Separate neural correlates for the mnemonic components of successive discrimination and working memory tasks

We have used positron emission tomography to map the mnemonic components of two tasks at the extremes of the visual short-term/ working memory spectrum. The successive discrimination task requires only storage of a single item for very short time (ultra-short- term memory), while the 2back task requires both maintenance (i.e. storage and rehearsal) and manipulation of several items (working memory). We tested whether or not the storage component, common to the two tasks, engaged the same cerebral regions. To remove unnecessary confounds, we reduced the cues available to the subjects to a single elementary attribute, the orientation of a grating presented in central vision. This prevented subjects from using verbal strategies or vestibular cues and allowed equating of difficulty among tasks. Ultra-short-term memory for orientation engaged a large expanse of occipito-temporal cortex with a rate-dependent antero-posterior gradient: a fast trial rate engaged posterior regions, a slow trial rate anterior regions. On the other hand, working memory for orientation involved the left inferior parietal cortex, left dorsolateral prefrontal cortex and a left superior frontal sulcus region, and to a lesser degree the symmetrical right superior frontal region and a left superior parietal region. Direct comparison of the two orientation memory networks confirmed their functional segregation. We conclude that at least the storage of orientation information engages distinct regions depending on whether or not short-term memory/working memory involves rehearsal and/or manipulative processes.     

Isolating rule- versus evidence-based prefrontal activity during episodic and lexical discrimination: a functional magnetic resonance imaging investigation of detection theory distinctions

Dorsolateral and frontopolar prefrontal cortices (PFCs) are often implicated in neuroimaging studies of memory retrieval, with this activity ascribed to controlled monitoring processes indicative of difficult or demanding retrieval. Difficulty, however, is multiply determined, with success rates governed both by the available evidence and by the nature of decision rules applied to that evidence. Using event-related functional magnetic resonance imaging, we isolated these factors by 1) contrasting different decision rules across matched evidence and 2) manipulating the level of evidence within a fixed decision rule. For identically constructed retrieval probes (1 old and 1 new item), same-different (are these different?) compared with forced-choice (which one is old?) decision rules yielded bilateral dorsolateral and right frontopolar PFC increases. However, these regions were unaffected when the available evidence was greatly lowered within forced-choice decisions. Thus, the regions were simultaneously sensitive to the type of decision rule and yet insensitive to the level of evidence supporting those decisions. Analogous lexical tasks yielded similar patterns, demonstrating that the PFC responses were not episodic memory specific. We discuss the mechanistic differences between same-different versus forced-choice decisions and the implications of these data for current theories of PFC activity during episodic remembering and executive control.     

Functional specializations in lateral prefrontal cortex associated with the integration and segregation of information in working memory

Control processes are thought to play an important role in working memory (WM), by enabling the coordination, transformation, and integration of stored information. Yet little is known about the neural mechanisms that subserve such control processes. This study examined whether integration operations within WM involve the activation of distinct neural mechanisms within lateral prefrontal cortex (PFC). Event-related functional magnetic resonance imaging was used to monitor brain activity while participants performed a mental arithmetic task. In the integration (IN) condition, a WM preload item had to be mentally inserted into the last step of the math problem. This contrasted with the segregation (SG) condition, which also required maintenance of the WM preload while performing mental arithmetic but had no integration requirement. Two additional control conditions involved either ignoring the preload (math only condition) or ignoring the math problem (recall only condition). Left anterior PFC (Brodmann's Area [BA] 46/10) was selectively engaged by integration demands, with activation increasing prior to, as well as during the integration period. A homologous right anterior PFC region showed selectively increased activity in the SG condition during the period in which the math problem and preload digit were reported. Left middorsolateral PFC regions (BA 9/46) showed increased, but equivalent, activity in both the SG and IN conditions relative to both control conditions. These results provide support for the selective role of lateral PFC in cognitive control over WM and suggest more specific hypotheses regarding dissociable PFC mechanisms involved during the integration and segregation of stored WM items.     

Activation of Human Prefrontal Cortex during Spatial and Nonspatial Working Memory Tasks Measured by Functional MRI

Separate working memory domains for spatial location, and forobjects, faces, and patterns, have been identified in the prefrontalcortex (PFC) of nonhuman primates. We have used functional magneticresonance imaging to examine whether spatial and nonspatialvisual working memory processes are similarly dissociable inhuman PFC. Subjects performed tasks which required them to remembereither the location or shape of successive visual stimuli. Wefound that the mnemonic component of the working memory tasksaffected the hemispheric pattern of PFC activation. The spatial(LOCATION) working memory task preferentially activated themiddle frontal gyrus (MFG) in the right hemisphere, while thenonspatial (SHAPE) working memory task activated the NIFG inboth hemispheres. Furthermore, the area of activation in theleft hemisphere extended into the inferior frontal gyrus forthe nonspatial SHAPE task. A perceptual target (DOT) detectiontask also activated the MFG bilaterally, but at a level approximatelyhalf that of the working memory tasks. The activation in theMFG occurred within 3–6 s of task onset and declined followingtask offset. Time-course analysis revealed a different patternfor the cingulate gyrus, in which activation occurred upon taskcompletion. Cingulate activation was greatest following theSHAPE task and was greater in the left hemisphere. The presentresults support the prominent role of the PFC and, specifically,the MFG in working memory, and indicate that the mnemonic contentof the task affects the relative weighting of hemispheric activation.     

Age-related differences in brain activity underlying working memory for spatial and nonspatial auditory information

We used functional magnetic resonance imaging and a 1-back task to assess working memory (WM) for spatial (sound location) and nonspatial (sound category) auditory information in younger and older adults. A mixed block-event-related design was used to measure sustained activity during each task block and transient activity to targets (repetitions of location or category). In both groups, there was increased sustained activity for category WM in left anterior temporal cortex and inferior prefrontal cortex (PFC) and increased activity for location WM in right inferior parietal cortex and dorsal PFC. There were no reliable age differences in this pattern of activity. Older adults had more sustained activity than younger adults in left PFC during both tasks, suggesting that additional PFC recruitment in older adults reflects nonspecific engagement of frontally mediated task-monitoring processes. Both groups showed lower transient than sustained activity in auditory cortex bilaterally; however, older adults showed smaller target-related reductions of activity during the category task. A greater reduction of activity to category targets in left auditory cortex was associated with better performance on this task in older adults, suggesting that a failure to modulate activity appropriately when a stimulus is repeated, or when a particular feature of the stimulus is repeated, could lead to reduced ability to detect this repetition.     

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.     

Analogical reasoning and prefrontal cortex: evidence for separable retrieval and integration mechanisms

The present study examined the contributions of prefrontal cortex (PFC) subregions to two component processes underlying verbal analogical reasoning: semantic retrieval and integration. Event-related functional magnetic resonance imaging data were acquired while subjects performed propositional analogy and semantic decision tasks. On each trial, subjects viewed a pair of words (pair 1), followed by an instructional cue and a second word pair (pair 2). On analogy trials, subjects evaluated whether pair 2 was semantically analogous to pair 1. On semantic trials, subjects indicated whether the pair 2 words were semantically related to each other. Thus, analogy--but not semantic--trials required integration across multiple retrieved relations. To identify regions involved in semantic retrieval, we manipulated the associative strength of pair 1 words in both tasks. Anterior left inferior PFC (aLIPC) was modulated by associative strength, consistent with a role in controlled semantic retrieval. Left frontopolar cortex was insensitive to associative strength, but was more sensitive to integration demands than was aLIPC, consistent with a role in integrating the products of semantic retrieval to evaluate whether distinct representations are analogous. Right dorsolateral PFC exhibited a profile consistent with a role in response selection rather than retrieval or integration. These findings indicate that verbal analogical reasoning depends on multiple, PFC-mediated computations.     

Dissociating the roles of right ventral lateral and dorsal lateral prefrontal cortex in generation and maintenance of hypotheses in set-shift problems

Although patient data have traditionally implicated the left prefrontal cortex (PFC) in hypothesis generation, recent lesion data implicate right PFC in hypothesis generation tasks that involve set shifts (lateral transformations). To test the involvement of the right prefrontal cortex in a hypothesis generation task involving set shifts, we scanned 13 normal subjects with fMRI as they completed Match Problems (a classic divergent thinking task) and a baseline task. In Match Problems subjects determined the number of possible solutions for each trial. Successful solutions are indicative of set shifts. In the baseline condition subjects evaluated the accuracy of hypothetical solutions to match problems. A comparison of Match Problems versus baseline trials revealed activation in right ventral lateral PFC (BA 47) and left dorsal lateral PFC (BA 46). A further comparison of successfully versus unsuccessfully completed Match Problems revealed activation in right ventral lateral PFC (BA 47), left middle frontal gyrus (BA 9) and left frontal pole (BA 10), thus identifying the former as a critical component of the neural mechanisms of set-shift transformation. By contrast, activation in right dorsal lateral PFC (BA 46) covaried as a function of the number of solutions generated in Match Problems, possibly due to increased working memory demands to maintain multiple solutions 'on-line', conflict resolution, or progress monitoring. These results go beyond the patient data by identifying the ventral lateral (BA 47) aspect of right PFC as being a critical component of the neural systems underlying lateral transformations, and demonstrate a dissociation between right VLPFC and DLPFC in hypotheses generation and maintenance.     

Specific cerebral networks for maintenance and response organization within working memory as evidenced by the 'double delay/double response' paradigm

Most of the working memory (WM) tasks used in functional imaging studies are based on the principle of the delayed response in which both the storage and the response organization are present during the delay period. It is therefore difficult to isolate activation specific to the storage function from that specific to the organization of the response. To determine the specific neural networks associated with these two WM operations, we performed a functional MRI study in healthy subjects using a new paradigm, 'the double delay/double response' tasks. This paradigm isolates maintenance from response organization by dividing the delay into two separate parts, the first being dedicated to memory, while the second includes response organization. Activation within the dorsolateral prefrontal cortex (DLPFC) followed a relative hemispheric dissociation: activation related to maintenance was predominant in the right DLPFC but was only detected when the load exceeded three items. Activation related to response organization was predominant in the left DLPFC, regardless of whether this response was based on information held in WM ('memory guided') or was independent of WM ('visually-guided'). These results suggest that activation of the DLPFC, should be interpreted in terms of executive processing for both maintenance and response organization.     

Domain-general and domain-sensitive prefrontal mechanisms for recollecting events and detecting novelty

Recollecting the past and discriminating novel from familiar memoranda depend on poorly understood prefrontal cortical (PFC) mechanisms hypothesized to vary according to memory task (e.g. recollection versus novelty detection) and domain of targeted memories (e.g. perceptual versus conceptual). Using event-related fMRI, we demonstrate that recollecting conceptual or perceptual details surrounding object encounters similarly recruits left frontopolar and posterior PFC compared with detecting novel stimuli, suggesting that a domain-general control network is engaged during contextual remembering. In contrast, left anterior ventrolateral PFC coactivated with a left middle temporal region associated with semantic representation, and right ventrolateral PFC with bilateral occipito-temporal cortices associated with representing object form, depending on whether recollections were conceptual or perceptual. These PFC/posterior cortical dissociations suggest that during recollection, lateralized ventrolateral PFC mechanisms bias posterior conceptual or perceptual feature representations as a function of memory relevance, potentially improving the gain of bottom-up memory signals. Supporting this domain-sensitive biasing hypothesis, novelty detection also recruited right ventrolateral PFC and bilateral occipito-temporal cortices compared with conceptual recollection, suggesting that searching for novel objects heavily relies upon perceptual feature processing. Collectively, these data isolate task- from domain-sensitive PFC control processes strategically recruited in the service of episodic memory.     

Working memory specific activity in auditory cortex: potential correlates of sequential processing and maintenance

Working memory (WM) tasks involve several interrelated processes during which past information must be transiently maintained, recalled, and compared with test items according to previously instructed rules. It is not clear whether the rule-specific comparisons of perceptual with memorized items are only performed in previously identified frontal and parietal WM areas or whether these areas orchestrate such comparisons by feedback to sensory cortex. We tested the latter hypothesis by focusing on auditory cortex (AC) areas with low-noise functional magnetic resonance imaging in a 2-back WM task involving frequency-modulated (FM) tones. The control condition was a 0-back task on the same stimuli. Analysis of the group data identified an area on right planum temporale equally activated by both tasks and an area on the left planum temporale specifically involved in the 2-back task. A region of interest analysis in each individual revealed that activation on the left planum temporale in the 2-back task positively correlated with the task performance of the subjects. This strongly suggests a prominent role of the AC in 2-back WM tasks. In conjunction with previous findings on FM processing, the left lateralized effect presumably reflects the complex sequential processing demand of the 2-back matching to sample task.     

Frontal and parietal lobe activation during transitive inference in humans

Cortical areas engaged in knowledge manipulation during reasoning were identified with functional magnetic resonance imaging (MRI) while participants performed transitive inference (TI) on an ordered list of 11 items (e.g. if A < B and B < C, then A < C). Initially, participants learned a list of arbitrarily ordered visual shapes. Learning occurred by exposure to pairs of list items that were adjacent in the sequence. Subsequently, functional MR images were acquired as participants performed TI on non-adjacent sequence items. Control tasks consisted of height comparisons (HT) and passive viewing (VIS). Comparison of the TI task with the HT task identified activation resulting from TI, termed 'reasoning', while controlling for rule application, decision processes, perception, and movement, collectively termed 'support processes'. The HT-VIS comparison revealed activation related to support processes. The TI reasoning network included bilateral prefrontal cortex (PFC), pre-supplementary motor area (preSMA), premotor area (PMA), insula, precuneus, and lateral posterior parietal cortex. By contrast, cortical regions activated by support processes included the bilateral supplementary motor area (SMA), primary motor cortex (M1), somatic sensory cortices, and right PMA. These results emphasize the role of a prefrontal-parietal network in manipulating information to form new knowledge based on familiar facts. The findings also demonstrate PFC activation beyond short-term memory to include mental operations associated with reasoning.     

Hemispheric specialization in human prefrontal cortex for resolving certain and uncertain inferences

Uncertainty is a fact of life that must be accommodated in real-world decision making. Although it has been suggested that the right prefrontal cortex (PFC) has a special role to play in decision making under uncertainty, there is very little hard data to support this hypothesis. To better understand the roles of left and right PFCs in reasoning and decision making in situations with complete and incomplete information, we administered simple inference problems to 18 patients with lateralized focal lesions to PFC (9 right hemisphere, 9 left hemisphere) and 22 age- and education-matched normal controls. The stimuli were systematically manipulated for completeness of information regarding the status of the conclusion. Our results demonstrated a 2-way interaction such that patients with left PFC lesions were selectively impaired in trials with complete information, whereas patients with right PFC lesions were selectively impaired in trials with incomplete information. These results provide compelling evidence for hemispheric specialization for reasoning in PFC and suggest that the right PFC has a critical role to play in reasoning about incompletely specified situations. We postulate this role involves the maintenance of ambiguous mental representations that temper premature overinterpretation by the left hemisphere.     

Cross-modal integration and plastic changes revealed by lip movement, random-dot motion and sign languages in the hearing and deaf

Sign language activates the auditory cortex of deaf subjects, which is evidence of cross-modal plasticity. Lip-reading (visual phonetics), which involves audio-visual integration, activates the auditory cortex of hearing subjects. To test whether audio-visual cross-modal plasticity occurs within areas involved in cross-modal integration, we used functional MRI to study seven prelingual deaf signers, 10 hearing non-signers and nine hearing signers. The visually presented tasks included mouth-movement matching, random-dot motion matching and sign-related motion matching. The mouth-movement tasks included conditions with or without visual phonetics, and the difference between these was used to measure the lip-reading effects. During the mouth-movement matching tasks, the deaf subjects showed more prominent activation of the left planum temporale (PT) than the hearing subjects. During dot-motion matching, the deaf showed greater activation in the right PT. Sign-related motion, with or without a lexical component, activated the left PT in the deaf signers more than in the hearing signers. These areas showed lip-reading effects in hearing subjects. These findings suggest that cross-modal plasticity is induced by auditory deprivation independent of the lexical processes or visual phonetics, and this plasticity is mediated in part by the neural substrates of audio-visual cross-modal integration.     

Neural processes underlying memory attribution on a reality-monitoring task

A relatively common form of memory distortion arises when individuals must discriminate items they have seen from those they have imagined (reality monitoring). The present fMRI investigation (at 1.5 T) focused on the processes that relate to memory assignment regardless of accuracy (e.g. that correspond with the belief that an item was presented as a picture, regardless of whether that belief is correct). Prior to the scan, participants (n = 16) viewed concrete nouns and formed mental images of the object named. Half of the names were followed by the object's photo. During the scan, participants saw the object names and indicated whether the corresponding photo had been studied. Activity in visual-processing regions (including the precuneus and fusiform gyrus) corresponded with the attribution of an item to a pictorial presentation. In contrast, activity in regions thought to be important for self-referential processing (including the ventromedial prefrontal cortex and posterior cingulate gyrus) was associated with attribution to a nonpresented source. These neural findings converge with behavioral evidence indicating that individuals use the amount of different types of information retrieved (e.g. perceptual detail, information about cognitive operations) to determine whether an item was imagined or perceived.     

Where Is ELSA? The Early to Late Shift in Aging

Studies of cognitive and neural aging have recently provided evidence of a shift from an early- to late-onset cognitive control strategy, linked with temporally extended activity in the prefrontal cortex (PFC). It has been uncertain, however, whether this age-related shift is unique to PFC and executive control tasks or whether the functional location might vary depending on the particular cognitive processes that are altered. The present study tested whether an early-to-late shift in aging (ELSA) might emerge in the medial temporal lobes (MTL) during a protracted context memory task comprising both anticipatory cue (retrieval preparation) and retrieval probe (retrieval completion) phases. First, we found reduced MTL activity in older adults during the early retrieval preparation phase coupled with increased MTL activity during the late retrieval completion phase. Second, we found that functional connectivity between MTL and PFC regions was higher during retrieval preparation in young adults but higher during retrieval completion in older adults, suggesting an important interactive relationship between the ELSA pattern in MTL and PFC. Taken together, these results critically suggest that aging results in temporally lagged activity even in regions not typically associated with cognitive control, such as the MTL.     

Face-selective neurons during passive viewing and working memory performance of rhesus monkeys: evidence for intrinsic specialization of neuronal coding.

The functional organization of prefrontal cortex (PFC) is a central issue in cognitive neuroscience. Previous physiological investigations have often failed to reveal specialization within the PFC. However, these studies have generally not been designed to examine this issue. Methodological issues such as statistical criteria for specificity, the number of neurons sampled, the extent of cortex sampled, and the number, location and nature of the stimuli used are among the variables that need to be considered in evaluating the results of studies on functional localization. In the present study, we have examined neurons in macaque monkeys trained to fixate while viewing visual stimuli, including faces, or to use them as memoranda on a working memory task. Visual responses of over 1500 neurons were recorded throughout a wide expanse of the PFC (areas 12, 9, 46, 8 and 45). Neurons were considered selective for faces if the best response to a face was over twice as strong as that to any of a wide variety of non-face stimuli. Full electrode track reconstructions in three monkeys revealed in each that neurons which met this criterion were concentrated almost exclusively in three distinct subregions within the projection region of the temporal lobe visual areas. We further show that for all neurons, the most visually selective neurons (for faces, objects or color patterns) were also the most concentrated in the temporal lobe recipient PFC. Similar face selectivity, regional specialization, and delay or delay-like activity were observed in monkeys whether trained on memory tasks or not, which suggests that these are naturally occurring properties of prefrontal neurons. These results confirm neuronal and regional specialization for information processing in PFC and elucidate how heretofore unexamined experimental variables have a strong influence on the detection of regional specialization.     

Modulation of ventral prefrontal cortex functional connections reflects the interplay of cognitive processes and stimulus characteristics

Emerging ideas of brain function emphasize the context-dependency of regional contributions to cognitive operations, where the function of a particular region is constrained by its pattern of functional connectivity. We used functional magnetic resonance imaging to examine how modality of input (auditory or visual) affects prefrontal cortex (PFC) functional connectivity for simple working memory tasks. The hypothesis was that PFC would show contextually dependent changes in functional connectivity in relation to the modality of input despite similar cognitive demands. Participants were presented with auditory or visual bandpass-filtered noise stimuli, and performed 2 simple short-term memory tasks. Brain activation patterns independently mapped onto modality and task demands. Analysis of right ventral PFC functional connectivity, however, suggested these activity patterns interact. One functional connectivity pattern showed task differences independent of stimulus modality and involved ventromedial and dorsolateral prefrontal and occipitoparietal cortices. A second pattern showed task differences that varied with modality, engaging superior temporal and occipital association regions. Importantly, these association regions showed nonzero functional connectivity in all conditions, rather than showing a zero connectivity in one modality and nonzero in the other. These results underscore the interactive nature of brain processing, where modality-specific and process-specific networks interact for normal cognitive operations.     

Prefrontal cortex asymmetry for memory encoding of words and abstract shapes

Previous work suggested a differential contribution of prefrontal cortex (PFC) to successful encoding depending on the stimulus material. Here, we tested the hypothesis that encoding of words preferentially involves the left PFC, while encoding of nonverbal items (abstract shapes) relies on the right PFC. We used an experimental design that evaluated encoding of both words and abstract shapes in the same healthy volunteers. A transient virtual lesion of the left or the right PFC was elicited with transcranial magnetic stimulation (TMS) while subjects memorized verbal and nonverbal items. We found that encoding of verbal material was disrupted by left PFC stimulation, whereas encoding of nonverbal material was disrupted by right PFC stimulation. These results demonstrate a functionally relevant lateralization of prefrontal contribution for verbal and nonverbal memory encoding.     

Striatal dopamine and working memory

Recent studies have emphasized the importance of dopamine projections to the prefrontal cortex (PFC) for working memory (WM) function, although this system has rarely been studied in humans in vivo. However, dopamine and PFC activity can be directly measured with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), respectively. In this study, we examined WM capacity, dopamine, and PFC function in healthy older participants in order to test the hypothesis that there is a relationship between these 3 factors. We used the PET tracer 6-[18F]fluoro-L-m-tyrosine to measure dopamine synthesis capacity in the striatum (caudate, putamen), and event-related fMRI to measure brain activation during different epochs (cue, delay, probe) of a WM task. Caudate (but not putamen) dopamine correlated positively with WM capacity, whereas putamen (but not caudate) dopamine correlated positively with motor speed. In addition, delay-related fMRI activation in a left inferior prefrontal region was related to both caudate dopamine and task accuracy, suggesting that this may be a critical site for the integration of WM maintenance processes. These results provide new evidence that striatal dopaminergic function is related to PFC-dependent functions, particularly brain activation and behavioral performance during WM tasks.