Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto‐temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto‐temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1‐week of antipsychotic treatment. Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto‐temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1‐week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto‐temporal dysconnectivity. Patterns of fronto‐temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. Hum Brain Mapp 36:1442–1457, 2015. © 2014 Wiley Periodicals, Inc.     

The relationship between task‐related and subsequent memory effects

The primary aim of this fMRI study was to assess the proposal that negative subsequent memory effects—greater activity for later forgotten relative to later remembered study items—are localized to regions demonstrating task‐negative effects, and hence to potential components of the default mode network. Additionally, we assessed whether positive subsequent memory effects overlapped with regions demonstrating task‐positive effects. Eighteen participants were scanned while they made easy or difficult relational judgments on visually presented word pairs. Easy and hard task blocks were interleaved with fixation‐only rest periods. In the later unscanned test phase, associative recognition judgments were required on intact word pairs (studied pairs), rearranged pairs (pairs formed from words presented on different study trials) and new pairs. Subsequent memory effects were identified by contrasting the activity elicited by study pairs that went on to be correctly endorsed as intact versus incorrectly endorsed as rearranged. Task effects were identified by contrasting all study items and rest blocks. Both task‐negative and task‐positive effects were evident in widespread cortical regions and negative and positive subsequent memory effects were generally confined to task‐negative and task‐positive regions respectively. However, subsequent memory effects could be identified in only a fraction of task‐sensitive voxels and, unlike task effects, were insensitive to the difficulty manipulation. The findings for the negative subsequent memory effects are consistent with recent proposals that the default mode network is functionally heterogeneous, and suggest that these effects are not accurately characterized as reflections of the modulation of the network as a whole. Hum Brain Mapp 35:3687–3700, 2014. © 2013 Wiley Periodicals, Inc .     

Repetition related changes in activation and functional connectivity in hippocampus predict subsequent memory

Using fMRI, this study examined the relationship between repetition‐related changes in the medial temporal lobe (MTL) activation during encoding and subsequent memory for similarity of repetitions. During scanning, subjects classified pictures of objects as natural or man‐made. Each object‐type was judged twice with presentations of either identical pictures or pictures of different exemplars of the same object. After scanning, a surprise recognition test required subjects to decide whether a probe word corresponded to pictures judged previously. When a subject judged the word as “old,” a second judgment was made concerning the physical similarity of the two pictures. Repetition related changes in MTL activation varied depending on whether or not subjects could correctly state that pictures were different. Moreover, psychophysiological interactions analyses showed that accuracy in recalling whether the two pictures were different was predicted by repetition‐related changes in the functional connectivity of MTL with frontal regions. Specifically, correct recollection was predicted by increased connectivity between the left posterior hippocampus and the right inferior frontal gyrus, and also by decreased connectivity between the left posterior hippocampus and the left precentral gyrus on the second stimulus presentation. The opposite pattern was found for trials that were incorrectly judged on the nature of the repetition. These results suggest that successful encoding is predicted by a combination of increases and decreases in both the MTL activation and functional connectivity, and not merely by increases in activation and connectivity as suggested previously. © 2012 Wiley Periodicals, Inc.     

Impact of emotional salience on episodic memory in attention-deficit/hyperactivity disorder: a functional magnetic resonance imaging study.

BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) show episodic memory deficits especially in complex memory tasks. We investigated the neural correlates of memory formation in ADHD and their modulation by stimulus salience. METHODS: We recorded event-related functional magnetic resonance imaging during an episodic memory paradigm with neutral and emotional pictures in 12 male ADHD subjects and 12 healthy adolescents. RESULTS: Emotional salience did significantly augment memory performance in ADHD patients. Successful encoding of neutral pictures was associated with activation of the anterior cingulate cortex (ACC) in healthy adolescents but with activation of the superior parietal lobe (SPL) and precuneus in ADHD patients. Successful encoding of emotional pictures was associated with prefrontal and inferior temporal cortex activation in both groups. Healthy adolescents, moreover, showed deactivation in the inferior parietal lobe. CONCLUSIONS: From a pathophysiological point of view, the most striking functional differences between healthy adolescents and ADHD patients were in the ACC and SPL. We suggest that increased SPL activation in ADHD reflected attentional compensation for low ACC activation during the encoding of neutral pictures. The higher salience of emotional stimuli, in contrast, regulated the interplay between ACC and SPL in conjunction with improving memory to the level of healthy adolescents.     

Disrupted functional connectivity for controlled visual processing as a basis for impaired spatial working memory in schizophrenia

Although regional brain abnormalities underlying spatial working memory (SWM) deficits in schizophrenia have been identified, little is known about which brain circuits are functionally disrupted in the SWM network in schizophrenia. We investigated SWM-related interregional functional connectivity in schizophrenia using functional magnetic resonance imaging (fMRI) data collected during a memory task that required analysis of spatial information in object structure. Twelve schizophrenia patients and 11 normal control subjects participated. Patients had SWM performance deficits and deficient neural activation in various brain areas, especially in the high SWM load condition. Examination of the covariation of regional brain activations elicited by the SWM task revealed evidence of functional disconnection between prefrontal and posterior visual association areas in schizophrenia. Under low SMW load, we found reduced functional associations between dorsolateral prefrontal cortex (DLPFC) and inferior temporal cortex (ITC) in the right hemisphere in patients. Under high SWM load, we found evidence for further functional disconnection in patients, including additional reduced functional associations between left DLPFC and right visual areas, including the posterior parietal cortex (PPC), fusiform gyrus, and V1, as well as between right inferior frontal cortex and right PPC. Greater prefrontal-posterior cortical functional connectivity was associated with better SWM performance in controls, but not in patients. These results suggest that prefrontal-posterior functional connectivity associated with the maintenance and control of visual information is central to SWM, and that disruption of this functional network underlies SWM deficits in schizophrenia.     

Extratemporal functional connectivity impairments at rest are related to memory performance in mesial temporal epilepsy

Mesial temporal lobe epilepsy (MTLE) is the most frequent form of focal epilepsy. At rest, there is evidence that brain abnormalities in MTLE are not limited to the epileptogenic region, but extend throughout the whole brain. It is also well established that MTLE patients suffer from episodic memory deficits. Thus, we investigated the relation between the functional connectivity seen at rest in fMRI and episodic memory impairments in MTLE. We focused on resting state BOLD activity and evaluated whether functional connectivity (FC) differences emerge from MTL seeds in left and right MTLE groups, compared with healthy controls. Results revealed significant FC reductions in both patient groups, localized in angular gyri, thalami, posterior cingulum and medial frontal cortex. We found that the FC between the left non‐pathologic MTL and the medial frontal cortex was positively correlated with the delayed recall score of a non‐verbal memory test in right MTLE patients, suggesting potential adaptive changes to preserve this memory function. In contrast, we observed a negative correlation between a verbal memory test and the FC between the left pathologic MTL and posterior cingulum in left MTLE patients, suggesting potential functional maladaptative changes in the pathologic hemisphere. Overall, the present study provides some indication that left MTLE may be more impairing than right MTLE patients to normative functional connectivity. Our data also indicates that the pattern of extra‐temporal FC may vary as a function of episodic memory material and each hemisphere's capacity for cognitive reorganization. Hum Brain Mapp 34:2202–2216, 2013. © 2012 Wiley Periodicals, Inc.     

Hippocampal functional connectivity and episodic memory in early childhood

Episodic memory relies on a distributed network of brain regions, with the hippocampus playing a critical and irreplaceable role. Few studies have examined how changes in this network contribute to episodic memory development early in life. The present addressed this gap by examining relations between hippocampal functional connectivity and episodic memory in 4- and 6-year-old children (n = 40). Results revealed similar hippocampal functional connectivity between age groups, which included lateral temporal regions, precuneus, and multiple parietal and prefrontal regions, and functional specialization along the longitudinal axis. Despite these similarities, developmental differences were also observed. Specifically, 3 (of 4) regions within the hippocampal memory network were positively associated with episodic memory in 6-year-old children, but negatively associated with episodic memory in 4-year-old children. In contrast, all 3 regions outside the hippocampal memory network were negatively associated with episodic memory in older children, but positively associated with episodic memory in younger children. These interactions are interpreted within an interactive specialization framework and suggest the hippocampus becomes functionally integrated with cortical regions that are part of the hippocampal memory network in adults and functionally segregated from regions unrelated to memory in adults, both of which are associated with age-related improvements in episodic memory ability.     

Long‐lasting enhancements of memory and hippocampal‐cortical functional connectivity following multiple‐day targeted noninvasive stimulation

Noninvasive stimulation can alter the function of brain networks, although the duration of neuroplastic changes are uncertain and likely vary for different networks and stimulation parameters. We have previously shown that multiple‐day repetitive transcranial magnetic stimulation can influence targeted hippocampal‐cortical networks, producing increased functional MRI connectivity of these networks and concomitant improvements in memory that outlast stimulation by ～24 h. Here, we present new analyses showing that multiple‐day targeted stimulation of hippocampal‐cortical networks produces even longer‐lasting enhancement. The ability to learn novel, arbitrary face‐word pairings improved over five consecutive daily stimulation sessions, and this improvement remained robust at follow‐up testing performed an average of 15 days later. Furthermore, stimulation increased functional MRI connectivity of the targeted portion of the hippocampus with distributed regions of the posterior hippocampal‐cortical network, and these changes in connectivity remained robust at follow‐up testing. Neuroplastic changes of hippocampal‐cortical networks caused by multiple‐day noninvasive stimulation therefore persist for extended periods. These findings have implications for the design of multiple‐day stimulation experiments and for the development of stimulation‐based interventions for memory disorders. © 2015 Wiley Periodicals, Inc.     

Overlap between hippocampal pre‐encoding and encoding patterns supports episodic memory

It is well‐established that whether the information will be remembered or not depends on the extent to which the learning context is reinstated during post‐encoding rest and/or at retrieval. It has yet to be determined, however, if the fundamental importance of contextual reinstatement to memory extends to periods of spontaneous neurocognitive activity prior to learning. We thus asked whether memory performance can be predicted by the extent to which spontaneous pre‐encoding neural patterns resemble patterns elicited during encoding. Individuals studied and retrieved lists of words while undergoing fMRI‐scanning. Multivoxel hippocampal patterns during resting periods prior to encoding resembled hippocampal patterns at encoding most strongly for items that were subsequently remembered. Furthermore, across subjects, the magnitude of similarity correlated with a behavioral measure of episodic recall. The results indicate that the neural context before learning is an important determinant of memory.     

Predicting episodic and spatial memory performance from hippocampal resting‐state functional connectivity: Evidence for an anterior–posterior division of function

fMRI studies have identified distinct resting‐state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task‐related fMRI point to a role for the anterior hippocampus in nonspatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine‐learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole‐brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole‐brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting‐state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.     

Gamma oscillations during episodic memory processing provide evidence for functional specialization in the longitudinal axis of the human hippocampus

The question of whether the anterior and posterior hippocampus serve different or complementary functional roles during episodic memory processing has been motivated by noteworthy findings in rodent experiments and from noninvasive studies in humans. Researchers have synthesized these data to postulate several models of functional specialization, However, the issue has not been explored in detail using direct brain recordings. We recently published evidence that theta power increases during episodic memory encoding occur in the posterior hippocampus in humans. In our current investigation we analyzed an expanded data set of 32 epilepsy patients undergoing stereo EEG seizure mapping surgery with electrodes precisely targeted to the anterior and posterior hippocampus simultaneously who performed an episodic memory task. Using a repeated measures design, we looked for an interaction between encoding versus retrieval differences in gamma oscillatory power and anterior versus posterior hippocampal location. Our findings are consistent with a recently articulated model (the HERNET model) favoring posterior hippocampal activation during retrieval related processing. We also tested for encoding versus retrieval differences in the preferred gamma frequency band (high versus low gamma oscillations) motivated by published rodent data.     

Altered neural function during episodic memory encoding and retrieval in major depression

Memory impairments are common in major depression. Neural processing during non‐emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty‐six participants (23 depressed patients) performed a non‐emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval. Hum Brain Mapp 35:4293–4302, 2014. © 2014 Wiley Periodicals, Inc .     

Oxytocin selectively facilitates learning with social feedback and increases activity and functional connectivity in emotional memory and reward processing regions

In male Caucasian subjects, learning is facilitated by receipt of social compared with non‐social feedback, and the neuropeptide oxytocin (OXT) facilitates this effect. In this study, we have first shown a cultural difference in that male Chinese subjects actually perform significantly worse in the same reinforcement associated learning task with social (emotional faces) compared with non‐social feedback. Nevertheless, in two independent double‐blind placebo (PLC) controlled between‐subject design experiments we found OXT still selectively facilitated learning with social feedback. Similar to Caucasian subjects this OXT effect was strongest with feedback using female rather than male faces. One experiment performed in conjunction with functional magnetic resonance imaging showed that during the response, but not feedback phase of the task, OXT selectively increased activity in the amygdala, hippocampus, parahippocampal gyrus and putamen during the social feedback condition, and functional connectivity between the amygdala and insula and caudate. Therefore, OXT may be increasing the salience and reward value of anticipated social feedback. In the PLC group, response times and state anxiety scores during social feedback were associated with signal changes in these same regions but not in the OXT group. OXT may therefore have also facilitated learning by reducing anxiety in the social feedback condition. Overall our results provide the first evidence for cultural differences in social facilitation of learning per se, but a similar selective enhancement of learning with social feedback under OXT. This effect of OXT may be associated with enhanced responses and functional connectivity in emotional memory and reward processing regions. Hum Brain Mapp 36:2132–2146, 2015. © 2015 Wiley Periodicals, Inc.     

Evidence for a differential contribution of early perceptual and late cognitive processes during encoding to episodic memory impairment in schizophrenia

Objectives: Schizophrenia is characterised by significant episodic memory impairment that is thought to be related to problems with encoding, however the neuro-functional mechanisms underlying these deficits are not well understood. The present study used a subsequent recognition memory paradigm and event-related potentials (ERPs) to investigate temporal aspects of episodic memory encoding deficits in schizophrenia.

Methods: Electroencephalographic data was recorded in 24 patients and 19 healthy controls whilst participants categorised single words as pleasant/unpleasant. ERPs were generated to subsequently recognised versus unrecognised words on the basis of a forced-choice recognition memory task. Subsequent memory effects were examined with the late positive component (LPP). Group differences in N1, P2, N400 and LPP were examined for words correctly recognised.

Results: Patients performed more poorly than controls on the recognition task. During encoding patients had significantly reduced N400 and LPP amplitudes than controls. LPP amplitude correlated with task performance however amplitudes did not differ between patients and controls as a function of subsequent memory. No significant differences in N1 or P2 amplitude or latency were observed.

Conclusions: The present results indicate that early sensory processes are intact and dysfunctional higher order cognitive processes during encoding are contributing to episodic memory impairments in schizophrenia.     

轻度认知损害患者情节记忆的编码和提取

为了研究轻度认知损害患者情节记忆编码和提取的改变 ,采用神经心理学方法评定正常老年人和轻度认知损害患者 (MCI)情节记忆编码和提取。结果表明 :除存在记忆力损害以外 ,MCI组定向力、语言能力、执行等能力显著低于正常老年组 (P <0 .0 1) ;MCI组患者情节记忆编码正确率显著低于正常老年组 (P <0 .0 1) ,下降约2 2 .81% ;MCI组情节记忆提取正确率显著低于正常老年组 (P <0 .0 5 ) ,下降约 6 .84 %。提示轻度认知损害患者情节记忆编码和提取均存在不同程度的损害 ,而情节记忆编码的损害更明显。     

The effects of study task on prestimulus subsequent memory effects in the hippocampus

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre‐stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as “Remembered,” “Known,” or “New.” As expected, “deep” animacy judgments led to better memory for study items than did “shallow” syllable judgments. In both study tasks, pre‐stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre‐stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre‐stimulus hippocampal subsequent memory effects depends on whether an optimal pre‐stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories. © 2015 Wiley Periodicals, Inc.     

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal–thalamus–hippocampus network

The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long‐term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ‐aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face–name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory‐related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory‐related functional connectivity in a medial prefrontal–thalamus–hippocampus network.     

The functional dissociation of posterior parietal regions during multimodal memory formation

The incidental acquisition of multimodal associations is a key memory function for everyday life. While the posterior parietal cortex has been frequently shown to be involved for these memory functions, ventral and dorsal regions revealed differences in their functional recruitment and the precise difference in multimodal memory processing with respect to the associative process has not been differentiated. Using an incidental multimodal learning task, we isolated the associative process during multimodal learning and recollection. The result of the present functional magnetic resonance imaging (fMRI) study demonstrated that during both learning and recollection a clear functional differentiation between ventral and dorsal posterior parietal regions was found and can be related directly to the associative process. The recruitment of a ventral region, the angular gyrus, was specific for learning and recollection of multimodal associations. In contrast, a dorsal region, the superior parietal lobule, could be attributed to memory guided attentional processing. Independent of the memory stage, we assumed a general role for the angular gyrus in the generation of associative representations and updating of fixed association, episodic memory.     

Interleaved practice enhances skill learning and the functional connectivity of fronto‐parietal networks

Practice of tasks in an interleaved order generally induces superior learning compared with practicing in a repetitive order, a phenomenon known as the contextual‐interference (CI) effect. Increased neural activity during interleaved over repetitive practice has been associated with the beneficial effects of CI. Here, we used psychophysiological interaction (PPI) analysis to investigate whether the neural connectivity of the dorsal premotor (PM) and the dorsolateral prefrontal (DLPFC) cortices changes when motor sequences are acquired through interleaved practice. Sixteen adults practiced a serial reaction time task where a set of three 4‐element sequences were arranged in a repetitive or in an interleaved order on 2 successive days. On Day 5, participants were tested with practiced sequences to evaluate retention. A within‐subjects design was used so that participants practiced sequences in the other condition (repetitive or interleaved) 2–4 weeks later. Functional magnetic resonance images were acquired during practice and retention. On Day 2 of practice, there was greater inter‐regional functional connectivity in the interleaved compared with the repetitive condition for both PM‐seeded and DLPFC‐seeded connectivity. The increased functional connectivity between both seeded regions and sensorimotor cortical areas correlated with the benefit of interleaved practice during later retention. During retention, a significant PPI effect was found in DLPFC‐seeded connectivity, with increased DLPFC‐supplementary motor area connectivity correlated with the benefits of interleaved practice. These data suggest that interleaved practice benefits learning by enhancing coordination of sensorimotor cortical regions, and superior performance of sequences learned under CI is characterized by increased functional connectivity in frontal cortex. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Evidence for cortical encoding specificity in episodic memory: memory-induced re-activation of picture processing areas

Functional magnetic resonance imaging (fMRI) was used to examine whether neural pathways used to encode pictures into memory were re-activated during retrieval of those memories. At encoding, subjects semantically classified common objects presented as pictures or words. At retrieval, subjects performed yes/no recognition memory judgments on words that had been encoded as pictures or as words. The retrieval test probed memory for the encoded item, but not memory for the modality of the encoded item (picture/word). Results revealed that a subset of the brain regions involved specifically in encoding of pictures were also engaged during recognition memory for the encoded pictures. Specifically, encoding of pictures relative to words engaged bilateral extrastriate visual cortex, namely fusiform, lingual, middle occipital, and inferior temporal gyri (Broadman area (BA) 18/19/37). Recognition memory judgments about words that were encoded as pictures relative to those that were encoded as words activated fusiform and inferior temporal gyri primarily in the left hemisphere. Thus, cortical areas originally involved in perception of a visual experience become part of the long-term memory trace for that experience. These findings suggest a neural basis for encoding specificity and transfer appropriate processing in human memory.