Developmental differences in prefrontal activation during working memory maintenance and manipulation for different memory loads

The ability to keep information active in working memory is one of the cornerstones of cognitive development. Prior studies have demonstrated that regions which are important for working memory performance in adults, such as dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and superior parietal cortex, become increasingly engaged across school-aged development. The primary goal of the present functional MRI study was to investigate the involvement of these regions in the development of working memory manipulation relative to maintenance functions under different loads. We measured activation in DLPFC, VLPFC, and superior parietal cortex during the delay period of a verbal working memory task in 11-13-year-old children and young adults. We found evidence for age-related behavioral improvements in working memory and functional changes within DLPFC and VLPFC activation patterns. Although activation profiles of DLPFC and VLPFC were similar, group differences were most pronounced for right DLPFC. Consistent with prior studies, right DLPFC showed an interaction between age and condition (i.e. manipulation versus maintenance), specifically at the lower loads. This interaction was characterized by increased activation for manipulation relative to maintenance trials in adults compared to children. In contrast, we did not observe a significant age-dependent load sensitivity. These results suggest that age-related differences in the right DLPFC are specific to working memory manipulation and are not related to task difficulty and/or differences in short-term memory capacity.     

The utility of visuospatial mnemonics is dependent on visuospatial aptitudes

Classic studies in cognition have demonstrated that the use of appropriate memory mnemonics can reliably increase recall performance. However, is the facilitative effect of mnemonics consistent across all individuals? As some mnemonics explicitly contain a large visuospatial component, does normal variance in visuospatial aptitudes predict the effectiveness of such strategy usage? To explore this question, participants who varied in visuospatial ability were asked to recall several lists of words, and either did or did not use a visuospatial mnemonic. Results indicated that effective mnemonic usage was directly dependent on participants' visuospatial ability, and those lower in visuospatial aptitudes actually produced lower recall performance when asked to use such a mnemonic. Similarly, those lower in visuospatial aptitude also reported that mnemonic usage made the task significantly more difficult. These findings suggest that individual differences in relevant cognitive abilities can influence the effectiveness of memory strategies commonly used to enhance recall.     

Task difficulty modulates brain-behavior correlations in language production and cognitive control: Behavioral and fMRI evidence from a phonological go/no-go picture-naming paradigm

Language production and cognitive control are complex processes that involve distinct yet interacting brain networks. However, the extent to which these processes interact and their neural bases have not been thoroughly examined. Here, we investigated the neural and behavioral bases of language production and cognitive control via a phonological go/no-go picture-naming task. Naming difficulty and cognitive control demands (i.e., conflict monitoring and response inhibition) were manipulated by varying the proportion of naming trials (go trials) and inhibition trials (no-go trials) across task runs. The results demonstrated that as task demands increased, participants’ behavioral performance declined (i.e., longer reaction times on naming trials, more commission errors on inhibition trials) whereas brain activation generally increased. Increased activation was found not only within the language network but also in domain-general control regions. Additionally, right superior and inferior frontal and left supramarginal gyri were sensitive to increased task difficulty during both language production and response inhibition. We also found both positive and negative brain–behavior correlations. Most notably, increased activation in sensorimotor regions, such as precentral and postcentral gyri, was associated with better behavioral performance, in both successful picture naming and successful inhibition. Moreover, comparing the strength of correlations across conditions indicated that the brain–behavior correlations in sensorimotor regions that were associated with improved performance became stronger as task demands increased. Overall, our results suggest that cognitive control demands affect language production, and that successfully coping with increases in task difficulty relies on both language-specific and domain-general cognitive control regions.     

The role of spatial configuration in tests of working memory explored with functional neuroimaging

While the importance of the prefrontal cortex for "higher-order" cognitive functions is largely undisputed, no consensus has been reached regarding the fractionation of functions within this region. Several recent functional neuroimaging studies have suggested that the mid-ventrolateral frontal cortex may play an important role in various aspects of human memory. Thus, similar patterns of activation have been observed in this region during analogous spatial, verbal and visual span tasks. In the present study, however, activation was observed in a more dorsolateral region of the lateral frontal cortex during a modified version of the spatial span task, which differed only in the spatial configuration of the array employed. The results of a supplementary behavioral study, designed to investigate this effect further, suggest that in spatial memory tasks certain stimulus configurations may encourage subjects to adopt mnemonic strategies, which may depend upon dorsolateral, rather than ventrolateral, regions of the frontal cortex. These findings shed further light on the functional relationship between dorsal and ventral regions of the lateral frontal cortex and, more specifically, how the "executive" processes assumed to be dependent upon these regions might contribute to aspects of human memory.     

Directed remembering: subliminal cues alter nonconscious memory strategies

Much research on memory function has focused on changes in recognition performance brought about by differences in the processes engaged during encoding. In most of this work, participants either receive explicit instructions to remember particular items or they perform orienting (i.e., encoding) tasks that support different levels of memory performance. In daily life, however, the retention or dismissal of information often occurs without conscious intent, thereby suggesting an alternative, nonconscious route through which purposive remembering and forgetting can occur. Based on this line of reasoning, we speculated that recognition performance in a standard item-based forgetting paradigm may be moderated by subliminal cues that trigger the automatic activation of different mnemonic strategies. We report the results of two experiments that supported this prediction. In each experiment, the basic item-based forgetting effect was replicated, but via the subliminal presentation of "remember" and "forget" cues. In addition, cue-dependent differences in memory performance were traced to the operation of a covert rehearsal mechanism during encoding. We consider the implications of these findings for the non-conscious#10; operation of memory processes in everyday life.     

Introducing the concept of neurobiological foundation of Rorschach responses using the example of Oral Dependent Language

We introduce the concept of “neurobiological foundation” of Rorschach interpretations as an extension of the concept of behavioral representation as a foundation for interpretation of R‐PAS variables. Here, we propose that if there is a parallelism between the mental, verbal and perceptual behaviors occurring within the microcosm of the Rorschach task and those occurring in the external environment [behavioral foundation], then the same brain regions engaged by the test‐taker when producing of a given code, should be engaged also when reproducing, in the external environment, the same psychological processes underlying that specific Rorschach code [neurobiological foundation]. To investigate this concept, we used archival, fMRI data and tested whether producing Oral Dependency Language (ODL) responses would associate with increased activation in brain regions associated with dependency‐related, psychological processes. Results from a sample of 21 non‐clinical volunteers partially confirmed our hypothesis, providing some support to the neurobiological foundation of the ODL code.     

Directed remembering: Subliminal cues alter nonconscious memory strategies

Much research on memory function has focused on changes in recognition performance brought about by differences in the processes engaged during encoding. In most of this work, participants either receive explicit instructions to remember particular items or they perform orienting (i.e., encoding) tasks that support different levels of memory performance. In daily life, however, the retention or dismissal of information often occurs without conscious intent, thereby suggesting an alternative, nonconscious route through which purposive remembering and forgetting can occur. Based on this line of reasoning, we speculated that recognition performance in a standard item-based forgetting paradigm may be moderated by subliminal cues that trigger the automatic activation of different mnemonic strategies. We report the results of two experiments that supported this prediction. In each experiment, the basic item-based forgetting effect was replicated, but via the subliminal presentation of “remember” and “forget” cues. In addition, cue-dependent differences in memory performance were traced to the operation of a covert rehearsal mechanism during encoding. We consider the implications of these findings for the non-conscious operation of memory processes in everyday life.     

Functional asymmetry of human prefrontal cortex: encoding and retrieval of verbally and nonverbally coded information

There are several views about the organization of memory functions in the human prefrontal cortex. One view assumes a process-specific brain lateralization according to different memory subprocesses, that is, encoding and retrieval. An alternative view emphasizes content-specific lateralization of brain systems involved in memory processes. This study addresses this apparent inconsistency between process- and content-specific lateralization of brain activity by investigating the effects of verbal and nonverbal encoding on prefrontal activations during encoding and retrieval of environmental novel sounds using fMRI. An intentional memory task was applied in which subjects were required either to judge the sounds' loudness (nonverbal encoding task) or to indicate whether or not a sound can be verbally described (verbal encoding task). Retrieval processes were examined in a subsequent yes/no recognition test. In the study phase the right posterior dorsolateral prefrontal cortex (PFC) was activated in both tasks. During verbal encoding additional activation of the left dorsolateral PFC was obtained. Retrieval-related fMRI activity varied as a function of encoding task: For the nonverbal task we detected an activation focus in the right posterior dorsolateral PFC whereas an activation in the left dorsolateral PFC was observed for the verbal task. These findings indicate that the right dorsolateral PFC is engaged in encoding of auditory information irrespective of encoding task. The lateralization of PFC activity during retrieval was shown to depend on the availability of verbal codes, with left hemispheric involvement for verbally and right hemispheric activation for nonverbally coded information.     

Intelligence is differentially related to neural effort in the task-positive and the task-negative brain network

Previous studies on individual differences in intelligence and brain activation during cognitive processing focused on brain regions where activation increases with task demands (task-positive network, TPN). Our study additionally considers brain regions where activation decreases with task demands (task-negative network, TNN) and compares effects of intelligence on neural effort in the TPN and the TNN. In a sample of 52 healthy subjects, functional magnetic resonance imaging was used to determine changes in neural effort associated with the processing of a working memory task. The task comprised three conditions of increasing difficulty: (a) maintenance, (b) manipulation, and (c) updating of a four-letter memory set. Neural effort was defined as signal increase in the TPN and signal decrease in the TNN, respectively. In both functional networks, TPN and TNN, neural effort increased with task difficulty. However, intelligence, as assessed with Raven's Matrices, was differentially associated with neural effort in the TPN and TNN. In the TPN, we observed a positive association, while we observed a negative association in the TNN. In terms of neural efficiency (i.e., task performance in relation to neural effort expended on task processing), more intelligent subjects (as compared to less intelligent subjects) displayed lower neural efficiency in the TPN, while they displayed higher neural efficiency in the TNN. The results illustrate the importance of differentiating between TPN and TNN when interpreting correlations between intelligence and fMRI measures of brain activation. Importantly, this implies the risk of misinterpreting whole brain correlations when ignoring the functional differences between TPN and TNN.     

Executive working memory load induces inattentional blindness

When attention is engaged in a task, unexpected events in the visual scene may go undetected, a phenomenon known as inattentional blindness (IB). At what stage of information processing must attention be engaged for IB to occur? Although manipulations that tax visuospatial attention can induce IB, the evidence is more equivocal for tasks that engage attention at late, central stages of information processing. Here, we tested whether IB can be specifically induced by central executive processes. An unexpected visual stimulus was presented during the retention interval of a working memory task that involved either simply maintaining verbal material or rearranging the material into alphabetical order. The unexpected stimulus was more likely to be missed during manipulation than during simple maintenance of the verbal information. Thus, the engagement of executive processes impairs the ability to detect unexpected, task-irrelevant stimuli, suggesting that IB can result from central, amodal stages of processing.     

Neural substrates of successful working memory and long-term memory formation in a relational spatial memory task

Working memory (WM) tasks may involve brain activation actually implicated in long-term memory (LTM). In order to disentangle these two memory systems, we employed a combined WM/LTM task, using a spatial relational (object-location) memory paradigm and analyzed which brain areas were associated with successful performance for either task using fMRI. Critically, we corrected for the performance on the respective memory task when analyzing subsequent memory effects. The WM task consisted of a delayed-match-to-sample task assessed in an MRI scanner. Each trial consisted of an indoor or outdoor scene in which the exact configuration of four objects had to be remembered. After a short delay (7–13 s), the scene was presented from a different angle and spatial recognition for two objects was tested. After scanning, participants received an unexpected subsequent recognition memory (LTM) task, where the two previously unprobed objects were tested. Brain activity during encoding, delay phase and probe phase was analyzed based on WM and LTM performance. Results showed that successful WM performance, when corrected for LTM performance, was associated with greater activation in the inferior frontal gyrus and left fusiform gyrus during the early stage of the maintenance phase. A correct decision during the WM probe was accompanied by greater activation in a wide network, including bilateral hippocampus, right superior parietal gyrus and bilateral insula. No voxels exhibited supra-threshold activity during the encoding phase, and we did not find any differential activity for correct versus incorrect trials in the WM task when comparing LTM correct versus LTM incorrect trials.     

In search of the neurobiological underpinnings of the differential outcomes effect

Correlating unique rewards with to-be-remembered events (the Differential Outcomes Procedure [DOP]) enhances learning and memory performance in a range of species. Recently, we have demonstrated that the DOP can be used to reduce or eliminate the learning and memory impairments associated with animal models of amnesia and dementia. This powerful phenomenon, the Differential Outcomes Effect (DOE), has led to the question: How does such a simple manipulation exert such dramatic influence on learning and memory performance? A revised two-process account of the DOE states that using the DOP results in the activation of reward expectancies through Pavlovian mechanisms. The use of unique reward expectancies alters the nature of cognitive processing used to solve discrimination tasks. The change in cognitive processing is represented by utilization of a different memory system than that commonly used to acquire and remenber information when a Nondifferential Outcomes Procedure (NOP) is used. Using neurochemical manipulations, it has been demonstrated that different, potentially independent, brain systems modulate memory performance when subjects are trained with a NOP versus a DOP. This memory-based DOP/NOP distinction resembles other dissociative memory theories in which two psychological processes are purportedly served by distinct neurobiological mechanisms. In addition, such results have important ramifications for the treatment of memory disorders because they demonstrate that stimulus and behavioral manipulations, like drugs, can influence neurotransmitter functioning.     

Lateralized Changes in Regional Cerebral Blood Flow during Performance of Verbal and Facial Recognition Tasks: Correlations with Performance and “Effort”

Functional neuroimaging has been used to investigate neural substrates of mnemonic processes, and cerebral blood flow (CBF) measures have been sensitive to activation with memory tasks. Studies of memory with two-dimensional¹³³Xenon clearance techniques found that word and face recognition tasks produced contralateral CBF changes in mid-temporal cortical regions. This study replicated the activation paradigm, expanding to the three-dimensional resolution of positron emission tomography (PET). Word and face recognition, and a control baseline task were administered to 19 healthy right-handed volunteers (11 men, 8 women) during successive 10 min PET¹⁵O-water measures of CBF. Quantitative CBF rates were calculated with the arterial input function and the equilibrium model. Redistributions of blood flow were compared across tasks using both absolute and relative (region/whole brain) CBF.Replicating the¹³³Xenon clearance findings, CBF was “appropriately” lateralized during task performance (left–right for words > left–right for faces) in the mid-temporal region. Contrary to predictions, the recognition tasks did not activate expected mesolimbic or prefrontal areas. The task-induced CBF changes also correlated with performance. Bilateral CBF in mid-temporal and parahippocampal gyrus regions of interest correlated with the ability to correctly identify word targets (sensitivity). Left-lateralized CBF in the amygdala and hippocampus correlated with better word sensitivity as well as specificity (ability to correctly reject foils). Complementally, right-lateralized CBF in the parahippocampal gyrus correlated with better face specificity performance. In addition, left-lateralized CBF in the amygdala and right-lateralized CBF in the parahippocampal gyrus and hippocampus correlated with “mental effort” indices (task performance relative to basal ability) for word and face memory tasks, respectively. Thus, whereas this recognition task showed the expected lateralized increase in the mid-temporal region and not in frontal and limbic areas, lateralized activation in some of these areas was associated with better performance. Exploratory analyses on other regions showed lateralized changes in one additional temporal region, the occipital-temporal, and several limbic regions.     

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.     

In Search of the Neurobiological Underpinnings of the Differential Outcomes Effect

Correlating unique rewards with to-be-remembered events (the Differential Outcomes Procedure [DOP]) enhances learning and memory performance in a range of species. Recently, we have demonstrated that the DOP can be used to reduce or eliminate the learning and memory impairments associated with animal models of amnesia and dementia. This powerful phenomenon, the Differential Outcomes Effect (DOE), has led to the question: How does such a simple manipulation exert such dramatic influence on learning and memory performance? A revised two-process account of the DOE states that using the DOP results in the activation of reward expectancies through Pavlovian mechanisms. The use of unique reward expectancies alters the nature of cognitive processing used to solve discrimination tasks. The change in cognitive processing is represented by utilization of a different memory system than that commonly used to acquire and remember information when a Nondifferential Outcomes Procedure (NOP) is used. Using neurochemical manipulations, it has been demonstrated that different, potentially independent, brain systems modulate memory performance when subjects are trained with a NOP versus a DOP. This memory-based DOP/NOP distinction resembles other dissociative memory theories in which two psychological processes are purportedly served by distinct neurobiological mechanisms. In addition, such results have important ramifications for the treatment of memory disorders because they demonstrate that stimulus and behavioral manipulations, like drugs, can influence neurotransmitter functioning.     

Neural mechanisms underlying subsequent memory for personal beliefs:An fMRI study

Many fMRI studies have examined the neural mechanisms supporting emotional memory for stimuli that generate emotion rather automatically (e.g., a picture of a dangerous animal or of appetizing food). However, far fewer studies have examined how memory is influenced by emotion related to social and political issues (e.g., a proposal for large changes in taxation policy), which clearly vary across individuals. In order to investigate the neural substrates of affective and mnemonic processes associated with personal opinions, we employed an fMRI task wherein participants rated the intensity of agreement/disagreement to sociopolitical belief statements paired with neural face pictures. Following the rating phase, participants performed an associative recognition test in which they distinguished identical versus recombined face–statement pairs. The study yielded three main findings: behaviorally, the intensity of agreement ratings was linked to greater subjective emotional arousal as well as enhanced high-confidence subsequent memory. Neurally, statements that elicited strong (vs. weak) agreement or disagreement were associated with greater activation of the amygdala. Finally, a subsequent memory analysis showed that the behavioral memory advantage for statements generating stronger ratings was dependent on the medial prefrontal cortex (mPFC). Together, these results both underscore consistencies in neural systems supporting emotional arousal and suggest a modulation of arousal-related encoding mechanisms when emotion is contingent on referencing personal beliefs.     

Developmental differences in the mental effort requirements for the use of an organizational strategy in free recall

The mental effort requirements of free recall and the use of an organization strategy for recall were investigated in two experiments. Interference on a secondary task (finger tapping) was assessed to measure the mental effort requirements of the memory tasks. In a first experiment, it was found that comparable expenditure of mental effort resulted in better memory performance for adults and seventh-graders compared with third-graders, and for related lists compared with unrelated lists. In a second experiment, third- and seventh-graders were instructed to use an organizational strategy to remember a list of words. Although both third- and seventh-graders employed the organizational strategy and showed comparable expenditure of mental effort, this led to increased levels of performance only for the seventh-graders. The results suggest that when memory strategies are imposed on young children, what mental effort is expended on implementing the mnemonic reduces the amount of mental capacity available for other activities, resulting in only modest gains in memory performance.     

Automatic and conscious processing in retarded and nonretarded adolescents

Educable mentally retarded and nonretarded adolescents participated in incidental learning tasks that emphasized the utilization of processes that were consciously controlled but not deliberately aimed at memory (Experiment 1). Retarded individuals' performance on a standard recognition test was equivalent to that of nonretarded subjects following phonetic encoding and nonstrategic encoding, but was deficient following semantic encoding. Retarded subjects also demonstrated a lower level of performance on a rhyme recognition task. In Experiment 2, retarded subjects provided a pattern of responding identical to that of nonretarded subjects on a picture-word interference task designed to assess automatic processing. The two groups produced equivalent levels of semantic activation. It was argued that the results of the two experiments indicate deficient semantic processing on the part of retarded individuals relative to that of nonretarded individuals that cannot be accommodated by a structural-deficiency model, a developmental-lag model, or a hypothesis that predicts intelligence-related differences only when the task involves the use of deliberate mnemonic strategies.     

Effects of verbal and nonverbal interference on spatial and object visual working memory

We tested the hypothesis that a verbal coding mechanism is necessarily engaged by object, but not spatial, visual working memory tasks. We employed a dual-task procedure that paired n-back working memory tasks with domain-specific distractor trials inserted into each interstimulus interval of the n-back tasks. In two experiments, object n-back performance demonstrated greater sensitivity to verbal distraction, whereas spatial n-back performance demonstrated greater sensitivity to motion distraction. Visual object and spatial working memory may differ fundamentally in that the mnemonic representation of featural characteristics of objects incorporates a verbal (perhaps semantic) code, whereas the mnemonic representation of the location of objects does not. Thus, the processes supporting working memory for these two types of information may differ in more ways than those dictated by the "what/where" organization of the visual system, a fact more easily reconciled with a component process than a memory systems account of working memory function.     

Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout

The synaptic Ras/Rap-GTPase-activating protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D-aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters, many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity.