Chronometry of parietal and prefrontal activations in verbal working memory revealed by transcranial magnetic stimulation

We explored the temporal dynamics of parietal and prefrontal cortex involvement in verbal working memory employing single-pulse transcranial magnetic stimulation (TMS). In six healthy volunteers the left or right inferior parietal and prefrontal cortex was stimulated with the aid of a frameless stereotactic system. TMS was applied at 10 different time points 140-500 ms into the delay period of a two-back verbal working memory task. A choice reaction task was used as a control task. Interference with task accuracy was induced by TMS earlier in the parietal cortex than in the prefrontal cortex and earlier over the right than the left hemisphere. This suggests a propagation of information flow from posterior to anterior cortical sites converging in the left prefrontal cortex. Significant interference with reaction time was observed after 180 ms with left prefrontal cortex stimulation. These effects were not observed in the control task, underlining the task specificity of our results. We propose that the interference with right-sided prefrontal cortex stimulation leads to impaired performance due to disturbed input into the left prefrontal cortex, whereas left-sided TMS interferes directly with the final information processing. Left- and right-sided brain areas might be involved in parallel processing of semantic and object features of the stimuli, respectively.     

Cross-modal processing in auditory and visual working memory

This study aimed to further explore processing of auditory and visual stimuli in working memory. Smith and Jonides (1997) [Smith, E.E., Jonides, J., 1997. Working memory: A view from neuroimaging. Cogn. Psychol. 33, 5-42] described a modified working memory model in which visual input is automatically transformed into a phonological code. To study this process, auditory and the corresponding visual stimuli were presented in a variant of the 2-back task which involved changes from the auditory to the visual modality and vice versa. Brain activation patterns underlying visual and auditory processing as well as transformation mechanisms were analyzed. Results yielded a significant activation in the left primary auditory cortex associated with transformation of visual into auditory information which reflects the matching and recoding of a stored item and its modality. This finding yields empirical evidence for a transformation of visual input into a phonological code, with the auditory cortex as the neural correlate of the recoding process in working memory.     

Linear and nonlinear prefrontal and parietal activity during multiple-item working memory

Most parts of the prefrontal and posterior parietal cortices show sustained activity during short-term maintenance of visual information and their activity increases with increasing memory set size. To investigate the interplay of feature selectivity, memory load and inter-item interaction (or interference) on sustained activity, we compared and contrasted fMRI signal during the retention of two items from the same or different visual feature categories (e.g., two line orientations versus a line and a color) relative to the retention of single items. Data from 16 young adults revealed three types of activation patterns in the prefrontal and posterior parietal cortices. First, among the prefrontal and posterior parietal areas that showed preferential responses to line orientations, some exhibited linear increases in sustained activity whereas others exhibited nonlinear increases in correspondence to the number of lines in the memory set. Second, the right lateral prefrontal and ventral posterior parietal areas, albeit not showing differential sustained activity relative to lines or colors, were disproportionately more active during holding two lines in comparison to holding a line and a color. Third, the left posterior intraparietal sulcus showed a weak effect of memory set size regardless of the items' visual features. These observations suggest that rather than number of items, a combination of factors such as visual feature and memory-set homogeneity may have the greater influence on prefrontal and parietal activity during multiple-item working memory. This is consistent with the view that working memory capacity is influenced by the level of interaction or interference between visual stimuli, which is stronger between items from the same feature category.     

Functional dissociations within the inferior parietal cortex in verbal working memory

Neuroimaging studies of working memory have revealed two sites in the left supramarginal gyrus that may support the short-term storage of phonological information. Activation in the left dorsal aspect of the inferior parietal cortex (DIPC) has been observed in contrasts of working memory load, whereas activation in the ventral aspect of the inferior parietal cortex (VIPC) has been found primarily in contrast of information type (verbal vs. nonverbal). Our goal was to determine whether these two areas are functionally distinct or if instead they are part of a homogeneous region with large variations in the focus of peak activity. Toward this end, we used fMRI to assess the neural response in two working memory tasks (N-back and item recognition) in which we also manipulated memory load and the type of information to be recalled (verbal vs. nonverbal). We found both DIPC and VIPC activation in the same group of subjects and further demonstrated that they have differential sensitivity to our experimental factors. Only the DIPC showed robust load effects, whereas only the VIPC showed reliable effects of information type. These results help to account for the differences observed in between-subject comparisons, and they indicate that the two regions are functionally dissociable. In contrast to the DIPC, activity of the VIPC was also recruited in the fixation and low-load conditions, a surprising result that has not been fully explored in prior studies. Despite their distinctive patterns of performance, neither of these regions displayed a pattern of activity that entirely corresponds to common assumptions of a dedicated phonological short-term store (STS). Instead, we hypothesize that the DIPC may support domain-general executive processes, while the VIPC may support phonological encoding-recoding processes central to a variety of language tasks.     

Functional MRI of auditory verbal working memory: long-term reproducibility analysis

Although functional MRI (fMRI) has shown to be a tool with great potential to study the normal and diseased human brain, the large variability in the detected hemodynamic responses across sessions and across subjects hinders a wider application. To investigate the long-term reproducibility of fMRI activation of verbal working memory (WM), eight normal subjects performed an auditory version of the 2-back verbal WM task while fMRI images were acquired. The experiment was repeated nine times with the same settings for image acquisition and fMRI task. Data were analyzed using SPM99 program. Single-session activation maps and multi-subject session-specific activation maps were generated. Regions of interest (ROIs) associated to specific components of verbal WM were defined based on the voxels' coordinates in Talairach space. Visual observation of the multi-subject activation maps showed similar activation patterns, and quantitative analysis showed small coefficients of variance of activation within ROIs over time, suggesting small longitudinal variability of activation. Visual observation of the activation maps of individual sessions demonstrated striking variation of activation across sessions and across subjects, and quantitative analysis demonstrated larger contribution from between-subject variation to overall variation than that from within-subject variation. We concluded that by multi-subject analysis of data from a relatively small number of subjects, reasonably reproducible activation for the 2-back verbal WM paradigm can be achieved. The level of reproducibility encourages the application of this fMRI paradigm to the evaluation of cognitive changes in future investigations. The quantitative estimation of the proportions of within-subject and between-subject variabilities in the overall variability may be helpful for the design of future studies.     

Collaborative activity between parietal and dorso-lateral prefrontal cortex in dynamic spatial working memory revealed by fMRI

Functional MRI was used to determine how the constituents of the cortical network subserving dynamic spatial working memory respond to two types of increases in task complexity. Participants mentally maintained the most recent location of either one or three objects as the three objects moved discretely in either a two- or three-dimensional array. Cortical activation in the dorsolateral prefrontal (DLPFC) and the parietal cortex increased as a function of the number of object locations to be maintained and the dimensionality of the display. An analysis of the response characteristics of the individual voxels showed that a large proportion were activated only when both the variables imposed the higher level of demand. A smaller proportion were activated specifically in response to increases in task demand associated with each of the independent variables. A second experiment revealed the same effect of dimensionality in the parietal cortex when the movement of objects was signaled auditorily rather than visually, indicating that the additional representational demands induced by 3-D space are independent of input modality. The comodulation of activation in the prefrontal and parietal areas by the amount of computational demand suggests that the collaboration between areas is a basic feature underlying much of the functionality of spatial working memory.     

Prolonged reaction time to a verbal working memory task predicts increased power of posterior parietal cortical activation

We used multislice functional magnetic resonance imaging (fMRI) to investigate the association between behavioral and neurophysiological measures of working memory task performance in 20 right-handed male healthy volunteers. Images were acquired over a 5-min period at 1.5 Tesla. We used a periodic design, alternating 30-s blocks of the "n-back" working memory task with 30-s blocks of a sensorimotor control task to activate verbal working memory systems. The power of functional response to the task was estimated by sinusoidal regression at each voxel. The relationship between power of fMRI response and mean reaction time over all 11 working memory trials was explored by multiple regression, with age and mean reaction time to the control task as covariates, at voxel and regional levels of analysis. All subjects were able to perform the n-back task accurately. A spatially distributed network was activated, including dorsolateral prefrontal cortex, inferior frontal gyrus, lateral premotor cortex, and supplementary motor area (SMA) in the frontal lobes. More posteriorly, there were major foci of activation in parietal and occipitoparietal cortex, precuneus, lingual, and fusiform gyri of the ventral occipital lobe, inferior temporal gyrus, and cerebellum. The power of functional response was positively correlated with reaction time in bilateral posterior parietal cortex (Talairach coordinates in x, y, z (mm) 35, -44, 37 and -32, -56, 42), indicating that subjects who found the task difficult, and responded with a slower reaction time, tended to activate these regions more powerfully. One interpretation of this regionally specific relationship between prolonged reaction time and increased power of posterior parietal activation is consistent with prior studies identifying similar areas of parietal cortex as the site of the phonological storage function in verbal working memory.     

Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex

Maintaining relevant information for later use is a critical aspect of working memory (WM). The lateral prefrontal cortex (PFC) and posterior sensory cortical areas appear to be important in supporting maintenance. However, the relative and unique contributions of these areas remain unclear. We have designed a WM paradigm with distraction to probe the contents of maintenance representations in these regions. During delayed recognition trials of faces, selective interference was evident behaviorally with face distraction leading to significantly worse performance than with scene distraction. Event-related fMRI of the human brain showed that maintenance activity in the lateral PFC, but not in visual association cortex (VAC), was selectively disrupted by face distraction. Additionally, the functional connectivity between the lateral PFC and the VAC was perturbed during these trials. We propose a hierarchical and distributed model of active maintenance in which the lateral PFC codes for abstracted mnemonic information, while sensory areas represent specific features of the memoranda. Furthermore, persistent coactivation between the PFC and sensory areas may be a mechanism by which information is actively maintained.     

A crossmodal crossover: opposite effects of visual and auditory perceptual load on steady-state evoked potentials to irrelevant visual stimuli

Mechanisms of attention are required to prioritise goal-relevant sensory events under conditions of stimulus competition. According to the perceptual load model of attention, the extent to which task-irrelevant inputs are processed is determined by the relative demands of discriminating the target: the more perceptually demanding the target task, the less unattended stimuli will be processed. Although much evidence supports the perceptual load model for competing stimuli within a single sensory modality, the effects of perceptual load in one modality on distractor processing in another is less clear. Here we used steady-state evoked potentials (SSEPs) to measure neural responses to irrelevant visual checkerboard stimuli while participants performed either a visual or auditory task that varied in perceptual load. Consistent with perceptual load theory, increasing visual task load suppressed SSEPs to the ignored visual checkerboards. In contrast, increasing auditory task load enhanced SSEPs to the ignored visual checkerboards. This enhanced neural response to irrelevant visual stimuli under auditory load suggests that exhausting capacity within one modality selectively compromises inhibitory processes required for filtering stimuli in another.     

Differences between auditory evoked responses recorded during spatial and nonspatial working memory tasks

Results from several recent studies suggest that neuronal processing of sound content and its spatial location may be dissociated. The use of modern neuroimaging techniques has allowed for the determination that different brain structures may be specifically activated during working memory processing of pitch and location of sound. The time course of these task-related differences, however, remains uncertain. In the present study, we performed simultaneous whole-head electroencephalogram and magnetoencephalogram recordings, using a new behavioral paradigm, to investigate the dynamics of differences between "what" and "where" evoked responses in the auditory system as a function of memory load. In the location task the latency of the N1m was shorter and its generator was situated more inferiorly than in the pitch task. Working memory processing of the tonal frequency enhanced the amplitude of the N2 component, as well as the negative-going deflection at a latency around 400 ms. A memory-load-dependent task-related difference was found in the positive slow wave which was higher during the location than pitch task at the low load. Late slow waves were affected by memory load but not type of task. These results suggest that separate neuronal networks are involved in the attribute-specific analysis of auditory stimuli and their encoding into working memory, whereas the maintenance of auditory information is accomplished by a common, nonspecific neuronal network.     

Methylphenidate enhances brain activation and deactivation responses to visual attention and working memory tasks in healthy controls

Methylphenidate (MPH) is a stimulant drug that amplifies dopamineric and noradrenergic signaling in the brain, which is believed to underlie its cognition enhancing effects. However, the neurobiological effects by which MPH improves cognition are still poorly understood. Here, functional magnetic resonance imaging (fMRI) was used together with working memory (WM) and visual attention (VA) tasks to test the hypothesis that 20mg oral MPH would increase activation in the dorsal attention network (DAN) and deactivation in the default mode network (DMN) as well as improve performance during cognitive tasks in healthy men. The group of subjects that received MPH (MPH group; N=16) had higher activation than the group of subjects who received no medication (control group: N=16) in DAN regions (parietal and prefrontal cortex, regions increasingly activated with increased cognitive load) and had increased deactivation in the insula and posterior cingulate cortex (regions increasingly deactivated with increased cognitive load) and these effects did not differ for the VA and the WM tasks. These findings provide the first evidence that MPH enhances activation of the DAN whereas it alters DMN deactivation. This suggests that MPH (presumably by amplifying dopamine and noradrenergic signaling) modulates cognition in part through its effects on DAN and DMN.     

Neurodevelopmental changes in verbal working memory load-dependency: an fMRI investigation

Development of working memory (WM) aptitude parallels structural changes in the frontal–parietal association cortices important for performance within this cognitive domain. The cerebellum has been proposed to function in support of the postulated phonological loop component of verbal WM, and along with frontal and parietal cortices, has been shown to exhibit linear WM load-dependent activation in adults. It is not known if these kinds of WM load-dependent relationships exist for cerebro-cerebellar networks in developmental populations, and whether there are age-related changes in the nature of load-dependency between childhood, adolescence, and adulthood. The present study used fMRI and a verbal Sternberg WM task with three load levels to investigate developmental changes in WM load-dependent cerebro-cerebellar activation in a sample of 30 children, adolescents, and young adults between the ages of 7 and 28. The neural substrates of linear load-dependency were found to change with age. Among adolescents and adults, frontal, parietal and cerebellar regions showed linear load-dependency, or increasing activation under conditions of increasing WM load. In contrast, children recruited only left ventral prefrontal cortex in response to increasing WM load. These results demonstrate that, while children, adolescents, and young adults activate similar cerebro-cerebellar verbal working memory networks, the extent to which they rely on parietal and cerebellar regions in response to increasing task difficulty changes significantly between childhood and adolescence.     

Maintenance and manipulation in spatial working memory: dissociations in the prefrontal cortex

Two experiments were conducted to compare thec ries of the functional organization of spatial working memory within the human prefrontal cortex. In Experiment I, memory set size for locations was parametrically varied, allowing for the assessment of BOLD signal across maintenance requirements. In the sec ond experiment, manipulation of spatial information held in working memory was contrasted with simple maintenance of that information. Both experiment evoked significant activity in a distributed spatia working memory network. Although dorsolateral prefrontal activation increased monotonically with memory set size, this region was differentially engaged in task conditions involving explicit manipulation of in ternal representations. Activation in the superior frontal sulcal region was associated with maintenance of spatial information, increasing with memory se size. In contrast, ventrolateral prefrontal activation was present only at the highest memory set size, possibly due to the differential use of organizational strategies with more complex stimuli. These results sup port claims that the dorsolateral prefrontal cortex is involved in the manipulation of internal representa tions and that the superior frontal sulcal region is involved in the maintenance of spatial information but they suggest a complex role for the ventrolatera prefrontal region.     

Maintenance versus manipulation in verbal working memory revisited: an fMRI study

Working memory (WM) is the ability to keep a limited amount of information "on line" for immediate use during short intervals. Verbal WM has been hypothesized to consist of neuroanatomically segregated components, i.e., maintenance (storage, rehearsal, and matching) and manipulation (reordering or updating), corresponding to ventrolateral and dorsolateral prefrontal cortex. Previous imaging studies of maintenance vs manipulation processes in WM have produced inconsistent results, which may have been due to methodological issues such as low statistical power and the use of insertion (subtraction) designs. In the present functional magnetic resonance imaging study we used parametric versions of both a prototypical maintenance task (Sternberg) and a prototypical manipulation task (n-letter back task) in 21 healthy subjects. Increased signal correlated with load common for both tasks was found in bilateral dorsolateral and anterior prefrontal, left ventrolateral prefrontal, and bilateral parietal regions. Workload x task interactions were found in bilateral dorsolateral prefrontal cortex for manipulation vs maintenance, but also for responding vs encoding (storage) in the maintenance task. Therefore, our data support a functional rather than a neuroanatomical distinction between maintenance and manipulation, given our finding that these tasks differentially activate virtually identical systems.     

Functional neuroanatomy of auditory working memory in schizophrenia: relation to positive and negative symptoms

Functional brain imaging studies of working memory (WM) in schizophrenia have yielded inconsistent results regarding deficits in the dorsolateral prefrontal (DLPFC) and parietal cortices. In spite of its potential importance in schizophrenia, there have been few investigations of WM deficits using auditory stimuli and no functional imaging studies have attempted to relate brain activation during auditory WM to positive and negative symptoms of schizophrenia. We used a two-back auditory WM paradigm in a functional MRI study of men with schizophrenia (N = 11) and controls (N = 13). Region of interest analysis was used to investigate group differences in activation as well as correlations with symptom scores from the Brief Psychiatric Rating Scale. Patients with schizophrenia performed significantly worse and were slower than control subjects in the WM task. Patients also showed decreased lateralization of activation and significant WM related activation deficits in the left and right DLPFC, frontal operculum, inferior parietal, and superior parietal cortex but not in the anterior cingulate or superior temporal gyrus. These results indicate that in addition to the prefrontal cortex, parietal cortex function is also disrupted during WM in schizophrenia. Withdrawal-retardation symptom scores were inversely correlated with frontal operculum activation. Thinking disturbance symptom scores were inversely correlated with right DLPFC activation. Our findings suggest an association between thinking disturbance symptoms, particularly unusual thought content, and disrupted WM processing in schizophrenia.     

Cerebrocerebellar networks during articulatory rehearsal and verbal working memory tasks

Converging evidence has implicated the cerebellum in verbal working memory. The current fMRI study sought to further characterize cerebrocerebellar participation in this cognitive process by revealing regions of activation common to a verbal working task and an articulatory control task, as well as regions that are uniquely activated by working memory. Consistent with our model's predictions, load-dependent activations were observed in Broca's area (BA 44/6) and the superior cerebellar hemisphere (VI/CrusI) for both working memory and motoric rehearsal. In contrast, activations unique to verbal working memory were found in the inferior parietal lobule (BA 40) and the right inferior cerebellum hemisphere (VIIB). These findings provide evidence for two cerebrocerebellar networks for verbal working memory: a frontal/superior cerebellar articulatory control system and a parietal/inferior cerebellar phonological storage system.     

Digital plethysmographic responses to auditory stimuli in patients with vibration disease.

Digital plethysmographic responses to auditory stimuli in 15 healthy men and 82 patients with vibration disease were analyzed in order to clarify the functional conditions of autonomic nervous system in this disease. The auditory stimuli given to healthy men caused a rapid decrease in the amplitude of the plethysmograms. After cessation of the auditory stimuli the decreased amplitude recovered to the control value within 30 sec. In the patients with vibration disease, however, the recovery of the decreased amplitude was delayed. The plethysmographic changes in the patients with vibration disease were divided into 4 types: normal (N), intermediate (I), delayed (D) and poor response (P) types. Each type of I, D and P was altered to type N by treatments consisting of therapeutic exercises, hot spring cures and so on. All healthy men showed type N. There were no significant differences between the time courses of the recovery of the plethysmographic changes and the amplitudes of the plethysmograms before the auditory stimuli. The results obtained seem to indicate that the autonomic nervous system in the patient with vibration disease is in disorder, and that the digital plethysmography with auditory stimuli is instrumental to detect the functional changes in the autonomic nervous system.     

Single trial variability of EEG and fMRI responses to visual stimuli

Recent EEG-fMRI studies have suggested a novel method of data fusion which uses single trial (ST) estimates of event-related potentials in the fMRI analysis. This is potentially very powerful, but rests on the assumption that the ST variability observed in EEG is reflected in the fMRI signal. The current study investigated this assumption and compared two different data processing strategies for each modality. Five subjects underwent separate EEG and fMRI sessions with checkerboard stimuli at two contrasts. EEG data were preprocessed using wavelet denoising and independent component analysis (ICA), whilst the general linear model and ICA were used for fMRI. Amplitudes and latencies of the P1 and N2 components of the visual evoked potential (VEP) were calculated for each trial. For fMRI, the amplitudes and latencies of the ST haemodynamic responses (HR) were calculated. Within modality, the results for the two processing methods were significantly correlated in the majority of data sets. Across modality, the average amplitudes of the VEPs and HRs were also significantly correlated. Examination of ST variability demonstrated that the amplitudes of the mean VEPs and HRs are both influenced by the latency variability of the ST responses to a greater extent than the amplitude variability. For high contrast stimuli the latency variability in EEG and fMRI was significantly correlated, with a similar trend seen for the low contrast stimuli. The results confirm the validity of examining both the EEG and fMRI signals on an ST basis and suggest an underlying neuronal origin in both modalities.     

Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study

Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.     

Left TPJ activity in verbal working memory: implications for storage- and sensory-specific models of short term memory

Patients with damage to the left temporoparietal junction (TPJ) have a low verbal span without concomitant deficits in speech perception. This pattern of cognitive impairment is taken as evidence for a dedicated phonological buffer that plays little role in perception (storage-specific account). In contrast, other research suggests that items are maintained and perceived in the same regions (sensory-specific account). In an fMRI study, we demonstrate that the left TPJ does not respond in a way predicted of a phonological buffer; that is, activity in this region is not sustained during encoding or maintenance. Instead, a region in the superior temporal gyrus that has been associated with both speech perception and production demonstrated the expected profile of a store: it was more active in the verbal condition than the object condition and was active during both encoding and maintenance. These results support the sensory-specific account of short term memory rather than the storage-specific account. Based on the pattern of activity in the left TPJ, we suggest that the impairment of verbal working memory observed in patients with TPJ damage may be due to diminished attentional processes rather than reduced storage capacity.