sex pairs were housed together, the male was vasectomised. All procedures were carried out under a Project Licence in accordance with the UK Animals (Scientific Procedures) Act 1986. Following preoperative testing (see Table 1 for complete testing schedule), each monkey was assigned to one of three groups that were matched as far as possible for learning ability. Monkeys A-D (two male, two female) received unilateral lesions of AT followed, after some cognitive testing, by contralateral suction ablations of IT (Group AT × IT). Monkeys E-H (one male, three female) received unilateral suction ablations of IT followed, after some cognitive testing, by contralateral excitotoxic lesions of AT (Group IT × AT). Monkeys I-L (two male, two female) were unoperated controls (Group C).

2.3. Unilateral ablation of the inferotemporal cortex (IT) The monkeys were premedicated with 0.05 ml ketamine (100 mg/ml i.m.), injected with 2 mg/kg dexamethasone (i.m.) to limit cerebral oedema, and anaesthetised with 18 mg/kg alphaxalone–alphadolone (i.m. Saffan, ScheringPlough UK). A supplementary injection of 10 mg/kg Saffan (i.m.) was given after ∼1.5 h if required. Following skin incision and unilateral retraction of the temporal muscles, a large craniotomy was performed. A stellate incision was made in the dura mater over one hemisphere and the temporal lobe exposed. The temporal lobe was gently elevated, when necessary, to expose the floor of the cranium, and cortical tissue was removed by suction using a bent, gauge-19, opthalmic (blunt) needle. The ablation was extended posteriorly to the place where the temporal lobe begins its

2.2. Unilateral excitotoxic lesion of the anterior thalamic (AT) nucleus The monkeys were anaesthetised with an intramuscular (i.m.) injection of 18 mg/kg alphaxalone–alphadolone (Saffan, Schering-Plough, Welwyn Garden City, UK). N-methyl-d-aspartic acid (NMDA, 0.12 M in 0.85% saline, adjusted to pH7.4 with 1N NaOH) was injected stereotaxically according to the atlas of Stephan, Baron, and Table 1 Number of trials to criterion (±S.E.M.) Task

Control

Group AT + IT

Group IT + AT

Significance

Preoperative Obj Dis 1 (90/100)a Obj Dis 2 (27/30) Vis Spat 1 (90/100)

80 ± 26 (0)b 38 ± 34 (0) 611 ± 240 (0)

108 ± 15 (0) 32 ± 10 (0) 787 ± 176 (0)

116 ± 60 (0) 157 ± 40 (0) 821 ± 71 (0)

n.s. n.s. n.s.

Post-surgery 1 Ret Vis Spat 1 (54/60) Vis Spat 2 (54/60)

128 ± 62 (0) 193 ± 59 (0)

101 ± 66 (0) 158 ± 66 (0)

247 ± 369 (0) 175 ± 35 (0)

n.s. n.s.

Control

Combined lesion groups

Post-surgery 2 Ret Vis Spat 2 (54/60) Vis Spat 3 (54/60) Succ Dis (54/60) Spat Vis (54/60) Vis Vis (54/60) Spatial (9/10 × 4) Background spat (54/60) Vis Spat 4 (54/60) a b

53 191 155 182 313 106 106 25

± ± ± ± ± ± ± ±

31 36 38 56 48 17 22 13

(0) (0) (0) (0) (0) (0) (0) (0)

166 376 213 393 437 198 198 173

± ± ± ± ± ± ± ±

31 (0) 24 (7) 37 (1) 7 (7) 42 (2) 31 (0) 31 (2) 41 (1)

Number of correct trials required/predetermined number of consecutive trials. Number of monkeys failing each task, see text.

P = 0.048 P = 0.008 n.s. P = 0.004 P = 0.048 P = 0.048 n.s. P = 0.016

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descent from the occipital lobe and medially, at that level, until the brain stem was sighted. The dorsolateral extremity of the ablation was the line of the superior temporal dimple (a small depression in the cortex equivalent to the superior temporal sulcus in macaques, running parallel to the lateral sulcus, midway between the lateral sulcus and the convexity of the temporal lobe). Anteriorly, the ablation was extended to leave the temporal pole intact and to avoid entering the lateral sulcus. Anteromedially, the ablation was extended to slightly beyond the depth of the temporal lobe to a cortical dimple equivalent to the rhinal sulcus in macaques. The dura mater were sewn using 6/0 vicryl sutures. The bone flap was repositioned, the temporal muscles were resewn with 3/0 Mersilk sutures and the skin resewn with 3/0 vicryl sutures. Monkeys recovered from surgery in incubators for two to three days. They were hand fed and watered as necessary. Welfare logs recording all drug administration and a rating scale of well-being were kept for all monkeys while they were housed in incubators. The five point rating scale was recorded at least twice per day along with a description of any unusual behaviours which were observed. Cognitive testing recommenced seven days after surgery.

keys were given about 40 trials per day, until a criterion of 90% correct was reached over a predetermined number of consecutive trials (see Table 1 for required criterion for each task). The intertrial interval was about 15 s. The measure of learning ability (the learning score) was the number of trials up to, but not including, those in criterion. Where monkeys were unable to reach criterion in 400 trials (or 600 trials for the visuovisual task which unlesioned monkeys found difficult), the monkeys were deemed to have failed the task and were awarded the score of 400 (or 600) trials. This score is an underestimate of the magnitude of their impairment but monkeys (like humans) may develop a ‘failure set’, and therefore, never learn a task which they find too difficult. The following types of task were used (see Figs. 1 and 2 for illustrative assistance).

2.4. Cognitive testing

2.4.2. Successive object task (Succ Dis) (see Fig. 2) Three different junk objects (G, H, and I) and the white test-tray with two food-wells were used. On each trial, either object G (rewarded) was presented together with object H (unrewarded) or object H (rewarded) was presented together with object I (unrewarded) in a pseudorandom order. Thus, object G was always rewarded, object I was never rewarded and object H was rewarded on half the trials. Inspection of object H on any trial was, therefore, uninformative and the monkey had to learn to approach object G and avoid object

The monkeys were tested in a Wisconsin general test apparatus using standard techniques (Baker & Ridley, 1986). For each task, the monkeys were given a series of trials on which small, multicoloured junk objets (e.g. pen tops, cotton reels mounted on small white plastic disks) were presented and the monkeys were required to displace one of the objects to uncover a reward (a small piece of marshmallow) or, if their choice was incorrect, an empty food-well. The mon-

2.4.1. Simple object discrimination (Obj Dis) (see Fig. 1) Two different junk objects (A and B) were used. The test-tray was white and contained two food-wells, one on the left and one on the right. The left/right position of the objects varied pseudorandomly from trial to trial but the reward was always to be found under object A irrespective of its position.

Fig. 2. Diagram illustrating the learning tasks with four types of trial per task. In the successive object task, object G was always rewarded, object I was never rewarded and object H was rewarded when presented together with object I but was not rewarded when presented together with object G. In the spatiovisual task, object J was rewarded when objects J and K were presented over the left food-wells, and object K was rewarded when objects J and K were presented over the right food-wells. In the visuovisual task, object L was rewarded when the objects were presented on background Y and object M was rewarded when the objects were presented on background Z.

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I when only one of these latter two objects was present on any one trial. This task was a non-spatial, non-conditional control task for the visuospatial task in which object pair D and D had to be discriminated from object pair E and E when only one pair of objects was present on any one trial (see below). 2.4.3. Spatial task (spatial) (see Fig. 1) One white test-tray with four food-wells (food-wells 1–4 arranged in a left to right row) and one pair of identical objects (C and C) were used. On some trials the objects were placed over food-wells 1–2 and on other trials over food-wells 3–4, in a pseudorandom order. The unused food-wells were open and empty. Initially (sub-task 1) the object on the left of the pair of objects (food-well 1 compared to 2 or food-well 3 compared to 4) was rewarded to a criterion of 9/10. Then (sub-task 2) the object on the right of the pair (food-well 2 compared to 1 or food-well 4 compared to 3) was rewarded to a criterion of 9/10. Then (sub-task 3) the object nearest the middle of the test tray (food-well 2 compared to 1 or food-well 3 compared to 4) and finally (sub-task 4) the object nearest the edges of the test-tray (food-well 1 compared to 2 or food-well 4 compared to 3) were rewarded to a criterion of 9/10. Although the task is spatial in that, in any one sub-task, two positions are rewarded and two are not, the monkey can solve the task egocentrically by moving to the appropriate places in space. The task does not rely crucially on allocentric topographical analysis of environmental space. This task is non-conditional in that, in any of the sub-tasks, two positions are always rewarded and two are not. The task is non-contextual because objects of different appearance do not have to be evaluated differently against different backgrounds. 2.4.4. Visuospatial task (Vis Spat) (see Fig. 1) Two pairs of identical objects (D and D) and (E and E) and one white test-tray with two food-wells, were used. On each trial, only one pair of identical objects was used and trials using each pair were presented in a pseudorandom order. On each trial one object was placed over the left food-well and the other, identical, object was placed over the right food-well. When pair D and D was used, reward was placed only in the left food-well, and when pair E and E was used, reward was placed only in the right food-well. The visuospatial task is a topographical object-in-place task because correct choice of an object depends on its appearance and its position on a test-tray. This task is also a conditional task, i.e. ‘when objects D and D are present, choose the object on the left; when objects E and E are present, choose the object on the right’. 2.4.5. Spatiovisual task (Spat Vis) (see Fig. 2) One white test-tray with four food-wells (food-wells 1–4 arranged in a left to right row) and two objects (J and K) were used. On some trials, objects J and K were placed over food-wells 1–2, and on other trials, over food-wells 3–4 in

a pseudorandom order. The unused food-wells were open and empty. When food-wells 1–2 were used, reward was always to be found under object J. When food-wells 3–4 were used, reward was always to be found under object K. The spatiovisual task is a topographical object-in-place task in that correct choice of an object depends on its appearance and its position on the test-tray. This task is also a conditional task, i.e. ‘when both objects are on the left half of the tray, choose object J; when both objects are on the right half of the test tray, choose object K’. 2.4.6. Visuovisual task (Vis Vis) (see Fig. 2) Two distinctively patterned coloured test-trays (Y and Z) each with two food-wells, and two junk objects (L and M) were used. When objects L and M were presented on test-tray Y, only object L was rewarded; when objects L and M were presented on test-tray Z, only object M was rewarded. The test-trays were presented in pseudorandom order across trials and the left/right position of the two objects, L and M, over the two food-wells varied across trials according to a different, superimposed, pseudorandom schedule. The Visuovisual Task is a conditional task, i.e. ‘when the test-tray is Y, choose object L and when the test-tray is Z, choose object M’. It differs from the visuospatial task in that the reward cannot be found by reference to the spatial location of an object and the task does not, therefore, assess topographical memory. It could, however, be referred to as an object-in-context task rather than an object-in-place task. 2.4.7. Background spatial task (Background Spat) (See Fig. 1) Two distinctively patterned coloured test-trays (trays W and X) each with two food-wells and two identical objects (F and F) were used. When the objects were presented on test-tray W, reward was in the left food-well; when the objects were presented on test-tray X, reward was in the right food-well. The test-trays were presented in pseudorandom order across trials. The background spatial task is conditional, i.e. ‘when the test-tray is W, go left; when the test-tray is X, go right’. This task is also spatial because the monkey can solve the task by moving to an appropriate place although that place is not defined by the object in that place. This task is also contextual in that correct response depends on the background presented. 2.5. Histology When all testing was finished, the lesioned monkeys were perfused for histological examination. Following premedication with 0.05 ml ketamine (100 mg/ml i.m.), the monkeys were deeply anaesthetised with 1.0 ml sodium pentobarbitone (200 mg/ml i.p.) and perfused transcardially with 350 ml saline followed by 300 ml 10% formalin in saline. The brains were removed and stored in 10% formalin/saline for approximately one week, after which they were cut into

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blocks and wax-embedded. Sections were cut at 8 ␮m thickness and were stained with cresyl violet.

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There were no differences between the three groups on the three tasks learnt prior to surgery.

Lesioned monkeys were also severely impaired on learning the spatiovisual task (Spat Vis, P = 0.004). Only one lesioned monkey (monkey B) was able to learn this task in <400 trials. Lesioned monkeys were impaired on learning the visuovisual task (Vis Vis, P = 0.048) and on learning the spatial task (Spatial, P = 0.048). Two monkeys (monkeys D and H) were unable to learn the visuovisual task in <600 trials but all monkeys were able to complete the spatial task. There was no impairment on learning the successive object task (P = 0.368), in which object G had to be discriminated from object I when only one of these objects was present on any one trial. It is, therefore, unlikely that the lesioned animals failed the visuospatial task because they could not compare objects DD and EE when only one pair was present on each trial. Performance on the background spatial task was not significantly impaired (P = 0.933) although two lesioned monkeys (monkeys D and H) could not learn this task in <400 trials.

3.3. Learning and retention after first surgery

3.5. Histology

There were no group differences on retention of the visuospatial task learnt prior to surgery (Ret Vis Spat 1), or on learning a new visuospatial task (Vis Spat 2) following unilateral excitotoxic lesion of AT, or unilateral suction ablation of IT. This is to be expected in monkeys where there is no evidence of lateralisation of specific visual functions. Subsequent impairment on this type of task following second surgery cannot be ascribed to the effect of either unilateral lesion alone.

The lesioned areas of AT and IT in each monkey are shown in diagrammatic form in Figs. 3 and 4 and photographs of AT in monkey H are shown in Fig. 5. The AT was substantially lesioned unilaterally in all monkeys. Within the lesioned area there was complete loss of neuronal cell bodies, severe gliosis and tissue shrinkage but no cavitation. The lesion incorporated the whole of the main anterior part of AT (at AP 7, Stephan et al., 1980) except for a small area in monkey C, and extended into the posterior part of AT (at AP 6) except for a very small part in monkeys A, E and F. The lesion did not extend into the stria terminalis or the thalamic and hypothalamic areas anterior to AT at AP 8. There was some damage in the anterior part of the dorsomedial thalamus at AP 6 and AP 5 in monkeys A, B, G and H. There was a small amount of damage in the ventroanterior thalamic nucleus at AP 7 in monkey F. The midline thalamic nuclei were spared and the lesion did not encroach into the other hemisphere in any monkey. The lesion, therefore, incorporated all of the intended area in all monkeys and did not extend consistently beyond the intended area. The mamillary body ipsilateral to the AT lesion showed shrinkage indicative of retrograde degeneration in all monkeys. The IT was ablated in the hemisphere opposite to the AT lesion in all monkeys (see Figs. 3 and 4). Posteriorly, the lesion extended to the point of descent of the temporal lobe in all monkeys except monkey A. Anteriorly, some tissue in the temporal pole was spared in all monkeys. Laterally, the lesion extended up to the superior temporal dimple (equivalent to the superior temporal gyrus in macaques) in monkeys A, B, E and F but was somewhat less extensive in monkeys C, D, G and H. Medially, the perirhinal cortex, i.e. the area between the perirhinal dimple and the rhinal dimple which comprises neocortex and is, therefore, part of IT, was

3. Results 3.1. Cognitive testing Since some learning tasks were curtailed at 400 or 600 trials, it was appropriate to compare groups using non-parametric tests. Kruskal–Wallis tests were used for three-group comparisons and Mann–Whitney tests were used for two-group comparisons. Learning scores are shown in Table 1. 3.2. Preoperative learning

3.4. Learning and retention after second surgery Since second surgery consisted of adding the other lesion to the contralateral hemisphere in both groups of monkeys, both lesioned groups now had the same combined lesion. Comparison of the learning scores of these two groups revealed that they did not differ from each other and so Group AT × IT and Group IT × AT were combined. Comparison of this combined group with the unoperated control group indicated that the crossed AT/IT lesion resulted in learning impairment on retention of the visuospatial task first learnt after the first surgery but before the second surgery (Ret Vis Spat 2, P = 0.048). This indicates that both the IT and the AT participate in the process of retention of this type of information. Lesioned monkeys were also very substantially impaired on new learning of a visuospatial task given shortly after the second surgery (Vis Spat 3, P = 0.008). Only one lesioned monkey (monkey F) was able to learn this task in <400 trials. Impairment on this type of task was also sustained. Lesioned monkeys remained impaired when given a further example of this type of task at the end of testing (Vis Spat 4, P = 0.016) and one monkey (monkey H) could not learn this final task in <400 trials.

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Fig. 3. Diagram illustrating the extent (shaded area) of the AT and the IT lesion in each of the four monkeys in Group AT × IT (monkeys A–D). The lesion distribution is shown at AP 7 (the level just in front of the mamillary bodies), AP 6 (the level of the mamillary bodies), AP 5 (the level of the substantia nigra) and AP 4 (the level of the habenula). Thalamic nuclei: A, anterior; MD, mediodorsal; M, midline; VA, ventroanterior; VL, ventrolateral; VP, ventroposterior; Ce, central; P, pulvinar; Hb, habenular nucleus; CC, corpus callosum.

ablated in monkeys C and H, ablated along part of its length in monkeys D and F and spared in monkeys A, B, E and G. The lesion did not encroach into the entorhinal cortex, medial to the rhinal dimple, nor into any of the medial temporal lobe structures in any monkey. Fig. 6 shows the intact temporal lobe and the lesioned temporal lobe in monkey A, where the IT ablation did not include the perirhinal cortex, and in monkey D, where the IT ablation did include the perirhinal cortex. It was not possible to correlate lesion size with impairment on the topographical memory tasks because 6/8 le-

sioned monkeys failed both the first visuospatial and the first spatiovisual tasks. Monkeys D and H showed a more widespread disability than the other lesioned monkeys. Monkey H failed to reach criterion on all the conditional tasks including the contextual, non-spatial visuovisual task, and the contextual, spatial background spatial task, and the final visuospatial task which most other lesioned monkeys learnt, albeit with difficulty. Monkey H failed all the conditional tasks and also failed to learn the non-conditional successive object task. Monkey H sustained the largest amount of damage within MD and the largest ablation within the perirhinal

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Fig. 4. Diagram illustrating the extent (shaded area) of the AT and the IT lesion in each of the four monkeys in Group IT × AT (monkeys E–H), see Fig. 3.

cortex, although the IT lesion was not large on the lateral surface. The additional impairment in this monkey cannot, however, be attributed to either of these two areas of damage alone. Monkey C sustained an equally large removal of the perirhinal cortex but was substantially impaired only on the visuospatial and spatiovisual tasks. Monkey D, who like monkey H, failed to learn the object-in-place tasks, the contextual, non-spatial visuovisual task and the contextual, spatial background spatial task, sustained no thalamic damage outside AT and only a partial ablation of the perirhinal cortex. There was no relationship between the amount of perirhinal damage and the degree of impairment. Monkey F, the only lesioned monkey to learn the first visuospatial

task and monkey A, the only lesioned monkey to learn the spatiovisual task, sustained AT and IT lesions with no obvious sparing compared to the damage in the other lesioned animals.

4. Discussion This series of tasks has shown that monkeys with crossed unilateral lesions of the anterior thalamus and unilateral ablations of the inferotemporal cortex are severely impaired at learning tasks which require the integration of information about the appearance of objects and their positions in

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Fig. 5. (A) Thalamic area in monkey H. The intact AT is on the right and the lesioned AT is on the left. Thalamic nuclei: A, anterior; M, midline; VA, ventroanterior; bar = 2 mm. (B) Intact neurones of the AT; bar = 100 ␮m. (C) Gliotic tissue within lesioned AT; bar = 100 ␮m.

space. These monkeys also show impairment on a spatial task, and on a task which requires the integration of information about the appearance of objects and the background on which the objects are situated irrespective of their positions. This combination of lesions does not disrupt performance of a successive visual discrimination or a task in which spatial responding depends solely on the background information.

Fig. 6. Temporal lobe area. (A) Intact side in monkey A. The area between the arrows indicates the perirhinal cortex. (B) Monkey A with IT ablation which spared the perirhinal cortex. This image has been flipped horizontally to make comparison with the others easier. (C) Monkey D with IT ablation which included the perirhinal cortex for part of its extent; bar = 1 mm.

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4.1. Anatomical basis of the impairment The current experiment demonstrates that information must be able to pass from the inferotemporal cortex to the anterior thalamic nucleus for certain memory functions to be sustained. One temporal lobe was intact and was able to sustain normal learning on the successive object task and the contextual background spatial task. Yet this tissue, in the absence of the unilateral AT, could not sustain acquisition of the topographical memory tasks (the majority of lesioned monkeys failed to acquire these tasks) and was inefficient at sustaining acquisition of other spatial, conditional or contextual tasks (the majority of lesioned monkeys did learn these tasks but with higher scores than the control monkeys). The hippocampal-diencephalic circuit was intact in the opposite hemisphere and was deprived only of the visual information normally processed in IT. The hippocampal-diencephalic circuit must, therefore, be dependent on information from IT for its normal function (the nature of which is considered in the next section). Here we will consider other lesions which produce a similar pattern of impairments on related tasks. Monkeys with bilateral lesions within the hippocampal-diencephalic circuit, like the monkeys in the current experiment, were severely impaired on the topographical memory tasks, i.e. the visuospatial task (Ridley, Aitken, & Baker, 1989; Ridley et al., 1991; Ridley et al., 1995) and the spatiovisual task (Ridley et al., 1995) and were also modestly impaired on the visuovisual task (Ridley et al., 1989; Ridley, Gribble, Clark, Baker, & Fine, 1992; Ridley et al., 1995). This latter observation indicates that the hippocampal-diencephalic circuit has conditional non-spatial functions, and therefore, agrees with the findings of others (Brasted, Bussey, Murray, & Wise, 2003). However, monkeys with fornix transection or lesions of the diagonal band, like the monkeys in the current experiment, were also impaired on purely spatial tasks (Ridley et al., 1989, 1991). Monkeys with lesions of the diagonal band, like the monkeys in the current experiment, were not impaired on the background spatial task (Ridley et al., 1989). This confirms that performance of the background spatial task is not dependent on the integrity of the hippocampal-diencephalic circuit, even though this task is contextual, conditional and spatial. Sziklas and Petrides (1999) found that rats with bilateral AT lesions were impaired on a task which was similar to the spatiovisual task but were not impaired on a task which resembed the background spatial task, emphasising the dependence of these two tasks on different cognitive strategies. Our previous experiments showed that bilateral lesions of AT + MD impaired performance on the visuospatial task while bilateral lesions of either AT or MD alone did not (Ridley et al., 2002). Although the lesions of AT in the current experiment may have encompassed a greater part of the intended area than some of the AT lesions in the previous experiment, one of the bilateral AT lesions in the previous experiment was very large and yet no learning

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impairment was seen in that monkey. The unilateral IT lesion in the monkeys in the current experiment would have reduced the visual information about objects flowing into MD (Russchen, Amaral, & Price, 1987) and into frontal cortex (Ungerleider, Gaffan, & Pelak, 1989) as well as into the hippocampal-diencephalic circuit. But this alone does not account for the impairment since unilateral IT lesions, in the absence of lesions in the other hemisphere, are without behavioural effect. However, the current experiment shows that, when there is visual dysfunction in unilateral IT cortex, hippocampal-diencephalic circuit, MD and frontal cortex, the addition of a contralateral AT lesion is sufficient to produce impairment. That MD and frontal cortex make an additive contribution is suggested by the greater effect of a unilateral MD plus frontal lesion, compared to a unilateral lesion of MD or frontal cortex alone, when crossed with an amygdala lesion (Gaffan & Murray, 1990; Gaffan, Murray, & Fabre-Thorpe, 1993) (albeit on a different task in macaques). Our series of experiments on thalamic lesions has not been able to show that AT and MD make different contributions to memory or that either thalamic nucleus is essential for certain forms of memory while the other is not. The observation that AT + MD lesions produce impairments which are not seen following lesions of AT or MD alone (Ridley et al., 2002) might suggest that each nucleus can substitute for the other, either by sustaining the same cognitive skill, or by providing an alternative cognitive skill by which the monkey can succeed on the relevant tasks. However, the results of the current experiment caste doubt on this interpretation. Here, MD is anatomically intact in both hemispheres and only deprived of some of its visual input in one hemisphere and yet memory is impaired, whereas bilateral lesions of MD did not result in impairment. The IT lesion is, therefore, contributing to the learning impairment by virtue of its effect on more areas than just MD. However, although IT ablation will reduce visual information in the ipsilesional AT (via the diencephalic circuit), this also is not sufficient to explain the impairment since bilateral AT lesions also did not result in impairment. The results of the current experiment are, however, compatible with the view that thresholds for impairment may be reached in relation to the amount of brain damage within certain disseminated brain systems. This may be observed in humans where substantial bilateral damage within the temporal lobes results in a denser clinical amnesia than damage confined to the hippocampal-diencephalic circuit (Gaffan & Gaffan, 1991; Kapur et al., 1994; Rempel-Clower, Zola, Squire, & Amaral, 1996; Scoville & Milner, 1957). A similar relation between amount of damage and degree of impairment has been reported in macaques with experimental lesions (Zola-Morgan, Squire, & Ramus, 1994), although not all authors have found this effect (Meunier, Hadfield, Bachevalier, & Murray, 1996). This possible effect of ‘mass action’, does not, however, indicate whether all these areas contribute to the same cogni-

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tive skill which is required to solve certain tasks, or whether the tasks which are impaired in this series of experiments can be solved using a combination of different cognitive skills so that different lesions make different, but cumulative, contributions to task performance. Some indication in favour of the latter may be gleaned from certain differences in the pattern of impairments which is seen after different lesions. For example there is a gradient of impairment on the visuovisual task which varies with locus of damage within the temporal lobe-diencephalic circuit. Crossed lesions which include CA1 and IT produce substantial impairment (Barefoot, Baker, & Ridley, 2002; Barefoot, Maclean, Baker, & Ridley, 2003), crossed lesions of IT and AT produce significant impairment (the current experiment), and bilateral lesions of AT and/or MD produce no impairment (Ridley et al., 2002). Thus, thalamic lesions cause impairments on this task only when there is additional damage in at least one temporal lobe. A less marked gradient exists for the visuospatial task; impairment was substantial in the current study and following AT + MD lesions (Ridley et al., 2002), fornix transection (Ridley et al., 1991) or bilateral CA1 lesions (Ridley et al., 1995). Only bilateral lesions of AT or MD alone did not disrupt performance of this task. This less marked gradient, together with the difference between the substantial impairment on the visuospatial task and the impairment on the visuovisual task in the current experiment, suggests a greater contribution of the thalamic nuclei to spatial than to non-spatial analysis. However, the severe impairment on the visuospatial task, the impairment on the spatial task, and the lack of impairment on the background spatial task in the current experiment indicate that not all forms of spatial processing are equally affected by the lesion. A differential degree of impairment on the visuospatial task and the spatial task is also seen following fornix transection (Ridley et al., 1991). Gaffan and Parker (1996) have argued that the fornix and the perirhinal cortex co-operate to integrate information about objects-in-place since the fornix serves spatial functions and the perirhinal cortex serves object identification (Meunier, Bachevalier, Mishkin, & Murray, 1993). We largely agree with this view but the impairment on visuovisual tasks, seen following crossed unilateral AT/IT lesions and other hippocampal-diencephalic lesions (see above) suggests that the hippocampal-diencephalic circuit, including AT, contributes to the non-spatial visual functions of the IT. Conversely, impairment on the spatial task seen following crossed unilateral AT/IT lesions suggests that the hippocampal-diencephalic circuit takes information from the IT even for the performance of purely spatial tasks within the visual domain. The greater effects of lesions within the temporal lobe compared with the effects of lesions of the anterior thalamus on these object-in-place and object-in-context tasks emphasises the role of other inputs into the temporal lobes, including the cholinergic inputs via the fornix and tem-

poral stem (Gaffan, 2002), and possibly outputs of the hippocampal-fornix circuit to destinations other than the thalamus. It is of interest to note that monkeys with AT/IT lesions were impaired on retention as well as new learning of the visuospatial task. Our previous experiments had shown that bilateral lesions of AT + MD impaired retention of this task whereas bilateral lesions of either AT or MD did not. This suggests that the entire temporal lobe-diencephalic circuit is activated when retention occurs. 4.2. The nature of the impairment We have shown that, when the visual perceptuo/memory functions are disrupted in one hemisphere, damage to AT alone in the other hemisphere is sufficient to impair performance of tasks requiring topographical memory (the visuospatial and the spatiovisual tasks). Both tasks are conditional and spatial because whether an object of a particular visual appearance is rewarded depends on the position of that object on the test-tray. No one position or object is consistently rewarded. To solve the task, the monkeys have to integrate information about the appearance of objects and their positions, i.e. both tasks are topographical object-in-place tasks. Although the monkeys could, perhaps, have learnt an egocentric motoric response (go leftwards, or go rightwards) on each type of trial, it is more likely that they chose between the two objects on the basis of the position of the objects relative to each other, i.e. allocentrically. This interpretation of the dependence of the visuospatial and spatiovisual tasks on topographical memory is strengthened by the lack of impairment on the background spatial task. Although the latter task has certain similarities to the visuospatial and the spatiovisual tasks, it differs in one crucial aspect. Like these tasks, no one position, object or background is consistently rewarded. However, unlike in the other two tasks, only two identical objects are used on every trial and the objects merely serve to indicate the positions of possible responses. The monkeys are, therefore, choosing an object on the left or the right in response to a background where the information driving that response is spread across the entire test-tray. The monkeys, therefore, do not have to integrate information about the appearance of the objects and their positions. This task is, therefore, not an object-in-place task and, even though it is both conditional and spatial, does not require topographical memory. All lesioned monkeys in the current experiment failed to learn at least one of the visuospatial and spatiovisual tasks and 6/8 lesioned monkeys failed both, when the failure score was more than twice the mean of the learning scores in the control monkeys and above the score of the highest scoring control monkey. This constitutes a severe impairment. Macaques with fornix transection are also severely impaired on both these tasks (Gaffan & Harrison, 1989)

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and a patient with mild diencephalic amnesia was unable to master the visuospatial task despite persistent effort (Frith, Cahill, Ridley, & Baker, 1992). These results indicate that lesions of the hippocampal-diencephalic circuit produce severe memory impairments within a limited domain. Object recognition tasks assess another domain of memory centred on the perirhinal cortex (Eacott, Gaffan, & Murray, 1994; Meunier et al., 1993) leading to an anatomical dissociation between topographical memory and recognition memory. Object recognition tasks can no longer be used to assess ‘amnesia’ in a non-specific sense. This dissociation within memory strengthens the view that memory processing is not located within one dedicated brain system but rather occurs in all those brain areas which are involved in the equivalent perceptual processing, e.g. topographical perceptual analysis and memory in the hippocampal-diencephalic circuit; object perception and recognition in the perirhinal cortex. That the business of the hippocampal-diencephalic circuit is topographical cognitive processing (during acquisition and retention) rather than memory per se is indicated by the observation that memory for a visuospatial task, which has been ‘destroyed’ by a CA1 lesion, can be ‘reinstated’ by transplantation of experientially na¨ıve, fetal hippocampal tissue into the lesioned hippocampal area (Virley et al., 1999). The lesioned monkeys were impaired on the visuovisual task. This task is conditional in that correct choice of object depends on which background the objects are presented on. It is not spatial because the background covers the entire test-tray and the rewarded object of the pair can appear over the left or right food-well. Correct solution does not depend on integrating information about the objects and their positions. It does depend, however, on integrating information about the objects and the visual context in which they appear. This task could be referred to as an object-in-context task but not as an object-in-place task. Topographical memory for the layout of stimuli and the position of rewarded object choices on previous trials may, however, provide a non-obligatory contribution to task solution and the loss of this facility may account for the impairment by lesioned monkeys on this task. A similar argument has been adduced to explain the mild impairment shown by macaques with fornix transections on object recognition tasks (Gaffan, 1992). The lesioned monkeys were also impaired on the spatial task, which is not a conditional task because, during any sub-task, reward was always to be found in two of the four food-wells and the objects were identical on all trials. It resembles the spatiovisual task in that trials on which the two food-wells on the left were used were interspersed with trials on which the two food-wells on the right were used. These tasks differ, however, in that for the spatiovisual task, correct choice is dependent on integrating information about the appearance of objects and their positions on the test-tray whereas in the spatial task correct choice is dependent merely on identifying the correct positions of the reward. Since this is very easy, the task was rendered more difficult by presenting four consecutive sub-tasks in each of

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which different combinations of food-wells were rewarded. The ability to change the rule from one sub-task to another may have been facilitated by the non-obligatory use of topographical memory and this may account for the impairment. However, all lesioned monkeys learnt all components of this task whereas 7/8 lesioned monkeys failed the spatiovisual task. 4.3. Conclusion In rodents, lesions of the AT lead to impairments on allocentric spatial working memory which are associated with hypoactivity in the hippocampal-diencephalic circuit, measured by c-Fos expression (Jenkins, Dias, Amin, & Aggleton, 2002). This indicates that lesions within the hippocampal-diencephalic circuit can have profound effects on the functioning of other, anatomically intact, parts of the circuit. The IT has direct and indirect inputs into the hippocampus (Suzuki & Amaral, 1990; Suzuki & Amaral, 1994; Witter & Amaral, 1991). The performance of the object-in-place scene memory task in macaques is dependent on the interaction of the perirhinal cortex and the fornix (Gaffan & Parker, 1996). The current experiment extends the neuroanatomy of this functional interaction by demonstrating that impairment is seen on object-in-place tasks after crossed unilateral lesions of IT (which did not include perirhinal cortex in all animals) and AT. Furthermore the scene memory task used in macaques is, strictly speaking, both an object-in-place and an object-in-context task since the objects to be remembered appear at unique positions against a unique patterned background. The current experiment shows that memory for both formulations depends on the hippocampal-diencephalic circuit but, using tasks which distinguish between them, we have found that this circuit probably makes a greater contribution to the integration of objects with place than with context. The scene memory task is (arguably) an episodic memory task (Gaffan, 1994) whereas the tasks used in the current experiment rely on slow, multi-trial, acquisition into long term memory which (arguably) require the use of semantic memory. Activation of AT has been shown following performance of working memory tasks in macaques (Friedman et al., 1990). This all suggests that the IT to AT circuit is required for the cognitive integration of visual and spatial information, irrespective of the type of memory which is involved. This ability may be crucial to various aspects of declarative memory because it is in declarative memory that objects have unique identities and unique occurrences. The perirhinal cortex makes a major contribution to the identification of objects by virtue of their individual appearance (Buckley & Gaffan, 1998; Murray & Bussey, 1999) but objects have an on-going uniqueness even in the presence of other objects of identical appearance. The hippocampal-diencephalic circuit may preserve this uniqueness by keeping track of individual objects across time and space.

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