1 INSERM U 289, , 2 Service d'Exploration Fonctionelles du Système Nerveux, , 3 Service de Neurologie I, , 4 Service de Neurochirurgie, Hôpital de la Salpêtrière, Paris, France and , 5 Klinik für Neurologie, Charité, Berlin, Germany
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Abstract |
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Introduction |
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Although the PHC appears to perform neuronal computations relevant for certain spatial tasks, previous lesion studies (Bohbot et al., 1998; Ploner et al., 1999
) did not clarify whether spatial memory functions of the medial temporal neocortex are confined to the PHC. Moreover, despite the fact that most of the communication between MTL and association cortices of the dorsal stream passes through the PHC, spatially selective neuronal activity is also present in the rostral MTL (Suzuki et al., 1997
). Disconnection of rostral MTL regions therefore remains a possible explanation for spatial memory deficits with PHC lesions. Up to now, the effects of PRC and PHC lesions on human spatial memory have not yet been compared. In the present study, we therefore investigated spatial memory in patients with postsurgical lesions involving the right PRC, in patients with postsurgical lesions involving the right PRC and PHC, and in controls. A delayed oculomotor response task (memory-guided saccades) with unpredictably varied memory delays of up to 30 s was used. This task assesses spatial memory in a retinotopic, egocentric frame of reference. It has previously been shown that patients with selective lesions of the hippocampal formation perform normally in this paradigm, whereas patients with additional involvement of the adjacent medial temporal neocortex show a persisting, lateralized, delay-dependent spatial memory deficit (Ploner et al., 1999
). Here, the question was addressed whether spatial memory functions of the human medial temporal neocortex are differentially represented in PRC and PHC.
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Materials and Methods |
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In humans, the rostral border of the PRC usually coincides with the rostral end of the collateral sulcus (Insausti et al., 1998). Laterally, the transition from the PRC to the inferotemporal cortex occurs within the lateral bank of the collateral sulcus (Insausti et al., 1998
). Medially, the PRC is bordered by the entorhinal cortex. The transition between both cortices occurs within the medial bank of the collateral sulcus (Insausti et al., 1995
, 1998
). Caudally, both the PRC and entorhinal cortex are replaced by the PHC, which occupies the caudal portion of the collateral sulcus and parts of the parahippocampal gyrus (Amaral and Insausti, 1990
). On sections perpendicluar to the anterior commissure/posterior commisure line (ACPC line) this transition is marked by the caudal end of the gyrus intralimbicus (Insausti et al., 1998
) and the rostral limit of the lateral geniculate nucleus (LGN) (Amaral and Insausti, 1990
; Insausti et al., 1995
). As the gyrus intralimbicus is removed in patients undergoing amygdalo-hippocampectomy or temporal lobe resections, the LGN is the critical landmark in these cases. On sections perpendicular to the ACPC line, the distance between temporal pole and the transition zone between PRC and PHC is ~4850 mm (Amaral and Insausti, 1990
; Insausti et al., 1998
). On sections perpendicular to the Sylvian fissure or the longtitudinal axis of the hippocampus, the spatial relationship between LGN and this transition zone changes. On such sections, the transition between PRC and PHC is several millimeters anterior to the rostral limit of the LGN, at ~4244 mm from the temporal pole (Ploner et al., 1999
). Sections at the level of the LGN therefore show the PHC.
Lesion Reconstruction
The patients' lesions were identified on coronal magnetic resonance imaging sections perpendicular to the Sylvian fissure (Fig. 1) and transposed on anatomical standard sections of a right human temporal lobe taken from the atlas of Matsui and Hirano (Matsui and Hirano, 1978
). Figure 2
shows sections at distances of 27, 39 and 50 mm from the temporal pole, arranged from rostral to caudal, showing the PRC (27 and 39 mm sections) and the PHC at the level of the LGN (50 mm section). Moreover, the distance between temporal pole and the posterior limit of collateral sulcus involvement was measured. Lesion volumes were determined by outlining lesions on individual sections with the help of an image analysis program (Scion Image, Scion Corp., USA).
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Patients were four women and two men (mean age 32.7 years), who had undergone partial resection of the right MTL for the treatment of pharmacoresistant epilepsy (Table 1). Speech representation was left-sided in all patients, as defined by preoperative intracarotid sodium amobarbital testing. All patients were outside the immediate post-operative period, with a minimum delay of 11 months between resection and testing. All patients were normal on neurological examination. All patients were free of additional neurological or psychiatric disorders and received comparable anticonvulsant medication in regular dosages. The control group consisted of three women and seven men with a mean age of 31.5 years (range 2350), without any history of neurological disorders. All subjects gave informed consent before participation in the study, which was approved by the local ethics committee and conducted in conformity with the Declaration of Helsinki.
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Eye Movement Recordings
Eye movements were recorded by using horizontal direct current electrooculography with bitemporal electrodes. Data were sampled at a frequency of 200 Hz. The system had a bandwith of 0100 Hz and a spatial resolution of 0.5°. Subjects were seated in complete darkness with the head fixed at the temples. Visual cues were presented at a distance of 85 cm with red light-emitting diodes (LEDs) forming a curved horizontal array. LEDs were 0.18° in size and 5 cd/m2 in luminance. Each recording session was preceded by 10 min of dark adaptation. Each subject performed two recording sessions on different days. Each session lasted ~30 min, with a break of 5 min to avoid fatigue.
Memory-guided Saccades
In this paradigm (Ploner et al., 1999), a visual cue was presented for 500 ms in one of six pseudorandomly varied horizontal positions at either 10°, 15° or 20° eccentricity, while the subject fixated on a central fixation point (Fig. 3
). After a delay of pseudorandom duration, during which fixation was maintained, the central fixation point was switched off and the subject moved his/her eyes as precisely as possible to the remembered cue position. After 3 s, the central fixation point was reilluminated and after an intertrial interval of 4 s the next trial began. Delays were varied between short (5 and 10 s), intermediate (15 and 20 s) and long (25 and 30 s) durations. Twelve trials were recorded for each delay group on each side, so that a total of 72 trials was analyzed per subject. Cues were not reilluminated after execution of saccades to preclude visual feedback of targeting errors. Repetition of cues in consecutive trials was avoided. Calibration was performed every fifth to seventh trial. A zero-delay condition with 12 trials in each direction was added at the end of the second recording session. Here, the subjects had to move their eyes as precisely as possible to the cue as soon as it appeared. Since instructions for the zero-delay condition differed from instructions for the memory condition, both conditions were run separately.
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Data were analyzed off-line. Memory-guided saccade trials with premature saccades were excluded from analysis (5.6% on average, P = 0.065 between groups, KruskalWallis ANOVA). The first saccade after central fixation offset was studied (Pierrot-Deseilligny et al., 1991; Ploner et al., 1999
). Horizontal saccade inaccuracy was expressed as amplitude error (Pierrot-Deseilligny et al., 1991
; Ploner et al., 1999
).
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Additional (corrective) saccades just after initial saccades were rare and did not decrease targeting errors. Therefore, data from final eye positions are similar to those of initial saccades and are not presented. Statistics were done with reference to Altman (Altman, 1991). Medians were used to describe a subject's average amplitude error and were calculated separately for right-and leftward saccades in each delay group. Since size of the patient groups was not sufficient to draw meaningful conclusions on the distribution of the data, non-parametric statistical tests were used throughout. Thus, KruskalWallis ANOVA and two-tailed MannWhitney tests, corrected for multiple comparisons, were used for statistical analysis. Spearman's correlation coefficients were used for correlation analysis.
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Results |
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Discussion |
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Previous lesion studies in humans suggest that spatial memory deficits in patients with temporal lobe lesions do not depend on resection size laterally to the collateral sulcus (Owen et al., 1995, 1996
), but possibly on rostrocaudal lesion extent (Smith and Milner, 1981
, 1989
; Rains and Milner, 1994
). However, because of the conventional surgical approaches to this region, rostrocaudal lesion extent and total lesion volume are in principle not independent variables, rendering the latter finding equivocal. Since in these studies both the posterior hippocampal formation and posterior medial temporal neocortex were involved, and patients with selective lesions of the posterior hippocampal formation were not tested with the same paradigms, the question of possible spatial memory functions of the PHC could not be addressed (Smith and Milner, 1989
; Rains and Milner, 1994
). Here, these ambiguities were largely ruled out, since we tested patient groups with comparable lesion volumes and we found no correlation between lesion volume and memory impairment. Likewise, damage to the posterior hippocampal formation is unlikely to account for the observed spatial memory deficits, as it has previously been shown that patients with selective lesions to the right hippocampal formation extending up to 5.7 cm caudal to the temporal pole perform normally in the paradigm used here (Ploner et al., 1999
). Hence, lesion to caudal medial temporal neocortex, i.e. PHC, may be responsible for the deficits in the PRC+PHC group. However, we cannot rule out the possibility that the observed spatial memory deficits in our PRC+PHC patients are due to conjoint damage of PHC and PRC or to conjoint damage of PHC and hippocampal formation. Despite these limitations, our study allows for the conclusion that the PHC is a critical component for spatial memory itself, at least for the type(s) of spatial memory assessed by an oculomotor delayed response task. Lesions of the PRC are obviously not sufficient to create a significant spatial memory deficit in this paradigm. In a recent study with patients having undergone selective thermocoagulation of MTL subregions performing an analog of the Morris water maze (Bohbot et al., 1998
), a similar conclusion was suggested. Their results from patients with lesions to the right PHC/PRC provided evidence for spatial memory functions of the medial temporal neocortex. Thus, our results extend our previous study (Ploner et al., 1999
) and complement the findings of Bohbot and colleagues (Bohbot et al., 1998
), by suggesting that (i) extrahippocampal spatial memory functions of the MTL may not be equally distributed in the medial temporal neocortex, but may be largely confined to the PHC, and (ii) damage to connections between cortices of the dorsal stream and rostral medial or inferotemporal regions of the temporal lobe is unlikely to account for the observed spatial memory deficits with PHC lesions.
In monkeys, direct connections with posterior parietal and dorsolateral prefrontal cortex put the PHC in a privileged position for spatial memory functions (Goldman-Rakic et al., 1984; Selemon and Goldman-Rakic, 1988
; Cavada and Goldman-Rakic, 1989
; Suzuki and Amaral, 1994a
). Within the MTL, most of the communication between PHC, PRC and hippocampal formation passes through the entorhinal cortex (Insausti et al., 1987
; Witter and Amaral, 1991
). Although the rostral entorhinal cortex is mainly connected to the PRC and its caudal part to the PHC (Suzuki and Amaral, 1994b
), spatially selective neuronal activity is equally distributed in the entorhinal cortex (Suzuki et al., 1997
). This suggests that the PRC relays, by virtue of its reciprocal connections to the PHC, spatial information from the PHC to the entorhinal cortex (Suzuki et al., 1997
). Thus, on a neuronal level, evidence for a functional specialization of the primate PHC for spatial memory is not yet available. We believe that, in the framework of the aforementioned human lesion studies, our results now support the hypothesis that differential extrinsic connections of primate PRC and PHC may be paralleled by a differential functional specialization of both regions regarding their memory functions. At least for spatial information in an egocentric frame of reference, the PHC may be relatively more important than the PRC. The idea of a relative specialization of both regions for memory of either visual or spatial information is further supported by the non-spatial visual memory deficits with PRC lesions that have already been demonstrated for monkeys (Meunier et al., 1993
; Zola-Morgan et al., 1993
) and humans (Buffalo et al., 1998
). Interestingly, the temporal properties of these deficits are similiar to the deficits observed in our PRC+PHC patients (Meunier et al., 1993
; Zola-Morgan et al., 1993
; Buffalo et al., 1998
). Apart from a possible relative specialization of PRC and PHC, this delay-dependency of memory deficits may also explain why previous studies found no deficits in monkeys with MTL lesions performing delayed response tasks (Mahut, 1971
; Murray and Mishkin, 1986
). Compared to our study and the aforementioned studies, delays were relatively short, i.e. 5 s (Mahut, 1971
) and 10 s (Murray and Mishkin, 1986
). Therefore, these results need not to be in conflict with ours. However, the possibility remains that the PRC is involved in more complex forms of spatial memory, where integration of object and spatial information is required (Murray et al., 1998
; Suzuki et al., 1997
).
Humans with lesions involving the PHC have previously been shown to suffer from a syndrome of anterograde topographical disorientation, i.e. an impairment in learning topographical information for navigation in previously unfamiliar environments (Habib and Sirigu, 1987; Barrash et al., 2000
). The possible cognitive deficits underlying this syndrome are probably manifold, as real-world navigation is a complex cognitive task that requires at least integration of spatial relationships and landmarks of the environment with the actual body coordinates of the subject (Aguirre and D'Esposito, 1999
). Anterograde topographical disorientation may thus either result from deficits in creating durable representations of landmarks and spatial relationships between items of the environment (i.e. allocentric spatial representations) and/or spatial relationships between environment and subject (i.e. egocentric spatial representations). In this context, the PHC has been related to representation of allocentric space (Aguirre and D'Esposito, 1999
; Barrash et al., 2000
). Results from functional imaging studies support this interpretation, since activation of the PHC was found with tasks that required encoding of allocentric spatial representations (Aguirre et al., 1996
; Epstein and Kanwisher, 1998
; Maguire et al., 1998
; Epstein et al., 1999
). In our study, memory deficits with PHC lesions were found in a task that required memory of egocentric spatial representations, i.e. in a frame of reference possibly related to functions of the posterior parietal cortex (Aguirre and D'Esposito, 1999
). There are at least two possible interpretations for this discrepancy. (i) Lesions of the PHC may impair functions of the posterior parietal cortex, since it is possible that MTL lesions may result in retrograde effects on afferent areas (Insausti and Munoz, 1999
). In this case, one would expect a more general visuo-spatial deficit that includes tasks without memory demands (Aguirre and D'Esposito, 1999
). The delay-dependency of the deficits in our PRC+PHC patients and in the patients of Bohbot and colleagues (Bohbot et al., 1998
) argues against this interpretation. (ii) PHC lesions may affect some basic function(s) relevant to both egocentric and allocentric forms of spatial memory. This hypothesis could be tested by administration of ego-and allocentric tasks, matched for complexity, to patients with lesions of the PHC. To our knowledge, such an experiment has not been carried out yet. It remains, therefore, to be determined whether an egocentric spatial memory deficit that is largely confined to the visual hemifield contralateral to the lesion side is related to a behaviorally relevant syndrome of anterograde topographical disorientation in free-viewing conditions.
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Notes |
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Address correspondence to Christoph J. Ploner, Klinik für Neurologie, Charité, Schumannstrasse 20/21, D-10117 Berlin, Germany. Email: christoph.ploner{at}charite.de.
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References |
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