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M E M O RY S Y S T E M S O p i n i O n

A model for memory systems based on processing modes rather than consciousness
Katharina Henke

that the hippocampus role in memory is not limited to conscious memory encoding or retrieval. I conclude by proposing a model of memory systems in which different types of memory are distinguished according to their processing characteristics.
Distinguishing memory types Consciousness of learning and retrieving is not the only variable that distinguishes between the types of memory that are spared and affected in individuals with medial temporal amnesia (BOX 1). First, different types of memory can also be distinguished on the basis of the number of learning trials that are required for memory formation. Skill and habit formation and classical conditioning, for example, typically require a large number of learning trials, whereas episodic memory formation and priming can proceed at once. Second, the cognitive complexity or the number of processing modules involved in a task can distinguish different types of memory; priming and classical conditioning require fewer processing modules than episodic memory. Episodic memories are formed on the spot and consist of multifaceted sensory, conceptual, emotional, temporal and spatial information. A third separating variable is the nature of the mental representation. Episodic memories are characterized by compositionality and flexibility 6. Compositionality refers to the mental representation of both the entire memory and its individual elements. The elements of a compositional memory are not blended into an inseparable or unitized representation but are accessible individually or in relation to each other. Thus, the compositionality of a memory permits retrieving the face of a student sitting in the lecture hall or retrieving the question that the student was asking. Because the elements and their associations are stored independently, they can be reactivated through many routes; that is, the memories have representational flexibility. This flexibility permits the inferential use of memories in new retrieval situations. An aspect of an event that is only remotely related to an encoded episode may reactivate the entire memorized episode by reactivating the neural associations of the element with all other elements of the memory. Nondeclarative memories can also consist of multiple and related elements, but these elements are usually blended into an inseparable or unitized representation6,7 and cannot be reactivated individually. Rigid memories are usually accessed through the sensory modality using retrieval cues that were present during the learning episode.
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Abstract | Prominent models of human long-term memory distinguish between memory systems on the basis of whether learning and retrieval occur consciously or unconsciously. Episodic memory formation requires the rapid encoding of associations between different aspects of an event which, according to these models, depends on the hippocampus and on consciousness. However, recent evidence indicates that the hippocampus mediates rapid associative learning with and without consciousness in humans and animals, for long-term and short-term retention. Consciousness seems to be a poor criterion for differentiating between declarative (or explicit) and nondeclarative (or implicit) types of memory. A new model is therefore required in which memory systems are distinguished based on the processing operations involved rather than by consciousness.
Memory is neither a unitary process nor does it serve a single function. In fact, humans and animals have several types of memory that are partially independent and that are mediated by disparate brain regions. They include procedural, episodic and semantic memory, priming, and classical conditioning. In daily life these memory systems typically operate in parallel, smoothly interacting and in the case of damage functionally compensating each other to some degree. To discern these memory systems, investigators have assessed the mnemonic function in patients with focal brain damage and animals with tailored brain lesions. Chiefly, studies of patients with lesions in the medial temporal lobe who are amnesic have suggested that some forms of memory are accessible to consciousness (those that are affected in these patients), whereas other forms are not (those that are spared in the patients). This distinction has inspired the prominent declarative versus nondeclarative1,2 (FIG. 1) and explicit versus implicit accounts of long-term memory 3 although the latter was originally developed to describe different types of memory and was not meant to postulate the existence of separate underlying memory systems According to these two theories, the basic distinction is between the capacity for conscious recollection of facts, general knowledge and personally experienced episodes (declarative or explicit memory), and a heterogeneous assembly of unconscious
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learning and retrieval capacities (nondeclarative or implicit memory). The distinction between declarative and nondeclarative memory was underscored by behavioural and neuroimaging experiments in healthy subjects and by findings in animals that showed that declarative and nondeclarative tasks dissociate behaviourally (for example, manipulations during encoding had different effects on retrieval performance depending on whether declarative or nondeclarative tasks were given) and in terms of neural activation2,4. Indeed, the medial temporal lobe, and in particular the hippocampus (used here to refer to the hippocampus proper together with the dentate gyrus and subicular cortex), was soon equated with conscious and only conscious forms of memory 5 and therefore with declarative (or explicit) memory. However, evidence for a role of the hippocampus in conscious memory does not exclude it from also having a role in forms of unconscious memory. In this Perspective, I review data showing that different types of memory are not solely distinguishable on the basis of consciousness of encoding or retrieval. First, I discuss evidence that the number of learning trials, the cognitive complexity and the nature of mental representation also distinguish between different types of memory. I then describe evidence from studies of humans and animals that supports the idea that consciousness is, in fact, a poor criterion for distinguishing between types of memory and

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The next section focuses on evidence for a role of the hippocampus in both conscious and unconscious forms of episodic memory. The summarized evidence suggests that episodic memory is characterized by rapid, associative encoding and flexible memory expression.
(Un)conscious episodic memory Episodic memory formation requires the rapid encoding of associations between different aspects of an event. Because of its anatomy and physiology, the hippocampus is in an ideal position to rapidly encode associations between aspects of events that have been experienced. There is accumulating evidence that an intact hippocampus is necessary for rapid associative learning with and without consciousness, in humans and animals, for long-term and short-term storage.

Hippocampal anatomy and physiology are suggestive of function. The functions of the hippocampus are indicated by its connectivity and neurophysiology. The primate

hippocampal formation is reciprocally connected with all neocortical association areas, either directly (from Cornu Ammonis area (CA)1, CA2 and CA3 or the subiculum to the frontal, temporal, cingulate and retrosplenial cortices8,9) or through the parahippocampal, perirhinal, and entorhinal cortices10 (FIG. 2). Cortical projections provide the hippocampus with highly elaborate information10 that can be related from moment to moment to build episodic memories. The many widespread associational fibres of CA3 (FIG. 2) led Rolls and Treves11 to suggest that the CA3 network acts as an auto-associative memory system that enables episodic memories to be formed on the spot based on associations between components of experienced events. The CA3 connectivity allows for the later retrieval of the entire event as a result of pattern completion, even if only a fragment of the original event is provided. For consolidation and retrieval, the hippocampus would then reinstate in the neocortex the activation pattern that was present during the original encoding

of the event 2,1217. New findings underscore the notion11 that the CA3 recurrent collaterals have a central role in flexibly integrating whatwherewhen information. Although CA3-lesioned rats could still retrieve what wherewhen information separately 18, the CA3 was crucial for the single-trial encoding and later retrieval of flexibly integrated whatwherewhen information. The number of learning trials required for successful retrieval may be one variable that distinguishes hippocampal encoding from neocortical encoding. Consistent with the assumption that the hippocampus is essential for single-trial associative encoding is the finding that long-term potentiation following a single train of high-frequency tetanic stimulation can be induced in the hippocampus19. By contrast, the neocortex requires stimulation trains that are repeated over many days in order to reach potentiation19. The multiple tetanization episodes needed for neocortical long-term potentiation parallel the multiple learning runs needed for encoding of information in

Long-term memory Declarative memory Nondeclarative memory

Episodic memory

Semantic memory

Procedural memory: skills, habits

Priming

Simple classical conditioning

Habituation, sensitization

Reflex pathways

Neocortex Basal ganglia Medial temporal lobe, diencephalon Amygdala, cerebellum

Figure 1 | The declarative versus nondeclarative memory account. In this model13, long-term memory is divided into two broad classes. One class is characterized by the capacity for conscious recollection and is called declarative memory. The other class encompasses diverse unconscious learning and memory abilities and is referred to as nondeclarative memory. Declarative memory consists of two subclasses: episodic memory, which consists of memories for autobiographical events; and semantic memory, which consists of facts and general knowledge34,35,143. Semantic memories are impersonal and devoid of autobiographical context, whereas episodic

memories are personal. These include where and when episodes happened Nature Reviews | Neuroscience and are accompanied by a feeling of retrieving personally experienced episodes (autonoetic consciousness34,35,143). In this model both episodic and semantic memories are dependent on the medial temporal lobe and diencephalon. Nondeclarative memory in this model includes procedural learning of sensorimotor and cognitive skills and habits, priming, simple conditioning, and habituation and sensitization (BOX 1), all of which are expressed in behavioural changes and are independent of the medial temporal lobe.

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patients with amnesia2025. Encoding in one single trial versus encoding over multiple trials puts different demands on memory systems and constitutes one variable, in terms of processing demands, in the memory model suggested in this Perspective. Animals exhibit episodic memory. Episodic memory in humans can be viewed as having evolved from a capacity for rapid associative encoding and flexible memory representation. Indeed, a role for the hippocampus in rapid associative encoding was first established in animals2629. Rats with hippocampal damage were selectively impaired in tasks that induce the encoding of associations between items28. A seminal study by Bunsey and Eichenbaum30 underscored flexibility as a crucial feature of hippocampus-dependent memory. They trained intact rats and rats with hippocampal lesions on odourodour associations and showed that intact rats exhibited two forms of flexibility of memory expression: transitivity, which is the ability to make inferential judgments across (for example) odourodour associations that share one odour; and symmetry, which is the ability to associate paired elements that are presented in the reverse of the training order. Hippocampus-lesioned rats had normal memory acquisition but showed neither transitivity nor symmetry, which suggested a deficit in flexible memory expression. However, Frank and colleagues31 provided an alternative explanation: they claimed that transitivity can be explained by reinforcement learning processes. Nevertheless, the flexibility of memory expression was also shown using other tasks and became an important defining feature of episodic memory 32,33. Flexibility of memory expression provides the foundation for mental time travel, foresight, planning and creativity. The more subjective defining attributes of episodic memory autonoetic consciousness (conscious experience of the self) and mental time travel34 and other criteria that are dependent on language cannot be investigated in animals. This impedes resolution of the debate between investigators of human3436 and animal behaviour 33 concerning whether animals possess episodic memory. In terms of behavioural criteria, the food-cache recovery pattern of birds37 and the memory for the order of a sequence of events in rats32 indicate that animals can flexibly integrate what, where and when information into memories of unique experiences and use these memories inferentially in novel situations. This indicates that at least some animal species have episodic memory.
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Box 1 | Forms of learning spared in patients with amnesia

sensorimotor skill learning The earliest demonstration that medial temporal amnesia can be conceived of as a deficit of declarative memory, sparing nondeclarative memory, was that patients with damage in the medial temporal lobe could be trained in handeye coordination skills, such as mirror drawing and rotary pursuit126,127. Further demonstrations of spared nondeclarative skills in amnesia include perceptual learning70,128, reading of mirror-reversed script129, visual category or prototype learning130 and visual and tactual maze learning70. Additional studies found that patients with amnesia were even capable of learning, over many sessions, to manipulate information on the computer screen20. They learned to write, edit and execute simple computer programs and to perform disk storage and retrieval operations. Although these patients did not remember the learning events, they showed sensorimotor learning when given extensive training opportunities. Priming When instructions for retrieval testing were indirect that is, when the subjects were not told that their memory would be tested patients with amnesia showed preserved perceptual21,131 and conceptual132 priming of single items. conditioning Patients with severe amnesia showed intact delay eye-blink classical conditioning94,133. In delay eye-blink conditioning, a tone (conditioned stimulus) is presented just before the onset of an air-puff (unconditioned stimulus) to the eye. The tone and air-puff temporally overlap and then cease simultaneously. cognitive skill learning Even in more cognitively complex tasks, patients with amnesia showed preserved learning abilities if there were many training sessions. For example, they showed preserved cognitive skill learning and learning of rule-governed complexities of stimulus sequences over time as implemented in artificial grammar learning134. Patients with amnesia due to hippocampal or diencephalic damage were as able as normal subjects to classify letter strings that had been generated according to the learned rules of an artificial grammar. However, they did so without recognizing the studied exemplars that had been used to teach patients the rules over several learning runs.

Patients with hippocampal damage lack flexible memory expression. There is unequivocal evidence that patients with hippocampal lesions exhibit deficits in episodic memory formation and retrieval when they are aware of the learning material and retrieval instructions. weiskrantz and warrington38 were the first to suggest that the episodic memory deficit of amnesic patients with medial temporal damage might originate in their inability to associate distant items by cognitive mediation. Indeed, these patients were disproportionately impaired in associative recognition compared with single-item recognition39 and also compared with recognition of intra-item associations (for example, features of a face) and associations of items of the same kind (for example, wordword associations)40. These last two recognition abilities might have been spared because recognition might have resulted from feelings of familiarity for the unitized representation of unimodular material without retrieval of contextual information4145. Feelings of familiarity depend on the rhinal cortex, a component of the parahippocampal gyrus (FIG. 2). It is possible that the dissociation between associative recognition and single-item recognition in these patients reflects the relative difficulty of memory tasks instead of differences in memory

processes. However, even when singleitem recognition was matched between the patients with amnesia and controls and when task load and task difficulty were equated between conditions40,46,47, the patients still exhibited a selective impairment of associative recognition. like associative demand, the fast encoding of episodic memories also requires intact hippocampus functioning 1517. In tests in which associative encoding had to be accomplished on the spot (as in real life), patients with damage to the hippocampus showed impaired learning. If, however, new associations were allowed to be built up over many learning trials, patients with medial temporal damage were able to slowly establish new associations, presumably through synaptic modifications in residual medial temporal tissue and the lateral temporal neocortex 2025. There is accumulating evidence that conscious and unconscious rapid associative encoding and retrieval are impaired in severely amnesic patients with hippocampal damage (BOX 2). Single-trial associative encoding and retrieval, with different presentation formats at study and test (which requires flexible memory expression), was impaired in patients with amnesia even when encoding and retrieval were implicit, that is, not directly instructed4851, whereas
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Cortical connections Hippocampal formation Subcortical connections

CA1 sc CA3 mf DG pp Anterior thalamic nuclei ErC Sub Fornix Mammillary bodies

PrC

PhC

CG

Figure 2 | Hippocampal connectivity. The primate hippocampal formation is reciprocally connected with all neocortical association areas either directly8,9 or through the parahippocampal cortex (PhC), perirhinal cortex (PrC) and entorhinal cortex (ErC)10. Projections from the ErC reach the granule cells of the dentate gyrus (DG) through the perforant path (pp). The DG cells project to the CA3 subfield through the mossy fibres (mf), which provide convergent input to CA3 pyramidal cells (around 50 mf per CA3 cell11,144). The largest number of synapses on CA3 neurons is provided by axon collaterals of other CA3 neurons (forming associational connections) throughout the entire hippocampal formation10,145. The CA3 system, with its many widespread associational fibres, thus allows each CA3 neuron to transmit information rapidly

to every other CA3 neuron. This is suggestive of an auto-associative network Nature Reviews | Neuroscience (represented by the schematic network in CA3 and neocortex) that can recreate the whole event from its parts11. CA3 neurons in turn give rise to the major Schaffer collateral (sc) projection to CA1. Unlike CA3 neurons, CA1 neurons do not project significantly to other levels of CA1 but to the subiculum (Sub)10. From the Sub the information is funnelled back to the ErC, from where it is redistributed to neocortical areas. The information flow through the hippocampal formation is mostly unidirectional. Some hippocampal efferents also travel in the fornix to the mammillary bodies, the anterior thalamic nuclei, the septal nuclei and through the cingulate gyrus (CG) to the retrosplenial cortex and back to the parahippocampal gyrus.

implicit single-item encoding and retrieval remained intact. This suggests a division between hippocampus-dependent rapid and flexible associative encoding and hippocampus-independent encoding of rigidly represented single items or blended itemitem pairs. This division is supported by evidence that patients with hippocampal-amnesia can acquire new semantic associations between labels and abstract shapes in a series of collaborative interactions with a communication partner who does not have amnesia52. learning in the patients with amnesia progressed at a normal rate compared to controls if the labels were meaningfully related to the shapes like siesta man for a shape that looks like a sleeping person but when the materials to be learned were selected so as to be only arbitrarily related, the patients with amnesia showed their usual severe learning impairment 52. Thus, the learned associations conformed to rather rigid, unitized, itemitem representations and therefore presumably involved extra-hippocampal areas. Another task that induces the encoding of rigidly represented items is the contextual cueing task53. An example of such a task is the repeated presentation of displays containing a rotated T among rotated ls that act as distracters and promote repetition
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priming. Amnesic patients with medial temporal lobe damage were impaired in this task53, as were subjects with temporary, pharmacologically (Midazolam) induced amnesia54. Contextual priming was associated with activity changes in the hippocampus and the parahippocampal gyrus55. Interestingly, it was preserved in amnesic patients with focal hippocampal damage but impaired in amnesic patients with large medial temporal damage that invaded the parahippocampal gyrus and lateral temporal cortex 56. This suggests that the unitized representation of visual items depends on parahippocampal rather than hippocampal processing. This interpretation is not at odds with the study on subjects with pharmacologically induced amnesia54, because the effects of the benzodiazepine (Midazolam) are not restricted to the hippocampus. Furthermore, contextual priming produced stronger effects in the parahippocampal gyrus than the hippocampus55 and was only associated with effects in the rhinal cortex in a further imaging study 57. Together, these data indicate that hippocampal processing seems to be necessary for the encoding of flexible associations, whereas extra-hippocampal structures support the formation of rigid, unitized representations.

The hippocampus supports rapid encoding of flexible associations even without consciousness. Many studies have reported increased hippocampal activation during the conscious encoding and retrieval of associations among spatial58,59, temporal5961, sensory 62 and conceptual58,6365 aspects of an episode or across multiple episodes, compared with the encoding of such aspects in isolation. However, there is also evidence of hippocampal activation during the unconscious formation and retrieval of flexible associations. Hannula and Ranganath66 reported that hippocampal activity during the presentation of a scene cue predicted whether the participant subsequently made eye movements to the face (out of three equally familiar faces) that had previously been shown in this scene. Remarkably, this correlation occurred even in trials in which the subjects could not consciously identify the correct face, suggesting that hippocampal activity supported the expression of relational memory even when intentional responses were incorrect. However, amnesic patients with hippocampal damage failed to show this eye movement effect51, confirming the role of the hippocampus in relational binding. Subliminal stimulus presentations can be used to study the role of the hippocampus in unconscious memory encoding and retrieval.
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In two such studies, combinations of faces and occupations were flashed briefly (17 ms), preceded and followed by visual noise patterns, to induce rapid and unconscious encoding of semantic associations67,68. In a retrieval test five minutes later, the faces were shown (for supraliminal duration) as retrieval cues and the participants were asked to guess the occupational category (academic, artist or workman) associated with each face. The paradigm therefore measured the reactivation of both flexible and conceptual associations. The hippocampus and the rhinal cortex were activated during unconscious associative encoding and retrieval67,68. In a subsequent study, unconscious encoding of faceoccupation pairs was followed by conscious encoding of supraliminally presented faceoccupation pairs consisting of the same faces combined with occupations that were semantically incongruous, semantically congruous or identical to those that had earlier been presented subliminally 69. In each of these situations, unconscious encoding engaged the hippocampus and interacted with subsequent conscious encoding; hippocampal activity increased during unconscious encoding and this activity correlated with the change in conscious retrieval performance that the subliminal encoding task had induced69. Furthermore, data from our laboratory show hippocampal activation during the integration (transitive inference) of subliminal word pairs that are presented spaced over time (T. Reber, P. Colella, D. oppliger, R. luechinger, P. Boesinger and K.H., unpublished observations). Together, there is mounting evidence that the hippocampus mediates both conscious and unconscious rapid encoding of compositional and flexible associations. The hippocampus supports long- and shortterm retention. when amnesic patients with medial temporal lesions are assessed with traditional tests of short-term memory (for example, the digit span task or the Corsi block-tapping task), they usually show intact performance. This has led to the notion that the medial temporal lobe is not involved in short-term memory 70. There is, however, evidence that it is involved in the retention of information in short-term memory, at least if retention intervals are longer than a few seconds71,72, if stimuli are novel73,74, if working memory load is high74,75 or if new associations must be formed76,77. Even if novel single faces (rather than associations) had to be retained over short time intervals, the hippocampus showed activation during maintenance72,73 and amnesic patients
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with hippocampal lesions showed retention deficits72. Because the stimulus faces were novel, hippocampal activity in these tasks might have been related to binding processes that enable the encoding of new faces (which lack prior representations in the brain) with existing representations in episodic and semantic memory. New faces typically evoke such spontaneous associations. As previously noted78, it may be the processing demands that decide whether a given brain structure (in this case, the hippocampus) is involved in a task, rather than the retention interval or as suggested in this Perspective the degree of conscious awareness of encoding or retrieval. Recent evidence indicates that working memory can even operate unintentionally and outside conscious awareness, engaging the same prefrontal areas as those involved in conscious working memory 79. This again suggests that different memory systems (even in domains other than long-term memory) should not be distinguished on the basis of whether they are involved in conscious or unconscious encoding or retrieval.
processing-based memory systems Based on the findings described above, I propose a processing-based model that presents a new organization of established types of memory (FIG. 3). The model distinguishes three processing modes: rapid encoding of flexible associations, slow encoding of rigid associations and

rapid encoding of single or unitized items. As their names indicate, these processing modes differ in three variables: rapid versus slow encoding, associative versus single-item encoding, and flexible and compositional versus rigid and unitized representation. In this model, the processing mode required by a particular learning situation selects the associated brain systems, which in turn generate qualitatively distinct memories that can be classified in traditional terms (episodic, procedural and semantic memory, classical conditioning, familiarity and priming). Importantly, conscious awareness of encoding and retrieval does not determine which memory system is engaged and is therefore not a variable in this model, and the term episodic memory can refer to both conscious and unconscious episodic memories. This processing-based model shares views with the levels-of-processing and transfer-appropriate processing frameworks proposed in the 1970s and 1980s80,81 by stressing the type of processing and the quality of cognitive operations at the time of encoding. Both frameworks predict that the type of operation carried out during learning will determine the type of retrieval operation. For example, Schacter 82 used the transfer-appropriate processing framework to describe dissociations between implicit and explicit retrieval from memory. of note, the transfer-appropriate processing framework was intended as an alternative to models claiming distinct neural memory systems

Box 2 | Unconscious associative learning and retrieval in patients with amnesia

Graf and Schacter3 asked patients with amnesia to study pairs of unrelated words (such as windowreason) in a single learning trial and later presented cues (such as windowrea) or new associations (like kitchenrea; kitchen had been studied with another word). Subjects had to use the first word that came to mind to complete the word stem. Only following elaborative semantic study of word pairs did controls and patients with amnesia exhibit unconscious memory for the studied word pairs. Other investigators135137 reported similar effects in mildly to moderately memory-impaired patients of various aetiologies using verification tasks (identification, reading and lexical decision) instead of completion or generation tasks to assess unconscious associative retrieval. Schacter and Graf138 subsequently reanalysed their original data3 and new data and concluded that the acquisition and unconscious retrieval of new wordword associations following elaborative semantic study is intact in mildly to moderately memory-impaired patients but absent in severely memory-impaired patients. This finding was underscored by Shimamura and Squire139, who presented patients with amnesia with sentences such as A BELL was hanging over the babys CRADLE and had them rate how well the sentence relates the two words. They examined whether subjects would respond with cradle to the word stem CRA when BELL was presented with either CRA or a new (unstudied) word. Unlike controls, patients with amnesia showed no evidence of associative priming, although they showed intact conceptual and perceptual priming for single items. Because the size of the associative-priming effects correlated with the patients scores on explicit tests of conscious memory, the authors assumed that the degree of residual conscious learning capabilities in the patients with amnesia determined the level of their unconscious associative learning. Based on further studies in healthy subjects140,141, Schacter142 finally concluded that acquiring and retrieving new associations requires intact medial temporal functioning and awareness that test items had been previously encountered as study items.

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for different types of memory. By contrast, the processing-based model proposed in this Perspective does in fact postulate specialized and neuroanatomically defined memory systems; memory systems differ with respect to their processing capabilities and are selected according to their specialization based on the demands imposed by the learning situation. Rapid encoding of flexible associations. The first processing mode in the proposed model (FIG. 3) is the rapid encoding of flexible associations. It proceeds in a single encoding trial15 and enables the formation of representations of events and the allocentric (viewer-independent) representation of spatial layouts in episodic memory 83. This processing mode depends on the hippocampus and the neocortex. It is unclear whether fear conditioning a form of rapid associative learning that depends on the amygdala and (at least in its contextual form) on the hippocampus belongs in this category because the extent to which it shows flexibility has not yet been resolved84,85. Slow encoding of rigid associations. The second processing mode is the slow encoding of rigid associations, which enables the formation of new rigid associations over multiple learning trials, resulting in procedural memory formation, habit formation, category learning, classical conditioning and the formation of new representations in semantic memory (FIG. 3). This encoding style engages the basal ganglia, cerebellum, parahippocampal gyrus and neocortex. Semantic knowledge can be established in long-term memory in at least two ways. The first uses the hippocampus and involves episodic memory formation. This is probably the usual way in individuals with intact hippocampal functions15,86,87. Most encoded episodes succumb to abstraction and loss of detail over time and undergo semanticization88, which occurs when regularities are extracted from several experienced episodes or when a single episodic experience is consolidated, reactivated, retrieved, reconsolidated and so on. The second way of establishing new semantic knowledge uses structures outside the hippocampus, and is engaged when there are many learning trials20,21,2325. This repetition of encoding trials parallels the reactivation and reconsolidation cycles of episodic memories undergoing the process of semanticization and neocorticalization. Both ways of semantic memory formation therefore involve multiple encoding and consolidation cycles and lead to neocortical memory representations that do not exhibit the flexibility of the memories that are processed by way of the hippocampus. The rare episodic memories that remain multifaceted, contextually rich and flexibly expressed over a long time seem to be reinstated by the hippocampus, irrespective of their age87. Classical conditioning, procedural learning, habit formation and category learning are also laborious forms of learning that require repeated encoding trials and result in rigid representations of new associations. Although the hippocampus is not mandatory for incremental forms of associative learning, it may become involved to increase efficacy and speed of the learning process. Hippocampal activation has been observed in cases of contextual and trace conditioning that profit from the contextual and temporal binding, respectively, provided by the hippocampus89. It has also been observed in conditional motor learning tasks90 and in the early phases of category learning 91 and visuomotor sequence learning 92,93. Hence, certain forms of conditioning seem to involve hippocampal processing, presumably because the hippocampus integrates the conditioned stimulus (CS) and the unconditioned stimulus (uS) with the experimental context and associates the CS with the uS across the time interval separating them. A recent study in rats showed that dorsal hippocampal dysfunction produced equal deficits in contextual and trace conditioning, which suggests that the dorsal hippocampus contributes to both through its role in contextual binding 89. Clark and Squire94 suggested that hippocampal processing assists trace eye-blink conditioning because it mediates the conscious awareness of the CSuS contingency. Patients with amnesia and controls watched a silent movie during the conditioning procedure. All patients with hippocampal damage and those control subjects who were unaware of the CSuS contingency failed to show trace conditioning. However, it is conceivable that the tone and its contingency
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Rapid encoding of flexible associations

Slow encoding of rigid associations

Rapid encoding of single or unitized items

Hippocampus Neocortex Basal ganglia Cerebellum Neocortex

Parahippocampal gyrus Neocortex

Episodic memory

Procedural memory Classical conditioning Semantic memory

Familiarity Priming

Figure 3 | A processing-based division among memory systems. The model distinguishes three Nature Reviews | Neuroscience basic processing modes that differ with respect to three variables: rapid versus slow encoding; associative versus single item encoding; and flexible and compositional versus rigid and unitized representation. The three processing modes select for specialized brain systems, which in turn generate qualitatively distinct memories that can be classified in traditional terms. Consciousness of encoding and retrieval does not select for memory systems and hence does not feature in this model. Episodic memory refers to rapidly encoded and flexibly represented associations of any kind and relies on the hippocampus and neocortex. The slow encoding of rigid associations engages the basal ganglia, cerebellum and neocortex for classical conditioning or for the creation of new procedural or semantic memories. The rapid encoding of single or unitized items involves the parahippocampal gyrus and neocortex to afford priming and familiarity.
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with the air-puff were perhaps insufficiently processed in these individuals even at the unconscious level, because the subjects focus on processing the visual aspects of the movie which they were asked to remember for a later test may have reduced the processing of the distracting tone. Accordingly, sufficient neural processing rather than consciousness of CS and CSuS contingency may predict successful trace conditioning. Rapid encoding of single or unitized items. The third processing mode is the rapid encoding of single or unitized items and requires only one exposure to a single item or item combination (FIG. 3). Memories resulting from this processing mode can be triggered by the presentation of a cue that is either identical or similar to the original event. Multiple items can be processed and retained in this way, but they are stored in a unitized and inflexible conceptual, spatial or perceptual representation4345,50. An initial encounter with an item or item combination that engages this processing mode may lead to priming 95 (more efficient processing with better accuracy and/or shorter reaction latencies on the second encounter) and to feelings of familiarity for the perceptual, spatial or conceptual aspects of an item41,42. Indeed, familiarity can be regarded as a form of memory that is related to priming because both are automatic, fast-acting, sensitive to the studytest interval96,97 and rely on repetition-induced processing fluency 42,98100 (the subjective ease of processing sensory or conceptual input). Moreover, both familiarity and priming are associated with reductions and sometimes enhancements of cortical activity 95,101, although it is unclear whether an enhancement in activity, if present, is indispensable for single-item familiarity and priming 96. However, although familiarity and priming share computational mechanisms42, they do not necessarily depend on the same neural circuitry; familiarity seems to strictly engage the perirhinal cortex 102, whereas priming does not always engage it 97,103. Furthermore, there are several types of priming that are associated with activation in different brain areas95. Indeed, priming reflects facilitation of information processing in the whole processing stream from bottom to top, whereas familiarity is confined to the upper (perirhinal cortex) end of information processing 102. Consequently, in patients with medial temporal damage, recognition through familiarity may be impaired, whereas perceptual priming remains
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intact 104,105. However, priming at the conceptual level and familiarity do share processing features42. They are also similar in that they modulate a frontal component of the event-related electrical potential (FN400)106, reduce activity in the perirhinal cortex 97,103,107 and are impaired following medial temporal damage that extends into the parahippocampal gyrus42. A parsimonious explanation for these findings is that only one mechanism records the occurrence of an item, irrespective of whether this occurrence results in priming or familiarity. Finally, it should be noted that crossmodal priming (for example, auditory word encoding followed by visual stem completion) is intact in patients with amnesia in spite of its apparent flexibility 108. Successful cross-modal priming might result from analysing the word-meaning 109,110 or from automatic dual encoding of words in both a phonological code and a visual code111. The role of the neocortex in the three processing modes. Neuroimaging studies in humans demonstrate that each processing mode involves sensory, spatial, temporal and conceptual knowledge representations in the neocortex 112. Conversely, lesion studies confirm that the rapid encoding of flexible associations and the rapid encoding of single or unitized items suffer if words, faces or objects become meaningless because their significance is lost as a result of degradation of the temporal neocortex in the course of semantic dementia113,114. The slow encoding of rigid associations is also impaired following temporal neocortical damage24. Perhaps the most dramatic demonstration of the importance of the neocortex for all processing modes is provided by congenitally decorticate children. In spite of their neartotal absence of cerebral cortex, they can discriminate between familiar and unfamiliar people but otherwise exhibit deficits in all memory processing modes115.
Comparison with other models of memory Comparing the processing-based model with the relational memory theory. The processing-based model was inspired by the relational memory theory, which characterizes declarative memory as being flexible, hippocampus-dependent and fundamentally relational (in the sense that it represents all of the various relations among constituent facets of an experience)6. The relational memory theory 6 is itself an elaboration and extension of the declarative memory theory 13. Both theories consider episodic and semantic memory to be forms of

declarative memory because the new learning of semantic knowledge also requires memory for relations and is decreased in amnesia116. By contrast, the processing-based model divides between episodic and semantic memory because only episodic memory seems to be hippocampus-dependent and truly flexible that is, flexible to the degree that it can support prospective thinking, creative imagination and problem solving 117. Although semantic memory formation is faster if the hippocampus and episodic memory are recruited24, semantic storage and retrieval seem to be independent of the hippocampus34,117. The processing-based model does not use the term declarative memory because not all hippocampal memories can be declared. It should be noted that in the relational memory theory consciousness is not considered to be a necessary feature of hippocampus-dependent relational memory formation49,118. Hence, in both the relational memory theory and the processing-based model, conscious awareness of encoding and retrieval is not a precondition for hippocampal processing. unlike the relational memory theory, but in line with computational models of memory 15,17, the processing-based model emphasizes the speed of relational memory formation during hippocampal processing, as no other brain structure is capable of associating the elements of our experiences on-line. Conscious episodic memory formation may still benefit from more than one learning trial because a second view would enable the encoding of additional details and associations119 that escaped initial scrutiny. However, with repeated encoding and reconsolidation, the learning material succumbs to semanticization and proceduralization while the hippocampus slowly disengages91,92. The resulting associations may not exhibit the same flexibility as associations that are still dependent on the hippocampus120. Other models distinguish types of memory based on processing modes. All models of hippocampal function that were generated from animal studies121 emphasize the processing aspects of memory. Consciousness-based distinctions between types of memory are typically found in models generated from human studies. Nevertheless, even in the recent human literature, there are reports that explain dissociations between types of memory based on processing characteristics. For example, Norman and oReilly 16 discriminated between recall and familiarity on the basis
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of the functional properties of hippocampus versus rhinal cortex; the hippocampus supports recall by assigning minimally overlapping CA3 representations to different events, whereas rhinal cortical representations of different events are more overlapping. Furthermore, Eichenbaum and colleagues122 made an anatomically and neurophysiologically guided, trans-species valid distinction between hippocampus-dependent recollection and perirhinal-dependent familiarity. Even Moscovitch now assumes117 that recollection is a two-stage process involving a rapid, unconscious retrieval followed by a slower, conscious retrieval, whereas he previously claimed that conscious recollection is necessarily associated with memories that are mediated by the medial temporal lobe and hippocampal complex.5 Consistent with the proposal of this Perspective, Reder et al.123 maintain that the unconscious nature of nondeclarative memory does not necessarily mean that it must be treated as a separate memory system. These authors argue that certain declarative and nondeclarative memory tasks for example, familiarity and priming have the same memory representations and that the crucial variable for the distinction between memory systems is whether or not the memory task requires the formation of a new association. However, in contrast to this Perspective, these authors do not distinguish between different types of association formation.
Future directions The processing-based model provides a parsimonious, comprehensive, biologically and evolutionarily plausible frame for thinking about memory. In fact, a processing-based division of labour instead of a consciousnessbased division of labour in the brain seems to be more economical because each specialized brain system offers its capabilities when required, independently of consciousness. Although certain aspects of the model have been raised before such as the notion that hippocampal memories may be formed without consciousness they neither took centre stage nor gave rise to a biologically based, overarching memory model. The current model provides a new perspective on memory that will hopefully inspire experimentation. The models predictions can be tested in animals, humans and computational models because introspection and language are no longer restrictions this will facilitate the cross-species comparison of mnemonic skills. Although consciousness is not considered to be a separating variable between memory processing modes, consciousness
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does modulate computations within them124. Investigations by Dehaene and colleagues124 suggest that conscious (as opposed to unconscious) encoding is associated with activity in distributed brain areas crucially involving the prefrontal cortex and that these areas are co-activated with increased and synchronized high-frequency oscillations in the gamma range. Therefore, conscious versus unconscious encoding involves an improved long-distance exchange of information across a broad cortical network, which is probably also the case at the time of retrieval. The wide-spread and coherent brain activity associated with conscious encoding might promote stronger encoding and consolidation and result in longerlasting memories that lend themselves to guiding behaviour strategically 125. The model predicts that hippocampal damage will impair the rapid associative encoding of compositional and flexible associations irrespective of consciousness of encoding and retrieval. It is conceivable that unconscious associative encoding is impaired following large but not small hippocampal lesions because neural networks tend to be more sparsely recruited for unconscious than for conscious information processing 68,124. The model also predicts that new associations can be established in a unitized and rigid representation without a functional hippocampus if there are many learning trials. However, hippocampal computations should become necessary for the flexible integration of discretely represented semantic information to yield new insights. The model treats familiarity as separate from episodic and semantic memory and instead groups it with priming. Thus, given that stimuli and processing demands are identical, activity decrements should be expected in a common neural network during priming and familiarity. Further investigations should address the differences between processing modes regarding consolidation.
Katharina Henke is at the Department of Psychology, University of Bern, Muesmattstrasse 45, 3000 Bern 9, Switzerland. email: henke@psy.unibe.ch doi:10.1038/nrn2850 Published online 9 June 2010
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Acknowledgements

The author would like to thank T. Reber, O. Markes, B. Meier and S. Duss for valuable help and discussions. K.H. is sup ported by Swiss National Science Foundation Grants 320000114012 and K13K1119953.

Competing interests statement

The author declares no competing financial interests.

FURTHER inFORMATiOn
Katharina Henkes homepage: http://www.apn.psy.unibe. ch/content/team/henke
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