Temporal dynamics of basal ganglia response and connectivity during verbal working memory

Research on the neural basis of working memory (WM) has generally focused on neocortical regions; comparatively little is known about the role of subcortical structures. There is growing evidence that the basal ganglia are involved in WM, but their contribution to different component processes of WM is poorly understood. We examined the temporal dynamics of basal ganglia response and connectivity during the encoding, maintenance and response phases of a Sternberg WM task. During the encoding and maintenance phases, WM-load-dependent activation was observed in the left anterior caudate, anterior putamen and globus pallidus; activation in the right anterior caudate was observed only during the maintenance phase. During the response phase, the basal ganglia were equally active in both the high-load and low-load WM conditions. Caudate and putamen activations were primarily localized to the (rostral) associative parts of the basal ganglia, consistent with the putative role of these regions in cognitive processing. Effective connectivity analyses revealed increased WM-load-dependent interaction of the left anterior caudate with the left posterior parietal cortex during all three phases of the task; with the visual association cortex, including the fusiform gyrus and inferior temporal gyrus, only during the encoding phase; with the ventrolateral prefrontal cortex during the encoding and maintenance phases; with the pre-supplementary motor area during the maintenance and response phases; and with the dorsolateral prefrontal and anterior cingulate cortices only during the response phase. Taken together with known neuroanatomy of the basal ganglia, these results suggest that the anterior caudate helps to link signals in distinct functional networks during different phases of the WM task. Our study offers new insight into the integrative and adaptive role of the basal ganglia in higher cognitive function.     

Complex span tasks and hippocampal recruitment during working memory

The working memory (WM) system is vital to performing everyday functions that require attentive, non-automatic processing of information. However, its interaction with long term memory (LTM) is highly debated. Here, we used fMRI to examine whether a popular complex WM span task, thought to force the displacement of to-be-remembered items in the focus of attention to LTM, recruited medial temporal regions typically associated with LTM functioning to a greater extent and in a different manner than traditional neuroimaging WM tasks during WM encoding and maintenance. fMRI scans were acquired while participants performed the operation span (OSPAN) task and an arithmetic task. Results indicated that performance of both tasks resulted in significant activation in regions typically associated with WM function. More importantly, significant bilateral activation was observed in the hippocampus, suggesting it is recruited during WM encoding and maintenance. Right posterior hippocampus activation was greater during OSPAN than arithmetic. Persitimulus graphs indicate a possible specialization of function for bilateral posterior hippocampus and greater involvement of the left for WM performance. Recall time-course activity within this region hints at LTM involvement during complex span.     

Neural system for updating object working memory from different sources: sensory stimuli or long-term memory

Working memory (WM) is the active maintenance of currently relevant information so that it is available for use. A crucial component of WM is the ability to update the contents when new information becomes more relevant than previously maintained information. New information can come from different sources, including from sensory stimuli (SS) or from long-term memory (LTM). Updating WM may involve a single neural system regardless of source, distinct systems for each source, or a common network with additional regions involved specifically in sensory or LTM processes. The current series of experiments indicates that a single fronto-parietal network (including supplementary motor area, parietal, left inferior frontal junction, middle frontal gyrus) is active in updating WM regardless of the source of information. Bilateral cuneus was more active during updating WM from LTM than updating from SS, but the activity in this region was attributable to recalling information from LTM regardless of whether that information was to be entered into WM for future use or not. No regions were found to be more active during updating from SS than updating from LTM. Functional connectivity analysis revealed that different regions within this common update network were differentially more correlated with visual processing regions when participants updated from SS, and more correlated with LTM processing regions when participants updated from the contents of LTM. These results suggest that a single neural mechanism is responsible for controlling the contents of WM regardless of whether that information originates from a sensory stimulus or from LTM. This network of regions involved in updating WM interacts with the rest of the brain differently depending on the source of newly relevant information.     

Prefrontal and hippocampal contributions to the generation and binding of semantic associations during successful encoding

The ability to form and bind associations between items is an important aspect of successful memory formation. We hypothesize that, during encoding, the left inferior frontal gyrus (IFG) supports generation of associations between items and the hippocampus then binds these associations. This study examined the parametric responses of these regions to varying amounts of generative and relational processing during successful encoding (i.e., for subsequently recognized items). Encoding involved presentation of word triads varying in the number of semantic associations among them (none, one or all); participants judged how many associations were present in each triad. Thus, triads with fewer associations had higher generative load while triads with more associations had higher relational load. Participants later completed a forced-choice recognition test for encoding triads. Successful encoding relative to a control task resulted in activation of bilateral IFG and left hippocampus, and the hippocampus also exhibited a significant subsequent memory effect (hits>misses). Linear parametric analyses revealed that generative load modulated activity in bilateral IFG while relational load correlated with activity in left hippocampus. Although univariate analyses distinguished IFG and hippocampal contributions to the generative and relational stages of encoding, respectively, effective connectivity between these regions did not differ according to condition. Furthermore, this analysis revealed that the left IFG played a pivotal role in coordinating associative encoding processes. Our findings illustrate that modulation of components in a memory network can be independent of patterns of mutual connectivity among those components in mediating successful encoding.     

The effect of word concreteness on recognition memory

Concrete words that are readily imagined are better remembered than abstract words. Theoretical explanations for this effect either claim a dual coding of concrete words in the form of both a verbal and a sensory code (dual-coding theory), or a more accessible semantic network for concrete words than for abstract words (context-availability theory). However, the neural mechanisms of improved memory for concrete versus abstract words are poorly understood. Here, we investigated the processing of concrete and abstract words during encoding and retrieval in a recognition memory task using event-related functional magnetic resonance imaging (fMRI). As predicted, memory performance was significantly better for concrete words than for abstract words. Abstract words elicited stronger activations of the left inferior frontal cortex both during encoding and recognition than did concrete words. Stronger activation of this area was also associated with successful encoding for both abstract and concrete words. Concrete words elicited stronger activations bilaterally in the posterior inferior parietal lobe during recognition. The left parietal activation was associated with correct identification of old stimuli. The anterior precuneus, left cerebellar hemisphere and the posterior and anterior cingulate cortex showed activations both for successful recognition of concrete words and for online processing of concrete words during encoding. Additionally, we observed a correlation across subjects between brain activity in the left anterior fusiform gyrus and hippocampus during recognition of learned words and the strength of the concreteness effect. These findings support the idea of specific brain processes for concrete words, which are reactivated during successful recognition.     

Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia

Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.     

Effects of semantic relatedness on age-related associative memory deficits: the role of theta oscillations

Growing evidence suggests that age-related deficits in associative memory are alleviated when the to-be-associated items are semantically related. Here we investigate whether this beneficial effect of semantic relatedness is paralleled by spatio-temporal changes in cortical EEG dynamics during incidental encoding. Young and older adults were presented with faces at a particular spatial location preceded by a biographical cue that was either semantically related or unrelated. As expected, automatic encoding of face-location associations benefited from semantic relatedness in the two groups of age. This effect correlated with increased power of theta oscillations over medial and anterior lateral regions of the prefrontal cortex (PFC) and lateral regions of the posterior parietal cortex (PPC) in both groups. But better-performing elders also showed increased brain-behavior correlation in the theta band over the right inferior frontal gyrus (IFG) as compared to young adults. Semantic relatedness was, however, insufficient to fully eliminate age-related differences in associative memory. In line with this finding, poorer-performing elders relative to young adults showed significant reductions of theta power in the left IFG that were further predictive of behavioral impairment in the recognition task. All together, these results suggest that older adults benefit less than young adults from executive processes during encoding mainly due to neural inefficiency over regions of the left ventrolateral prefrontal cortex (VLPFC). But this associative deficit may be partially compensated for by engaging preexistent semantic knowledge, which likely leads to an efficient recruitment of attentional and integration processes supported by the left PPC and left anterior PFC respectively, together with neural compensatory mechanisms governed by the right VLPFC.     

Putting names to faces: successful encoding of associative memories activates the anterior hippocampal formation

The ability to form associations between previously unrelated items of information, such as names and faces, is an essential aspect of episodic memory function. The neural substrate that determines success vs. failure in learning these associations remains to be elucidated. Using event-related functional MRI during the encoding of novel face-name associations, we found that successfully remembered face-name pairs showed significantly greater activation in the anterior hippocampal formation bilaterally and left inferior prefrontal cortex, compared to pairs that were forgotten. Functional connectivity analyses revealed significant correlated activity between the right and left hippocampus and neocortical regions during successful, but not attempted, encoding. These findings suggest that anterior regions of the hippocampal formation, in particular, are crucial for successful associative encoding and that the degree of coordination between hippocampal and neocortical activity may predict the likelihood of subsequent memory.     

Dissociating a common working memory network from different neural substrates of phonological and spatial stimulus processing.

Positron emission tomography was used to investigate common versus specific cortical regions for the maintenance of spatial versus phonological information in working memory (WM). Group and single-subject analyses of regional cerebral blood flow during a new 2 x 2 factorial n-back task were performed. Eight subjects had to memorize either phonological features or the location of serially presented syllables. Brain activation during phonological judgment and spatial judgment (0-back) was compared with that during two corresponding WM conditions (2-back). We observed a common network associated with the requirement of maintaining and sequencing items in WM. Seven or more subjects activated (posterior) superior frontal sulcus (pSFS, BA 6/8, global maximum) and/or adjacent gyri, posterior parietal cortex, and precuneus (BA 7). Less consistently, bilateral middle frontal gyrus (BA 9/46) was involved. Bilateral anterior (BA 39/40) and posterior (BA 7) intraparietal sulcus, as well as right pSFS, exhibited dominance for spatial WM. Although underlying stimulus processing pathways for both types of information were different, no region specific for phonological WM was found. Robust activation within the left inferior frontal gyrus (BA 44 and 45) was present, during both phonological WM and phonological judgment. We conclude that the controversial left prefrontal lateralization for verbal WM reflects more general phonological processing strategies, not necessarily required by tasks using letters. We propose a stimulus-independent role for the bilateral pSFS and its vicinity for maintenance and manipulation of different context-dependent information within working memory.     

Neural substrates of visual paired associates in young adults with a history of very preterm birth: Alterations in fronto-parieto-occipital networks and caudate nucleus

This study investigated neuronal activation during visuo-perceptual learning processing in adults who were born very preterm (VPT, < 33 weeks' gestation). A visual paired associates task was administered during functional magnetic resonance imaging (fMRI) and neuronal activation was compared between 21 VPT-born adults of both sexes and 22 matched controls. The task consisted of 4 conditions (encoding, recognition, same/different discrimination condition (baseline) and a low-level baseline), each containing 8 stimuli pairs. There were no group differences in terms of correctly recognized visual pairs. However, during encoding, VPT-born individuals showed increased BOLD signal response compared to controls in left caudate nucleus, right cuneus (BA 18) and left superior parietal lobule (BA 7), and decreased signal in right inferior frontal gyrus (BA 46). During recognition, VPT-born adults showed increased BOLD signal response compared to controls in right cerebellum and in anterior cingulate gyrus (BA 32) bilaterally. The fMRI data were additionally analyzed controlling for structural differences in the hippocampus bilaterally, where the VPT group showed decreased probability of the absolute amount of grey matter compared to controls. Results of our study suggest that despite good task performance, VPT-born individuals activate different neural networks during mnemonic processing of visuo-perceptual material which may indicate neural compensation for the adult consequences of perinatal brain injury following very preterm birth, as well as maturational delays.     

Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task

Acute tryptophan depletion (ATD), a well-recognized method to lower central serotonin levels, was used to examine the effects of lower central serotonin levels on memory function in healthy males. Functional Magnetic Resonance Imaging (fMRI) was used to examine changes in brain activation during the encoding and the retrieval phase of a visual verbal episodic memory task. ATD led to more positively rated words in the encoding phase and to poorer recognition of these positively rated words in the retrieval phase. Furthermore, encoding was accompanied by enhanced brain activation in occipital, middle and superior frontal, anterior and posterior cingulate and striatal areas. Retrieval attempt was accompanied by enhanced activation in the cuneus, inferior occipital gyrus and inferior and middle frontal areas. Retrieval success was accompanied by activation in an extensive network including frontal, parietal, temporal, cingulate, striatal and cerebellar areas. In the encoding phase ATD attenuated activation in the right hippocampus and ATD did not affect brain activity in the retrieval phase. These results show that serotonin is important in long term memory processes, and that serotonin acts on the encoding phase and not on the retrieval phase.     

Load response functions in the human spatial working memory circuit during location memory updating

Previous studies have emphasized that the dorsolateral prefrontal cortex is important for manipulating information in working memory, although activations in other frontal and parietal areas are commonly observed under the same conditions. We conducted an fMRI experiment to examine brain responses as a parametric function of memory updating, which is considered as an elemental process in working memory. In a variant spatial delayed-response task, human subjects performed updating operations over a 9-second delay period, during which they mentally transform the location of a memorized target in a 4 by 4 grid according to 3 to 12 instruction cues. Activity increased monotonically with increasing updating load in numerous cortical and subcortical regions including the rostrodorsal premotor (rdPM), lateral precentral sulcus, lateral prefrontal, posterior associative, striatal and cerebellar areas. The rdPM and superior parietal were particularly sensitive to the updating manipulation. There were several main findings. First, updating spatial working memory involved mostly the same cortical and subcortical regions that were activated during maintenance of spatial information. Second, the updating load response functions of regions in the spatial working memory circuit showed a strong linear component. However, none shows significant increases in activity from 9 to 12 updating operations. Third, activity in the right rdPM and anterior inferior frontal gyrus correlated positively with working memory performance in the high updating load condition. Our findings suggest that updating and maintenance of spatial information may share similar processes and that the rostrodorsal premotor cortex and anterior inferior frontal gyrus may be important for the success of tracking spatial information in working memory.     

Parahippocampal Activation during Successful Recognition of Words: A Self-Paced Event-Related fMRI Study

In this study, we investigated retrieval from verbal episodic memory using a self-paced event-related fMRI paradigm, similar to the designs typically used in behavioral studies of memory function. We tested the hypothesis that the medial temporal lobe (MTL) is involved in the actual recovery of verbal information (retrieval success) rather than in the attempt to retrieve information (retrieval attempt). To this end, we used a verbal recognition task, distinguishing correctly recognized words, correctly rejected words, and a low-level baseline condition. Directly contrasting correct recognition with correct rejection of words, we found activation in the left fusiform/parahippocampal gyrus, indicating that this region has a distinct role in the successful retrieval of verbal information. Furthermore, our results were in agreement with those of previous imaging studies that compared a fixed-paced verbal recognition task to a baseline condition, showing activation in bilateral inferior frontal cortex, left dorsolateral prefrontal cortex, left anterior insular cortex, and anterior cingulate. This demonstrates the applicability of a self-paced event-related design within imaging studies of memory function.     

fMRI BOLD response to increasing task difficulty during successful paired associates learning

We used functional magnetic resonance imaging (fMRI) to assess cortical activations associated with increasing task difficulty (TD) in a visuospatial paired associates learning task. Encoding and retrieval were examined when 100% successful retrieval of three, four, or six object-location pairs had been attained (thus ensuring that performance was matched across subjects). As memory load increased, in general, the number of attempts taken to achieve 100% successful retrieval increased, while the number of trials correctly completed on the first attempt decreased. By modelling parametric variations in working memory load with BOLD signal changes we were able to identify brain regions displaying linear and nonlinear responses to increasing load. During encoding, load-independent activations were found in occipitoparietal cortices (excluding the precuneus for which linear load dependency was demonstrated), anterior cingulate, and cerebellum, while linear load-dependent activations in these same regions were found during retrieval. Nonlinear load-dependent responses, as identified by categorical contrasts between levels of load, were found in the right DLPFC and left inferior frontal gyrus. The cortical response to increasing cognitive demands or TD appears to involve the same, rather than an additional, network of brain regions "working harder."     

Neural correlates of successful encoding of semantically and phonologically mediated inter-item associations

This experiment investigated whether the neural correlates of inter-item associative encoding vary according to study task. At study, pairs of unrelated words were subjected to either semantic or phonological relational judgments. Test items comprised studied word pairs (intact), pairs comprised of words belonging to different study pairs (rearranged), and novel pairs. The test requirement was to discriminate between these different classes of test item. fMRI was employed to contrast the neural activity elicited by studied pairs that were correctly endorsed as intact on the later associative recognition test, as opposed to pairs for which associative information was unavailable. In contrast to prior findings for the encoding of single items, there was no evidence that the loci of subsequent associative memory effects varied according to study task. Instead, in both tasks, pairs that were later correctly endorsed as intact elicited enhanced activity in mid- and ventral regions of the left ventrolateral prefrontal cortex (VLPFC). These findings were accompanied by extensive task-invariant reversed subsequent memory effects in medial and lateral parietal and frontal cortices. The findings suggest that the left VLPFC may play a domain-general role in the encoding of item-item associations, and in addition highlight the importance of elucidating the functional significance of reversed subsequent memory effects.     

Testosterone biases automatic memory processes in women towards potential mates

Female mate choice involves the comparative evaluation of potential mates. Females use a pooled comparison of sampled males to maximize the perceived reproductive fitness of their partner, implying the memorization of sampled males. However, hormonal and reproductive states influence female choosiness, and women's preference and memory for masculinity. Here, we investigated whether testosterone biases memory processes in women towards male faces using functional MRI. A single nasal testosterone dose was administered to healthy women in their early follicular phase, in a double-blind, placebo-controlled, crossover design. Testosterone increased the difference in reaction times to categorize male and female faces during encoding, without influencing subsequent recognition accuracy or response bias. The imaging results showed that testosterone shifted memory formation in the hippocampus and inferior temporal gyri from the encoding of female faces towards the encoding of male faces. In contrast, testosterone shifted memory formation in the left inferior frontal gyrus from the encoding of male faces towards the encoding of female faces. Furthermore, the hippocampal contribution to memory retrieval also shifted from female towards male faces. These results indicate that testosterone biases memory processes towards the relatively automatic encoding and retrieval of males in temporal brain regions and elaborate encoding of females in frontal brain regions, suggesting that testosterone may support female mate sampling and comparison by biasing automatic memory processes towards the encoding and retrieval of potential mates.     

Neural substrates of cross-modal olfactory recognition memory: an fMRI study

Ten young adults (aged 20 to 25 years) participated in a functional Magnetic Resonance Imaging (fMRI) study to investigate neural substrates of cross-modal olfactory recognition memory. Before entering the scanner, participants were presented with 16 familiar odors selected from the COLT (Murphy, C., Nordin, S., Acosta, L., 1997. Odor learning, recall, and recognition memory in young and elderly adults. Neuropsychology 11, 126-137) and were then scanned for 3 runs according to a paradigm derived from Stark and Squire (Stark, C.E., Squire, L.R., 2000. Functional magnetic resonance imaging (fMRI) activity in the hippocampal region during recognition memory. J. Neurosci. 20, 7776-7781). During each run, participants were shown names of odors presented (targets) or not presented (foils) at encoding. Participants distinguished targets from foils via button press. Each run alternated 4 'ON' periods containing 7 targets and 2 foils (36 s) and 4 'OFF' periods with 7 foils and 2 targets (36 s). Data were processed with AFNI (Cox, R.W., 1996. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput. Biomed. Res. 29, 162-173) and compared ON and OFF periods, extracting activation in regions that responded during the cross-modal olfactory recognition memory task. Group analysis showed that regions activated during the first run included right hippocampus, piriform/amygdalar area, superior temporal gyrus, anterior cingulate gyrus, inferior frontal/orbitofrontal gyrus, superior/medial frontal gyrus, and bilateral parahippocampal gyrus, inferior parietal lobule, supramarginal gyrus, cerebellum, lingual/fusiform area and middle/posterior cingulate gyrus. Region of interest analysis showed that degree of activation significantly decreased from run 1 to run 3 in the right hippocampus, fusiform gyrus, lingual gyrus, parahippocampal gyrus and middle frontal gyrus but not in other regions, suggesting that these regions sustain a specific function in olfactory recognition memory that attenuates as foils become more familiar with repeated presentation.     

Incidental effects of emotional valence in single word processing: an fMRI study

The present study aimed at identifying the neural responses associated with the incidental processing of the emotional valence of single words using event-related functional magnetic resonance imaging (fMRI). Twenty right-handed participants performed a visual lexical decision task, discriminating between nouns and orthographically and phonologically legal nonwords. Positive, neutral and negative word categories were matched for frequency, number and frequency of orthographic neighbors, number of letters and imageability. Response times and accuracy data differed significantly between positive and neutral, and positive and negative words respectively, thus, replicating the findings of a pilot study. Words showed distributed, mainly left hemisphere activations, indicating involvement of a neural network responsible for semantic word knowledge. The neuroimaging data further revealed areas in left orbitofrontal gyrus and bilateral inferior frontal gyrus with greater activation to emotional than to neutral words. These brain regions are known to be involved in processing semantic and emotional information. Furthermore, distinct activations associated with positive words were observed in bilateral middle temporal and superior frontal gyrus, known to support semantic retrieval, and a distributed network, namely anterior and posterior cingulate gyrus, lingual gyrus and hippocampus when comparing positive and negative words. The latter areas were previously associated with explicit and not incidental processing of the emotional meaning of words and emotional memory retrieval. Thus, the results are discussed in relation to models of processing semantic and episodic emotional information.     

Neural correlates of episodic retrieval success

Episodic memory retrieval involves multiple component processes, including those that occur when information is correctly remembered (retrieval success). The present study employed rapid-presentation event-related functional MRI that allowed different trial types with short intertrial intervals to be sorted such that the hemodynamic response associated with retrieval success could be extracted. Specifically, in an old/new episodic recognition task, hit trials (correctly recognized old items) and correct rejection trials (correctly rejected new items) were directly compared. The comparison revealed a mostly left-lateralized set of brain regions. Differential activation was most robust in left lateral parietal cortex and medial parietal cortex. Additional regions of differential activation included left anterior prefrontal cortex at or near Brodmann area 10, anterior insula, thalamus, anterior cingulate cortex, frontal cortex along inferior frontal gyrus, premotor cortex, and presupplementary motor area. These results suggest that left frontal and parietal regions modulate activity based on the successful retrieval of information from episodic memory. We discuss these findings in the context of several recent investigations that provide converging results as well as prior studies that have failed to detect these changes.     

Encoding activity in anterior medial temporal lobe supports subsequent associative recognition

The ability to bind information together, such as linking a name with a face or a car with a parking space, is a vital process in human episodic memory. To identify the neural bases for this binding process, we measured brain activity during a verbal associative encoding task using event-related functional MRI (fMRI), followed by an associative recognition test for the studied word pairs. Analysis of the encoding data sorted by the associative recognition accuracy allowed us to isolate regions involved in successfully creating associations. We found that encoding activity in bilateral anterior medial temporal lobe (MTL) regions was greater for successfully bound pairs, that is, those later recognized as intact, than for all other pairs. These findings provide evidence that the anterior medial temporal lobes support the successful binding of information in memory.