Associative memory encoding and recognition in schizophrenia: an event-related fMRI study.

BACKGROUND: We used an event-related functional Magnetic Resonance Imaging (fMRI) approach to examine the neural basis of the selective associative memory deficit in schizophrenia. METHODS: Fifteen people with schizophrenia and 18 controls were scanned during a pair and item memory encoding and recognition task. During encoding, subjects studied items and pairs of visual objects. In a subsequent retrieval task, participants performed an item recognition memory test (old/new decisions) and an associative recognition test (intact/rearranged decisions). The fMRI analysis of the recognition data was restricted to correct items only and a random effects model was used. RESULTS: At the behavioral level, both groups performed equally well on item recognition, whereas people with schizophrenia demonstrated lower performance on associative recognition relative to the control group. At the brain level, the comparison between associative and item encoding revealed greater activity in the control group in the left prefrontal cortex and cingulate gyrus relative to the schizophrenia group. During recognition, greater left dorsolateral prefrontal and right inferior prefrontal activations were observed in the control group relative to the schizophrenia group. CONCLUSION: This fMRI study implicates the prefrontal cortex among other brain regions as the basis for the selective associative memory encoding and recognition deficit seen in schizophrenia.     

Assembling and encoding word representations: fMRI subsequent memory effects implicate a role for phonological control

Novel word learning is central to the flexibility inherent in the human language capacity. Word learning may partially depend on long-term memory formation during the assembly of phonological representations from orthographic inputs. In the present study, event-related functional magnetic resonance imaging (fMRI) examined the contributions of phonological control-a component of the verbal working memory system-to phonological assembly and word learning. Subjects were scanned while making syllable decisions about visually presented familiar (English) and novel (pseudo-English and Foreign) words, a task that required retrieval and analysis of existing phonological codes or the assembly and analysis of novel representations. Results revealed that left inferior prefrontal cortex (LIPC) and bilateral parietal cortices were differentially engaged during the processing of novel words, suggesting that this circuit is recruited during phonological assembly. A subsequent memory analysis that examined the relation between fMRI signal and the subject's ability to later remember the words (a measure of effective memory formation) revealed that the magnitude of activation in LIPC, bilateral superior parietal, and left inferior parietal cortices was positively correlated with later memory. Moreover, although the magnitude of the subsequent memory effect in parietal cortex was not significantly affected by word type, this effect was greater in posterior LIPC for novel (pseudo-English) than for familiar (English) words. In the course of subserving the assembly of novel word representations, the phonological (articulatory) control component of the phonological system appears to play a central role in the encoding of novel words into long-term memory.     

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.     

Hippocampal PET activations of memory encoding and retrieval: The HIPER model

A meta-analysis of experimentally induced changes in blood flow (“activations”) in positron emission tomography (PET) studies of memory has revealed an orderly functional anatomic pattern: Activations in the hippocampal region associated with episodic memory encoding are located primarily in the rostral portions of the region, whereas activations associated with episodic memory retrieval are located primarily in the caudal portions. These findings are based on an analysis of a sample of 54 “hippocampal encoding and retrieval” activations that were culled from an overall database consisting of 52 published PET studies of memory. We refer to this general pattern of rostrocaudal gradient of encoding and retrieval PET activations as the HIPER (Hippocampal Encoding/Retrieval) model. The model suggests a division of memory-related labor between the rostral and caudal portions of the hippocampal formation. Because functional anatomic pattern of encoding and retrieval activation that defines the HIPER model was unprecedented and unexpected, it is difficult to relate the model to what is already known or thought about functional neuroanatomy of episodic memory in the hippocampal regions. The model is interesting primarily because its exploration may yield fresh insights into the neural basis of human memory. Hippocampus 1998;8:313–322. © 1998 Wiley-Liss, Inc.     

The neural correlates of visual working memory encoding: a time-resolved fMRI study

The encoding of information into visual working memory (VWM) is not only a prerequisite step for efficient working memory, it is also considered to limit our ability to attend to, and be consciously aware of, task-relevant events. Despite its important role in visual cognition, the neural mechanisms underlying visual working memory encoding have not yet been specifically dissociated from those involved in perception and/or VWM maintenance. To isolate the brain substrates supporting VWM encoding, here we sought to identify, with time-resolved fMRI, brain regions whose temporal profile of activation tracked the time course of VWM encoding. We applied this approach to two different stimulus categories - colors and faces - that dramatically differ in their encoding time. While several cortical and subcortical regions were activated during the VWM encoding period, one of these regions in the lateral prefrontal cortex - the inferior frontal junction - showed a temporal activation profile associated with the duration of encoding and that could not be accounted for by either perceptual or general attentional effects. Moreover, this region corresponds to the prefrontal area previously implicated in ‘attentional blink’ paradigms demonstrating attentional limits to conscious perception. These results not only suggest that the inferior frontal junction is involved in VWM encoding, they also provide neural support for theories positing that VWM encoding is a rate-limiting process underlying our attentional limits to visual awareness.     

Regional analysis of hippocampal activation during memory encoding and retrieval: fMRI study

Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.     

Common deactivation patterns during working memory and visual attention tasks: an intra-subject fMRI study at 4 Tesla

This parametric functional magnetic resonance imaging (fMRI) study investigates the balance of negative and positive fMRI signals in the brain. A set of visual attention (VA) and working memory (WM) tasks with graded levels of difficulty was used to deactivate separate but overlapping networks that include the frontal, temporal, occipital, and limbic lobes; regions commonly associated with auditory and emotional processing. Brain activation (% signal change and volume) was larger for VA tasks than for WM tasks, but deactivation was larger for WM tasks. Load-related increases of blood oxygenation level-dependent (BOLD) responses for different levels of task difficulty cross-correlated strongly in the deactivated network during VA but less so during WM. The variability of the deactivated network across different cognitive tasks supports the hypothesis that global cerebral blood flow vary across different tasks, but not between different levels of task difficulty of the same task. The task-dependent balance of activation and deactivation might allow maximization of resources for the activated network.     

Effects of aging on true and false memory formation: an fMRI study

Compared to young, older adults are more likely to forget events that occurred in the past as well as remember events that never happened. Previous studies examining false memories and aging have shown that these memories are more likely to occur when new items share perceptual or semantic similarities with those presented during encoding. It is theorized that decreased item-specific encoding and increased gist encoding contribute to these age differences in memory performance. The current study used a modified version of the Deese–Roediger–McDermott (DRM) paradigm to investigate the neural correlates of true and false memory encoding. Results indicated that, compared to young, older adults showed reduced activity in medial temporal lobes (MTL), left ventrolateral prefrontal cortex (VLPFC), and visual cortices associated with subsequent true memories. Despite these decreases older adults showed increased activity in right VLPFC and left superior temporal gyrus (STG) for subsequent true memories. Age-related increases in STG were also associated with subsequent false memories. Results support the theory that older adults engage in less item-specific encoding and greater gist encoding, and that these increases in gist encoding support both subsequent true and false memories. Furthermore, results extend findings of reduced frontal asymmetry in aging, often found in block designs, to the subsequent memory paradigm. Results suggest that greater bilateral frontal activity during encoding in aging are not just task-related, but may be associated with subsequent successful memory performance.     

Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An FMRI study.

BACKGROUND: Although major depressive disorder (MDD) represents one of the most serious psychiatric problems afflicting adolescents, efforts to understand the neural circuitry of adolescent MDD have lagged behind those of adult MDD. This study tests the hypothesis that adolescent MDD is associated with abnormal amygdala activity during evocative-face viewing. METHODS: Using functional magnetic resonance imaging (fMRI), between-group differences among MDD (n = 10), anxious (n = 11), and non-psychiatric comparisons (n = 23) were examined during successful vs. unsuccessful face encoding, with encoding success measured post-scan. RESULTS: Compared to healthy adolescents, MDD patients exhibited poorer memory for faces. fMRI analyses accounted for this performance difference through event-related methods. In an analysis comparing successful vs. unsuccessful face encoding, MDD patients exhibited greater left amygdala activation relative to healthy and anxious youth. CONCLUSIONS: Given prior findings among adults, this study suggests that adolescent and adult MDD may involve similar underlying abnormalities in amygdala functioning.     

An fMRI study of verbal episodic memory encoding in amnestic mild cognitive impairment

Amnestic mild cognitive impairment (aMCI) is a high-risk and often prodromal state for the development of Alzheimer's disease (AD) and is characterised by isolated episodic memory impairment. Functional neuroimaging studies in healthy subjects consistently report left prefrontal cortex (PFC) activation during verbal episodic memory encoding. The PFC activation at encoding is related to semantic processing which enhances memory. The purpose of this study was to ascertain whether impaired verbal episodic memory in aMCI is related to PFC dysfunction. Using functional magnetic resonance imaging (fMRI) we compared 10 aMCI patients with 10 elderly controls during verbal encoding. The encoding task was sensitive to the effects of semantic processing. Subsequent recognition was tested to measure encoding success. Behavioural results revealed impaired recognition and a lower false recognition rate for semantically related distracters (lures) in aMCI, which suggest impaired semantic processing at encoding. Both groups activated left hemispheric PFC, insula, premotor cortex and cerebellum, but group comparisons revealed decreased activation in left ventrolateral PFC in the aMCI group. The magnitude of activation in left ventrolateral PFC during encoding was positively correlated with recognition accuracy in the control group but not in the aMCI group. We propose that verbal episodic memory impairment in aMCI is related to PFC dysfunction which affects semantic processing at encoding.     

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 .     

Autobiographical memory in semantic dementia: A longitudinal fMRI study

Whilst patients with semantic dementia (SD) are known to suffer from semantic memory and language impairments, there is less agreement about whether memory for personal everyday experiences, autobiographical memory, is compromised. In healthy individuals, functional MRI (fMRI) has helped to delineate a consistent and distributed brain network associated with autobiographical recollection. Here we examined how the progression of SD affected the brain's autobiographical memory network over time. We did this by testing autobiographical memory recall in a SD patient, AM, with fMRI on three occasions, each one year apart, during the course of his disease. At the outset, his autobiographical memory was intact. This was followed by a gradual loss in recollective quality that collapsed only late in the course of the disease. There was no evidence of a temporal gradient. Initially, AM's recollection was supported by the classic autobiographical memory network, including atrophied tissue in hippocampus and temporal neocortex. This was subsequently augmented by up-regulation of other parts of the memory system, namely ventromedial and ventrolateral prefrontal cortex, right lateral temporal cortex, and precuneus. A final step-change in the areas engaged and the quality of recollection then preceded the collapse of autobiographical memory. Our findings inform theoretical debates about the role of the hippocampus and neocortical areas in supporting remote autobiographical memories. Furthermore, our results suggest it may be possible to define specific stages in SD-related memory decline, and that fMRI could complement MRI and neuropsychological measures in providing more precise prognostic and rehabilitative information for clinicians and carers.     

Anterior hippocampus orchestrates successful encoding and retrieval of non-relational memory: an event-related fMRI study

Episodic memory encoding and retrieval processes have been linked to different neural networks. However, the common brain regions associated with non-relational memory processing during successful encoding (subsequent memory effect) and successful retrieval (recognition effect) have not yet been investigated. Further, the majority of functional imaging studies have been conducted in young subjects, whereas patients from lesion studies, where most neuropsychological models are still based upon, are usually older. Inferences from younger subjects cannot necessarily be applied to the elderly, an issue becoming particularly relevant with our ageing society. Using an event-related fMRI approach we studied 29 healthy elderly subjects (mean age 67.8, SD 5.4 years) with a non-associative task of intentional word list encoding and retrieval. For each subject, behavioural responses were individually classified into four event types (hits test, misses test, false alarms, correct rejections). Brain areas activated during successful memory encoding comprised the anterior left hippocampus extending into the surrounding parahippocampal gyrus. Regions associated with successful memory retrieval involved a wide-spread network of anterior left parahippocampal gyrus, bilateral temporal cortices and bilateral ventral and dorsal prefrontal areas. Regions contributing to both successful encoding and retrieval, evidenced by a conjunction analysis, revealed prominent left lateralized activations of the anterior hippocampus and the inferior parietal lobe. Our results indicate that the anterior left hippocampus plays an important role during successful memory encoding and during successful memory retrieval in a task of simple, non-associative wordlist learning in healthy elderly subjects.     

Event congruency and episodic encoding: a developmental fMRI study

A known contributor to adults’ superior memory performance compared to children is their differential reliance on an existing knowledge base. Compared to those of adults, children's semantic networks are less accessible and less established, a difference that is also thought to contribute to children's relative resistance to semantically related false alarms. Using the “congruency effect” – the memory advantage of congruity, we manipulated the encoded stimuli in the present experiment such that the use of the knowledge base at encoding was more – or less – accessible in both children and adults. While being scanned, 15 children (ages 8–11) and 18 young adults saw printed noun/color combinations and were asked to indicate whether each combination existed in nature. A subsequent recognition test was administered outside of the scanner. Behaviorally, although overall memory was higher in the adult group compared to the children, both age groups showed the congruency effect to the same extent. A comparison of the neural substrates supporting the congruency effect between adults and children revealed that whereas adults recruited regions primarily associated with semantic-conceptual processing (e.g., the left PFC and parietal and occipito-temporal cortices), children recruited regions earlier in the processing stream (e.g., the right occipital cortex). This evidence supports the hypothesis that early in development, episodic encoding depends more on perceptual systems, whereas top-down frontal control and parietal structures become more prominent in the encoding process with age. This developmental switch contributes to adults’ superior memory performance but may render adults more vulnerable to committing semantically based errors.     

Social working memory and its distinctive link to social cognitive ability: an fMRI study

Engaging social working memory (SWM) during effortful social cognition has been associated with neural activation in two neurocognitive systems: the medial frontoparietal system and the lateral frontoparietal system. However, the respective roles played by these systems in SWM remain unknown. Results from this study demonstrate that only the medial frontoparietal system supports the social cognitive demands managed in SWM. In contrast, the lateral frontoparietal system supports the non-social cognitive demands that are needed for task performance, but that are independent of the social cognitive computations. Moreover, parametric increases in the medial frontoparietal system, but not the lateral frontoparietal system, in response to SWM load predicted performance on a challenging measure of perspective-taking. Thus, the medial frontoparietal system may uniquely support social cognitive processes in working memory and the working memory demands afforded by effortful social cognition, such as the need to track another person’s perspective in mind.     

The influence of emotional distraction on verbal working memory: an fMRI investigation comparing individuals with schizophrenia and healthy adults

The ability to maintain information over short periods of time (i.e., working memory) is critically important in a variety of cognitive functions including language, planning, and decision-making. Recent functional Magnetic Resonance Imaging (fMRI) research with healthy adults has shown that brain activations evoked during the delay interval of working memory tasks can be reduced by the presentation of distracting emotional events, suggesting that emotional events may take working-memory processes momentarily offline. Both executive function and emotional processing are disrupted in schizophrenia, and here we sought to elucidate the effect of emotional distraction upon brain activity in schizophrenic and healthy adults performing a verbal working memory task. During the delay period between the memoranda and memory probe items, emotional and neutral distractors differentially influenced brain activity in these groups. In healthy adults, the hemodynamic response from posterior cingulate, orbital frontal cortex, and the parietal lobe strongly differentiated emotional from neutral distractors. In striking contrast, schizophrenic adults showed no significant differences in brain activation when processing emotional and neutral distractors. Moreover, the influence of emotional distractors extended into the memory probe period in healthy, but not schizophrenic, adults. The results suggest that although emotional items are highly salient for healthy adults, emotional items are no more distracting than neutral ones to individuals with schizophrenia.     

Encoding activity in the medial temporal lobe examined with anatomically constrained fMRI analysis

Functional neuroimaging studies have produced a sizable number of observations of increased activity in the human medial temporal lobe (MTL) during encoding of novel memories. The studies have suggested possible functional specialization within the anatomical components of the MTL (hippocampus and the entorhinal, perirhinal, and parahippocampal cortical areas). Neuroimaging studies have just begun to link anatomical regions to specific functions. To address functional specialization hypothesis, a method is described for using high-resolution structural information from magnetic resonance imaging MRI to constrain the analysis of functional magnetic resonance imaging (fMRI) data, for independent assessment of functional activity change in each component of the MTL. With this method, increased activity was detected throughout the MTL in a group of participants (n = 5) who encoded novel pictures. A separate group (n = 5) who encoded words exhibited lower-levels of evoked activity. Laterality effects were found reflecting increased right hemisphere activity during picture encoding (parahippocampal cortex) and increased left hemisphere activity during word encoding (posterior hippocampus and parahippocampal cortex). Neither condition provided evidence for greater activity in the posterior hippocampus than in the anterior hippocampus during encoding, although the greatest increases in activity were observed in the parahippocampal cortex. The anatomically driven methodology is shown to provide detailed comparison of levels of activity change across specific brain areas and to provide increased sensitivity to functional change in each region of the MTL.     

A critical role for the anterior hippocampus in relational memory: evidence from an fMRI study comparing associative and item recognition

Neuroscientific research has established that the hippocampal formation, a structure within the medial temporal lobe (MTL), plays a critical role in memory for facts and events (declarative memory) (Milner et al., 1998). However, its precise role remains unclear. According to one view, the hippocampus has a special role in relating or binding together previously unrelated pieces of information, while another view proposes that the hippocampus is equally involved in all forms of declarative memory, regardless of their demands on relational processing. Using functional magnetic resonance imaging (fMRI), we show that hippocampal activation is modulated by the extent to which a retrieval task depends on relational processing.     

Stability of tactile- and pain-related fMRI brain activations: an examination of threshold-dependent and threshold-independent methods

Functional MRI can be used to assess brain plasticity over time. To confidently attribute changes in activation patterns to cortical plasticity, it is important to establish the stability of cortical activation patterns. Because little is known concerning the stability of somatosensory-evoked brain responses, we assessed the reproducibility of within-subject responses in key somatosensory regions [thalamus, primary and secondary cortex (S1, S2)] to tactile and painful stimuli using threshold-dependent and threshold-independent analyses. Six subjects underwent four biweekly scanning sessions during which tactile and painful stimuli were applied to the hand. Standard thresholding and voxel counting techniques were compared with a novel threshold-independent method utilizing percent signal change within the regions of interest. Contralateral S1 and S2 were qualitatively reproducible during tactile stimulation, with overlapping activations >85% of the time. S2 was also highly reproducible during painful stimulation (88%), whereas S1 was less reproducible (44%). However, activation in the thalamus to both tactile and painful stimulation was highly variable. Ipsilateral activation was consistent within S2 but sparse within S1 and thalamus. Deactivations within ipsilateral S1 occurred 48% of the time with tactile stimuli, and 90% of the time with painful stimuli. Within contralaterally activated regions intraclass correlations (ICCs) were very high using the unthresholded method regardless of the type of stimulation, whereas much lower ICCs arose from the thresholded analyses. These data indicate that a threshold-independent analysis can produce more reproducible outcomes than a standard threshold-dependent analysis.