Van Der Werf(1047-1062) - CiteSeerX

SPECIAL ISSUE CONTRIBUTIONS OF THALAMIC NUCLEI TO DECLARATIVE MEMORY FUNCTIONING Ysbrand D. Van Der Werf1, Jelle Jolles2, Menno P. Witter3 and Harry B.M. Uylings3,4 (1Cognitive Neuroscience Unit, Montreal Neurological Institute, McGill University, Montreal, Canada; 2Dept Biological Psychology, The Maastricht Brain and Behaviour Institute, The Netherlands; 3Graduate School for Neurosciences Amsterdam, Research Institute Neurosciences Vrije Universiteit Medical Center Amsterdam, Dept Anatomy; 4Netherlands Institute for Brain Research, KNAW, Amsterdam, The Netherlands)

ABSTRACT In spite of the acknowledged role that the thalamus plays in declarative memory, details about the precise memory processes it is involved in and which are the structures of the thalamus that contribute to these processes remain unknown. An overview is presented of human clinical and animal experimental findings showing the involvement of the thalamus, at the level of white matter tracts and separate nuclei, in aspects of memory functioning. The region in the thalamus that contributes to declarative memory is the anterior and medial division, containing the anterior nuclei, the medial dorsal nucleus and the intralaminar and midline nuclei. A lesion to the anterior nuclei or their afferent white matter tract, the mammillothalamic tract, results in deficits of encoding of new stimuli. Lesions to the medial dorsal nucleus affect executive processes pertaining to declarative memory, such as the use of memory strategies for retrieval; damage to the intralaminar and midline nuclei results in decreased arousal and thus affects the declarative memory process. Based on anatomical and functional data, a theory is proposed of how the thalamus might play a role at different levels of declarative memory functioning. Firstly, the anterior and mediodorsal nucleus are involved in processing the contents of the stimuli for storage and recall. The anterior nuclei influence the selection of material to be stored and remembered, whereas the mediodorsal nucleus is involved in the coordination and selection of the strategies used to retrieve material. Secondly, the intralaminar and midline nuclei and specifically the lateral and ventral components, maintain a necessary state of the cortical regions involved in the ongoing memory processes. The two types of function subserved by these groups of thalamic nuclei, focussing on contents vs. state, need to work in parallel to mediate and allow memory functioning, respectively. Key words: thalamus, diencephalon, memory, limbic, frontal, executive, thalamocortical

INTRODUCTION It is commonly appreciated that declarative memory can only be sustained by integrated circuits that encompass areas of the brain that are widely distant and of different structure (Mishkin, 1982; Zola-Morgan and Squire, 1993; Parker and Gaffan, 1997; Milner et al., 1998). An integral part of different circuits underlying memory processes, is the thalamus (Aggleton and Brown, 1999). Issues that remain, however, concern: 1) which thalamic structures are involved in human memory; 2) whether these thalamic structures are involved in some aspects of Cortex, (2003) 39, 1047-1062

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Ysbrand D Van Der Werf and Others

memory, or in all, and; 3) whether separate structures of the thalamus each play a different role in the various memory processes or whether they act in concert. Evidence for thalamic involvement in memory is derived amongst others from patients with infarctions, haemorrhages, mechanical injury or tumours interfering with the integrity of the thalamus. Studies like these have shown a role for the thalamus in the various cognitive functions related to memory: the formation of new memories (Squire et al., 1989; Graff-Radford et al., 1990; Bentivoglio et al., 1997), attention to stimuli and events (Bogousslavsky et al., 1988; Rousseaux, 1994) and the use of memory strategies, part of the so-called fronto-executive functions (Sandson et al., 1991; Van Der Werf et al., 1999). A role in memory, furthermore, has been suggested based on the finding that in patients with alcoholic Korsakoff’s syndrome, the lesions are mainly found in the thalamus (Squire, 1981; Victor et al., 1989; Kopelman, 1995; Mayes et al., 1997; Visser et al., 1999). The evidence for involvement of the thalamus in human memory is, however, often circumstantial and inconclusive due to the inherent variability of clinical studies. Over the years, we have been actively involved in the study of memory functions, using a variety of experimental approaches both in experimental animals and in humans. These include neuropsychological assessments of human cognitive function in normal, elderly and demented patients, the analysis of behavioural experiments in animals and anatomical and electrophysiological studies of the cortico-hippocampal, prefrontal and thalamic systems and their respective interactions (e.g. Dolleman-Van Der Weel and Witter, 1995; Dolleman-Van Der Weel et al., 1997; Groenewegen and Uylings, 2000; Jolles, 1986; Jolles et al., 1995; Tisserand et al., 2000; Uylings and Van Eden, 1990; Uylings et al., 2000; Van Boxtel et al., 2000; Witter et al., 1989). A recent emphasis has been on the the contributions of thalamic structures in cognitive processes (Van Der Werf, 2000, 2001; Van Der Werf et al., 1998, 1999, 2000, 2002; Visser et al., 1999; Witter and Van Der Werf, 1999). It is the aim of the present manuscript to describe the involvement of separate structures in the thalamus in different cognitive processes related to memory. We have restricted our focus to declarative memory, i.e. the memory for facts and events (or semantic and episodic memory). It should be noted, however, that the thalamus is involved in many different aspects of memory and other kinds of cognitive functioning that fall outside the scope of this paper. We will present an overview of findings from studies in healthy subjects, from clinical investigations and animal experimental studies. Based on these data, we will present our hypothesis of ‘focussing’, as the central aspect of the thalamic contribution to declarative memory. THE PLACE

OF THE

THALAMUS

IN

BRAIN CIRCUITRY

The concept of diaschisis The thalamus, located in a central position in the brain, regulates the flow of information from the brainstem and sensory organs en route to other areas, both

The thalamus and memory

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cortical and subcortical. Virtually the whole cortical mantle, and much of the subcortical structures, receive direct projections from the thalamus. The strong connections between thalamus and cortex are a fundamental aspect of the mammalian brain, leading researchers to subdivide the cortical surface on the basis of the input from the thalamus (e.g. Uylings and Van Eden, 1990). The socalled specific nuclei of the thalamus are implicated in sensory and motor circuits, whereas other nuclei are connected with limbic and associational circuits (Steriade et al., 1997, Van Der Werf et al, 2002). In view of its strong connections with other areas of the brain, it is evident that damage to the thalamus described in the clinical studies mentioned in the introduction interrupts the functioning of those areas. The dysfunction of a brain region due to damage elsewhere is called diaschisis and is of special relevance to the concept of cognitive deficits arising from thalamic damage. Diaschisis is visualized in studies that investigate cortical perfusion following a lesion to the thalamus (Baron et al., 1986, 1992; Bogousslavsky et al., 1991; Caselli et al., 1991; Chabriat et al., 1992; Levasseur et al., 1992; Van Der Werf et al., 1999). Similarly, alterations in cortical electrical activity can be seen after lesions in the thalamus (Mäkela et al., 1998). These data stress the fact that the thalamus is part of interconnected circuits including basal ganglia and cortex that underlie many different functions, not only cognitive but also motor and sensory-related (Alexander et al., 1990). The notion of thalamic participation in such networks illustrates why thalamic contributions to cognition are often described in terms of cortical processes, such as medial temporal and prefrontal memory functions (Aggleton and Brown, 1999; Van Der Werf et al., 2000). An example of the latter is the case of a 1-millimeter lesion in the right intralaminar nuclei of the thalamus, resulting in a cognitive profile indistinguishable from a lesion of the dorsal lateral prefrontal cortex (Van Der Werf et al., 1999). This was deducted from tests allowing to distinguish between prefrontal and hippocampal-like memory deficits. THE THALAMUS

IS INVOLVED IN

MEMORY FUNCTIONING

Clinical studies Evidence for the involvement of the thalamus in memory-related functions can be found in patients with lesions to the thalamus, specifically those with selective lesions such as can be found after infarctions of one of the arteries supplying the thalamus. This method relies on the rationale that the loss of cognitive functioning after lesioning of a structure is indicative of the role which that structure, or the circuit it is part of, plays in the intact brain. If possible, patients with lesions restricted to the thalamus and without comorbidities should be selected for such studies, to avoid diffuse damage or damage to other structures that may themselves be involved in memory functions (Van Boxtel et al., 1998). For instance, thalamic infarctions are often a sign of ‘small-vessel disease’ and are thus accompanied frequently by white matter lesions or small lesions in surrounding deep brain structures like the basal ganglia. Such white matter lesions have been shown to be associated with cognitive dysfunctions (De Groot et al., 2000).

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Infarctions do not generally follow anatomic boundaries and thus may damage on the one hand a combination of nuclei of the thalamus, or on the other hand may cause incomplete lesioning of a nucleus. It is therefore necessary to examine the overlap of the lesion patterns in combination with a careful comparison of the accompanying cognitive profile in the different patients. Over the years, such studies have given valuable insight into the kinds of memory processes the thalamus is involved in (e.g. Castaigne et al., 1981; Graff-Radford et al., 1990; Mennemeier et al., 1992, 1997; Van Der Werf et al., 1999; Wallesch et al., 1983). We have described that lesions of the thalamus result in striking deficits in the domain of encoding or retrieval (Van Der Werf et al., 2000). Sometimes the deficits are selective, but an infarction may also produce a dense memory deficit encompassing both encoding and retrieval. This can be shown by using tasks that are sensitive to selective aspects of the memory process, such as verbal word list learning tasks with separate short-term and long-term recall and recognition trials, and visual association paradigms exquisitely sensitive to encoding (Jolles, 1986; Lindeboom et al., 2002; Rombouts et al., 1997; Van Der Werf et al., 1999). A distinction can be made in the severity of memory deficits; they can be so extensive to qualify as an amnesic syndrome, characterized as an anterograde amnesia with a deficit of recall and recognition, or they can be mild and be referred to as forgetfulness. The declarative memory deficits can appear directly comparable to those seen after lesioning of the hippocampus, but may also result from deficits in semantic and strategic aspects of memory functioning that seem more related to functioning of the prefrontal cortex (Sandson et al., 1991; Mennemeier et al., 1992; Pepin and Auray-Pepin, 1993). Lateralization of thalamic contributions to memory The memory deficit following thalamic damage can be found in either the verbal or non-verbal domain, or in both. Ojemann (1977) stated that hemispheric dichotomy also holds at the level of the thalamus. Indeed, sometimes a sharp distinction can be found in patients with unilateral or asymmetrical lesions, for instance in tests of memory: left lateralized lesions may result in purely verbal amnesias, and rightsided infarctions may lead to non-verbal amnesias, and other deficits typically associated with rightsided brain damage, such as anosognosia and neglect. The idea of hemispheric specialization of the thalamus is contradicted, however, by the findings of unilateral lesions causing deficits not only in the domains thought to belong to the ipsilateral hemisphere, but also those of the contralateral (Wallesch et al., 1983; Baumgartner and Regard, 1993; Rousseaux et al., 1986; Van Der Werf et al., 1999). Similarly, decreases in cortical perfusions in the contralateral hemisphere have been shown following a unilateral lesion to the thalamus (Baron et al., 1992). We have suggested that the solution to the problem of ipsilateral vs. contralateral deficits may lie in the type of thalamic nuclei that are damaged. When lesions fall in the midline and intralaminar nuclei rather than in the medial dorsal and anterior nuclei, global and contralateral neuropsychological deficits can be observed (Van Der Werf et al., 1998). We will return to a possible fundamental difference in the functions of the intralaminar and midline nuclei vs. those of the anterior and medial dorsal nuclei in the following.


THALAMIC NUCLEI INVOLVED

IN

DIFFERENT ASPECTS

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MEMORY FUNCTIONING

Evidence from animal and human lesions studies have indicated that the region of the thalamus that is involved in processes of memory, comprises the medial and anterior portion (Bogousslavsky et al., 1988). The nuclei lying in this medial and anterior division of the thalamus are the anterior nuclei, the medial dorsal nucleus and the midline and intralaminar nuclei. Within this region dissociable contributions to memory can be found, showing that the different nuclei do not play a similar or global role but rather that each nucleus or set of nuclei has a separate function (Van Der Werf et al., 2000). Anterior nuclei: Encoding of memories After thalamic lesions, a distinction can be made between memory problems compatible with an amnesic syndrome and those that are not (Van Der Werf et al., 2000). The latter does not relate straightforwardly to damage to a specific structure in the thalamus, whereas in the case of the amnesic syndrome either the anterior group of nuclei or its afferent white matter fibre bundle, the mammillo-thalamic tract (MTT), shows consistent damage. Due to the encroachment of anterior lesions on adjacent structures in cases of human brain damage, often functions outside the domain of declarative memory are affected as well. Nevertheless, several cases with anterior lesions show a pure deficit of memory, illustrating the specificity of the anterior nuclei for declarative memory processes (Van Der Werf, 2000). In line with these data, studies in monkeys and rats show that damage to the anterior nuclei of the thalamus leads to severe memory deficits. They can be seen in paradigms of delayed non matching to position, delayed non matching to sample, associative memory, allocentric learning (Aggleton and Mishkin, 1983; Aggleton et al., 1996), and radial maze learning (Byatt and Dalrymple-Alford, 1996; Sziklas and Petrides, 1999). Strong evidence for the involvement of anterior thalamic nuclei in declarative memory comes from a primate study by Parker and Gaffan (1997), that employed an object-in-place scene memory paradigm for recognition of single events, thus corresponding as closely as possible to human episodic memory. They showed a dramatic deficit in performance after ablation of the anterior nuclei of the thalamus. Although it is hard to dissociate encoding deficits from disturbed retrieval in experimental animal procedures, the nature of the memory deficit can be inferred from its resemblance to those seen after hippocampal dysfunctioning; the memory deficit is most likely due to a deficient encoding of new material, in keeping with the proposed role of the hippocampus in encoding of novel associative information (Vargha-Khadem et al., 1997; Rombouts et al., 1997, 1999; Eichenbaum, 2000). The notion of hippocampal-like memory deficits resulting from anterior thalamic damage is corroborated further by a recent disconnection study showing the conjoint importance of these two structures for memory performance in rats (Warburton et al., 2001). The similarity of anterior thalamus-related memory deficits and those following hippocampal damage can be understood from their place in the so-

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called Delay-Brion circuit (Delay and Brion, 1969). In short, areas of the hippocampal formation, the subiculum, pre- and parasubiculum project via the fornix to the medial and lateral mammillary bodies. The mammillary nuclei provide input to the anterior thalamic nuclei via the mammillothalamic tract. The anterior nuclei then project onto the medial limbic cortex, i.e. the anterior and posterior cingulate, retrosplenial and subicular areas. Interruption of this circuit at either of the nodes would necessarily result in a similar memory deficit, if the different structures were to function as a closed circuit. This has been tested by Parker and Gaffan in an experimental animal study (Parker and Gaffan, 1997). They showed that the severity of memory deficits was not equally strong after lesioning of each of the nodes in the circuit separately; damage to the anterior and posterior cingulate cortex did not result in a memory deficit as strong as that seen following hippocampal or thalamic damage. These data weaken the strength of the proposition that the Delay-Brion circuit would act as a closed circuit. In addition, anatomical data have shown that the circuit is by no means closed but that there are extensive projections to areas outside of the circuit (Witter et al., 1989). Direct connections between the different structures within the circuit, e.g. from the subicular cortex directly to the anterior nuclei, discard further the notion of a simple orderly sequence of information transfer (Aggleton et al., 1986; Witter, 1993; Witter et al., 1990). It appears that of the different areas in the circuit originally described by Delay and Brion, lesioning of the anterior nuclei of the thalamus or the hippocampus most reliably produces severe declarative memory deficits (Zola-Morgan and Squire, 1993; Aggleton and Brown, 1999). Medial Dorsal nucleus: Executive aspects of declarative memory Clinical data show an involvement of the medial dorsal nucleus in several cognitive functions, among which declarative memory (Sandson et al., 1991, Pepin and Auray-Pepin, 1993; Van Der Werf, 2000). These memory deficits are apparent especially when tests are used that address the ability of the subject to use strategies for memory retrieval, rather than when simple recall is tested. The lesion falling in the medial dorsal nucleus needs to be large and encompass a substantial part of the nucleus before memory disruption on tests for verbal and visual recall and recognition can be seen (Kritchevksy et al., 1987). Also, the combination of lesioning of structures surrounding the medial dorsal nucleus, such as the intralaminar and midline nuclei (see below), with that of the medial dorsal nucleus, increases the likelihood of memory deficits due to defective strategy use (Van Der Werf et al., 2000). In animal experiments, lesions of the medial dorsal nucleus of the thalamus result in deficits of delayed non matching to sample (Aggleton and Mishkin, 1983; Zola-Morgan and Squire, 1985), delayed matching to sample (Parker et al., 1997) and delayed matching to position (Hunt and Aggleton, 1998). Gaffan and Parker (2000), using the same object-in-place scene memory task mentioned in the previous paragraph, showed impaired performance following medial dorsal thalamic damage in monkeys. At first glance, the deficits following medial dorsal lesioning resemble those seen following anterior lesions and


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indeed appear using the same tasks. Closer inspection of the data, however, shows differences in the type of deficit. Gaffan and Parker (2000) noted that the deficit affected more aspects of the memory performance than seen following anterior thalamic lesions, reflecting a different role in episodic memory. This was corroborated by Hunt and Aggleton (1998), who described the deficits after a mediodorsal thalamic nucleus lesion as a decreased ability to shift responses rather than the inability to learn per se. Further, Floresco and colleagues showed in a spatial delayed responding task that the interaction between the medial dorsal thalamus and the prefrontal cortex mediates ‘context-dependent retrieval and manipulation of recently acquired information’ (Floresco et al., 1999). The cause of the deficient memory performance following medial dorsal thalamic damage seems to lie in an impairment in the use of memory strategies. These prefrontal-like effects of lesioning of the medial dorsal nucleus on memory are compatible with the fact that this nucleus in all mammals has the vast majority of its reciprocal cortical connections with the prefrontal cortex, in a topographically organized fashion (Groenewegen, 1988; Uylings and Van Eden, 1990). In addition, the medial dorsal nucleus receives a wide range of inputs from limbic structures, basal ganglia and brain stem nuclei (Groenewegen, 1988). We appreciate the fact that the prefrontal cortex is involved in many different functions, often loosely grouped under the header of ‘executive functions’. Thus, the prefrontal cortex contributes to switching of attention, sequencing, selection of appropriate responses, maintenance of information, manipulation of information, et cetera. Lesions of the medial dorsal nucleus therefore generally result in deficits of combinations of these functions, not solely restricted to declarative memory. Among the deficits most relevant to declarative memory are those involving the guidance of selecting the appropriate information to be retrieved; in other words, what Petrides calls ‘active retrieval’ (Petrides, 1996). Despite the difference in the mechanism underlying memory deficits following anterior or medial dorsal thalamic damage, however, it remains difficult to separate the relative contributions of these two sets of nuclei. Patients and experimental animals with lesions to either the anterior or medial dorsal nuclei of the thalamus will perform defectively on the same tasks, even though the underlying mechanisms might be different. At the level of neuropsychological and behavioural testing, a double dissociation between these two regions of the thalamus is difficult to establish. Intralaminar/Midline nuclei: Attention, arousal, awareness The intralaminar and midline nuclei as a group have a more diffuse function than the medial dorsal or anterior nuclei, i.e. in the realm of arousal and awareness (Newman, 1995; Paus, 2000). Among the functions affected by lesions to these nuclei is declarative memory (Van Der Werf et al., 2000). Mennemeier et al. (1992, 1997) showed deficits of semantic memory, together with motor abnormalities, arising from a small ventral infarction encompassing part of the intralaminar nuclei of the left hemisphere. The combination of deficits was thought to arise from the combined deafferentation of selective

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striatal and cortical areas by the lesion in these nuclei of the thalamus. Van Der Werf et al. (1999) have shown that a lesion in the intralaminar nuclei of the right side of the thalamus resulted in declarative memory loss due to impaired use of mental flexibility. It was argued that these deficits arose from the loss of cortical activation, caused by the deafferentation of the prefrontal cortex through damage to the intralaminar nuclei. In studies in the rat, lesions restricted to the intralaminar nuclei have been found to disrupt memory processes. Disruptions of the ability to perform delayed matching to sample (Burk and Mair, 1998), delayed non matching to sample (Koger and Mair, 1994; Mair and Lacourse, 1992; Young et al., 1996), and delayed non matching to position (Savage et al., 1997) have been found. The deficits found are more similar to those seen after damage to the prefrontal cortex, rather than to those seen after lesions to the hippocampal system. (Young et al., 1996). In view of the small dimensions of the intralaminar nuclei in comparison with those of the surrounding nuclei, the selectivity of lesioning deserves mention. Most of the studies used radiofrequency lesions, that are known to be rather non-selective (Koger and Mair, 1994; Mair and Lacourse, 1992; Savage, et al., 1997; Young, et al., 1996), justifying doubt whether the memory deficits are in fact due to lesions of the intralaminar nuclei or to surrounding structures. The study by Burk and Mair (1998), however, used selective excititoxic lesions of the intralaminar nuclei that still produced memory decrements. Particularly convincing is the fact that excitotoxic lesions placed directly in the adjacent medial dorsal nucleus did not result in deficits of the same magnitude, making it unlikely that the effects seen in the intralaminarlesion group could be ascribed to the medial dorsal nucleus. In contrast to the intralaminar nuclei, lesions to the midline nuclei have not been systematically investigated in experimental animal lesion studies. Aggleton and Mishkin (1983) lesioned the midline thalamic region of one monkey as a control for the medial dorsal lesioned animals and found no effect on recognition memory. Outside of the domain of declarative memory, a role in classical conditional learning has been suggested for the midline nuclei (Beck and Fibiger, 1995; Brown et al., 1992). Based on careful and detailed analyses of tract tracing studies in the rat, the intralaminar and midline nuclei can be shown to project to widespread areas of the brain (Berendse and Groenewegen, 1991; Van Der Werf et al., 2002). Together, the intralaminar and midline nuclei reach the entire cortical mantle in a manner consistent across species (Jones and Leavitt, 1974; Groenewegen and Berendse, 1994). Within this group of nuclei, however, preferential patterns of projection can be seen (Groenewegen and Berendse, 1994). The issue of collateralization deserves attention because it is thought to be related to the type of contribution of these nuclei to memory. Thus, the more general nature of the influence of these groups of nuclei can be seen in the fact that they do not innervate one target only, but that a single cell projects to two (Royce, 1983; Dolleman-Van Der Weel and Witter, 1995) or even three targets (Cesaro et al., 1984; Deschenes et al., 1996). The targets innervated by single neurons are structures of different type, such as cortex, striatum, and the reticular nucleus of the thalamus. Within each of these targets, however, subregions receive input


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from separate intralaminar and midline cells (Bentivoglio et al., 1981; De Las Heras et al., 1999; Feger et al., 1994), illustrating the specificity of the projections. Based on the distinctly different patterns of afference and efference we recently hypothesized that the midline and intralaminar nuclei are involved in different functions (Van Der Werf et al., 2002). Thus, a dorsal group can be discerned, with a possible role in viscerolimbic functions; a ventral group, that on the basis of its connections might influence processing of different sensory modalities; a lateral group, involved in executive aspects of memory and other forms of cognition; and a posterior group, involved in motor responses to emotionally or motivationally significant stimuli. In summary, the lesion data indicate that the group of the intralaminar and midline nuclei is involved in declarative memory. The type of deficit is seen on the same tasks that show effects of anterior or medial dorsal thalamic lesioning, and a dissociation is therefore hard to make as to the type of contribution to the memory process. Indeed, the role of the intralaminar and midline nuclei in memory seems to be similar to that played by the medial dorsal nucleus and seems to lie in mental flexibility and the use of memory strategies. Anatomical data seem to indicate that the memory deficits arise from lesioning of the lateral group of intralaminar and midline nuclei, although a role for the ventral group cannot be excluded. Due to the small dimensions of the latter group of nuclei, however, experimental and clinical evidence is lacking. THE HYPOTHESIZED NATURE

OF THE THALAMIC MEMORY

ROLE

IN

DECLARATIVE

The thalamus is composed of more than 30 separate nuclei in each hemisphere, involved in separate functions ranging from motor and sensoryrelated to state setting properties (e.g. Jones, 2001). Even within the domain of memory, the separate structures are involved in different aspects as described above. The thalamus seems to be a heterogeneous structure and one can wonder whether there is a fundamental characteristic of the contribution of the different thalamic nuclei to memory or whether the unity lies merely in the fact that these nuclei are located in close proximity. The thalamus is often described as a relay station for information to the cortex. This is obvious in sensory processing, where information from all sensory modalities, except olfaction, are relayed in the thalamus before being sent on to the cortex (Steriade et al., 1997). In cognition, the different thalamic structures have similarly been thought to act as switches or gates, controlling the amount and type of information that is relayed to the cortex. This would allow for more efficient processing of that information, leading to a faster execution of cognitive processes (Van Der Werf et al., 2001). The concept of a switch, or gate, implies a rather passive shunting of information. We propose a more active role for the thalamus in declarative memory, namely one of ‘focussing’ the processes implicated in the memory process. First, the anterior and the medial dorsal nucleus would act to focus on the material to be processed and to discard information that is superfluous or not

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needed. In the case of the anterior nuclei, this would involve the selection of material for subsequent memory storage, in accord with the tight connections of these nuclei with the hippocampal system. Similar to the role proposed for the hippocampus, the anterior nuclei would perform the selection of material irrespective of its nature (Wood et al., 1999). Second, the medial dorsal nucleus, with its strong reciprocal connections with the prefrontal cortex, would be involved in governing the processes of active retrieval efforts (Fuster, 1997; Kapur et al., 1995; Petrides, 1996; Wagner et al., 1998). It is noteworthy that the control of executive processes is usually ascribed to networks in the prefrontal cortex itself, that are in turn under the influence of corticocortical connections with sensory and associational cortices (Fuster, 1997; Miller, 1999). We do not mean to say that, instead, it is the medial dorsal thalamus that controls these functions in the prefrontal cortex. Rather, the cortico-cortical networks in the prefrontal cortex would work together with the thalamus through their extensive bidirectional connections. The cortico-cortical networks would be involved in the fine-grained adaptations of the executive processes depending on the progress in the retrieval process, whereas the medial dorsal thalamus would play a more general role of adjusting these prefrontal executive processes in memory depending on the plans and intentions, the emotional state, and the physical priorities of the organism. All the required information would be represented in the medial dorsal nucleus through the extensive limbic, association cortical, amygdalar, brain stem and basal ganglia inputs (Groenewegen, 1988). Taken together, the medial dorsal and anterior nuclei would be involved in the contents of the declarative memory process and control focussing within this function. A second way in which the thalamus is involved in focussing would be subserved by the intralaminar and midline nuclei. These nuclei play a role in cognitive and non-cognitive processes. In the domain of cognition, the intralaminar and midline nuclei would not be related as much to the actual information that is being processed at a given time, but rather supply the necessary cortical activation of a region that is needed to carry out a cognitive process (Llinás and Paré, 1997). The intralaminar and midline nuclei, acting in concert with the intrathalamic connections arising from the reticular nucleus, may act to weigh against each other the importance of different sets of information in order to give one or more the right of way (McAlonan et al., 2000). In this way, the intralaminar, midline and reticular nuclei control the allocation of activation in the cortex. This allows for the performance of a process without interference by another process. We have argued in the above that the processes in which the different midline and intralaminar nuclei are involved are diverse, but that these all have to do with the regulation of arousal (see also Paus, 2000). Based on neuroanatomical relationships, the lateral and ventral cluster of the intralaminar and midline nuclei described in the above paragraph, seem most intimately involved in cognitive processes (Van Der Werf et al., 2002). More in particular, they influence the processes of memory formation and the executive active retrieval functions. The other clusters of nuclei exert their influence on different processes in the brain such as sensory, motor and visceral functions. An example of the latter would lie in alerting


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mechanisms (Steriade, 1997), in instances where a sudden stimulus in the environment arises that needs to be attended to. Such stimuli can be relatively benign, such as hearing one’s name when occupied with something else, or they can signal emergency situations such as life-threatening, harmful or painful situations. In these instances, the system of intralaminar and midline nuclei with the reticular intrathalamic system would act to temporarily suppress the performance of an ongoing process in favour of paying attention to salient stimuli. Thus, we see the lateral and ventral group of the intralaminar and midline nuclei as being involved not in the contents but rather in the state of the memory process, allowing switching between processes of cognition. CONCLUDING REMARKS The thalamus has been described before as a structure serving as a ‘spotlight’, ‘flashlight’ or ‘searchlight’ (Crick, 1984; Smythies, 1997). Also, the concept of thalamic ‘enhancement’has been described (LaBerge, 1997). These concepts were used as a metaphor to explain the role of the thalamus in narrowing the focus of an individual to a specific stimulus. However, Crick and Smythies applied their concepts to theories of consciousness rather than cognition as we do here. LaBerge described a specific role for the pulvinar of the thalamus in directing the attention to stimuli in the visual field. We now propose, in analogy to these concepts, that the role the thalamus plays in different aspects of the memory process is one of ‘focussing’. The two mechanisms of focussing on ‘contents’ and ‘state’ described above are thought to play a fundamental role in the decision about which part of the incoming information is selected for further processing, based on the weight, significance and relevance of the information, and depending on the current needs and priorities of the organism. We suggest that the thalamic influence on the decision is exerted at two different levels: the intralaminar and midline nuclei play a role in the activation of an area or a circuit needed for the execution of encoding or retrieval. Subsequently, the medial dorsal and anterior thalamic nuclei are involved in focussing on the material that is the subject matter of the memory process. This conceptualization of a bipartite contribution of the thalamus to memory is similar to the thalamic role in waking consciousness put forward by Llinás and Paré (1997); they argue that the thalamocortical connections from the intralaminar and midline nuclei (in their words the ‘nonspecific nuclei’) signify the context of a conscious experience, whereas the thalamocortical projections originating from the medial dorsal and anterior nuclei (the ‘relay nuclei’) carry its contents. The validity of the concept of two types of thalamic contribution to human memory will need to be established in future investigations, e.g. using functional neuroimaging studies in paradigms of memory, with a spatial resolution sufficient to allow a distinction between nuclei in the thalamus and a temporal resolution sufficient to obtain insight in the dynamics of the interactions between the thalamus and cortical regions. Acknowledgement of the role of the thalamus in several aspects of declarative

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