Segregation of areas related to visual working memory in the prefrontal cortex revealed by rTMS

The functional organization of working memory (WM) in the human prefrontal cortex remains unclear. Storage and processing functions might be segregated in ventral and dorsal areas of the prefrontal cortex, respectively. If so, storage functions might be spared, irrespective of informational domain, following damage or dysfunction in dorsolateral areas. Alternatively, WM and prefrontal function in general might be segregated according to informational domains (e.g. spatial versus object-based information). In the present study we used repetitive transcranial magnetic stimulation (rTMS) to directly test these competing hypotheses. We applied rTMS to transiently and selectively disrupt the function of the dorsomedial, dorsolateral or ventral prefrontal cortex in normal human volunteers performing either a spatial or a face-recognition delayed-response task. Performance in the spatial task was impaired by rTMS of the dorsomedial prefrontal cortex. Performance in the face-recognition (non-spatial) task was impaired by rTMS of the ventral prefrontal cortex. Transient disruption of the dorsolateral prefrontal cortex affected performance in both tasks. These findings provide evidence of domain-specific segregation of WM functions in widely separated areas of prefrontal cortex.     

Bilateral activation of fronto-parietal networks by incrementing demand in a working memory task

Working memory (WM) is known to activate the prefrontal cortex. In the present study we hypothesized that when additional contingencies are added to the instruction of a WM task, this would increase the WM load and result in the activation of additional prefrontal areas. With positron emission tomography we measured regional cerebral blood flow in nine subjects performing a control task and two delayed matching to sample tasks, in which the subjects were matching colours and patterns to a reference picture. The second of the two delayed matching tasks had a more complex instruction than the first, with additional contingencies of how to alternate between the matching of colours and patterns. This task thus required the subjects not only to remember a stimulus to match but also to perform this matching according to a specified plan. Both delayed matching tasks activated cortical fields in the middle frontal gyrus, the frontal operculum, upper cingulate gyrus, inferior parietal cortex and cortex lining the intraparietal sulcus, all in the left hemisphere. When alternated delayed matching was compared to simple delayed matching, increases were located in the right superior and middle frontal gyrus and the right anterior inferior parietal cortex. The increased demand during alternated matching thus resulted in bilateral activation of both dorsolateral prefrontal and inferior parietal cortex. The area in the inferior parietal cortex has previously been coactivated with the dorsolateral prefrontal cortex in several WM tasks, irrespective of the sensory modality of the stimuli, and during tasks involving planning.      

The role of dorsolateral prefrontal cortex in the preparation of forthcoming actions: an fMRI study

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory (WM). Yet its precise contribution (the storage, manipulation and/or utilization of information for the forthcoming response) remains to be determined. To test the hypothesis that the DLPFC is more involved in the preparation of actions than in the maintenance of information in short-term memory (STM), we undertook a functional magnetic resonance imaging investigation in normal subjects performing two delayed response tasks (matching and reproduction tasks) in a visuospatial task sequence (presentation, delay, response). In the two tasks, the presentation and delay phases were similar, but the expected response was different: in the matching task, subjects had to indicate whether a visuospatial sequence matched the sequence presented before the delay period; in the reproduction task, subjects had to reproduce the sequence and, therefore, to mentally organize their response during the delay. Using a fMRI paradigm focusing on the delay period, we observed a significant DLPFC activation when subjects were required to mentally prepare a sequential action based on the information stored in STM. When subjects had only to maintain a visuospatial stimulus in STM, no DLPFC activation was found. These results suggest that a parietal-premotor network is sufficient to store visuospatial information in STM whereas the DLPFC is involved when it is necessary to mentally prepare a forthcoming sequential action based on the information stored in STM.     

Active Representation of Shape and Spatial Location in Man

Neural activity during the delay period of spatial delayed response(DR) and delayed matching (DM) tasks was investigated by positronemission tomography. A distributed cortical system was activatedin each condition. The bilateral dorsolateral prefrontal cortex(DLPFC) was activated in the delay period of both tasks; activationwas of higher significance on the right in the DR task and theleft in the DM task, and extended to the anterolateral prefrontalcortex in the DM condition. Active representation of spatiallocation in the DR task was associated with co-activation ofthe medial and lateral parietal cortex and the extrastriatevisual cortex. Active representation of shape in the DM taskwas associated with co-activation of the medial and lateralparietal cortex and the inferior temporal cortex. Response-relatedactivity was observed in both tasks. Activation of anteriorcingulate, inferior frontal, lateral premotor and rostral inferiorparietal cortex was observed in the DR condition, a task characterizedby preparation of a movement to a predetermined location. Incontrast, preparation to move to an undetermined location inthe DM task was associated with activation predominantly inrostral SMA.     

Monitoring and the controlled processing of meaning: distinct prefrontal systems

Distinct prefrontal regions are specialized for the controlled processing of semantic information. We have dissociated components of this system used in semantic decision-making across different perceptual conditions. Nineteen subjects were presented with auditory word sequences, on which they made semantic or syllabic decisions, while neural activity was measured using PET. Contrasting the semantic with syllabic tasks, there was activation within left rostral prefrontal cortex (RPFC) when the stimuli were presented as clear speech, reducing when the stimuli were presented in acoustically degraded form. In contrast, activation of the right dorsolateral prefrontal cortex (DLPFC) was observed with the degraded stimuli, an effect that inversely correlated with accuracy on the task. We have thus demonstrated two prefrontal systems where activity is differentially modulated by the "quality" of information held in working memory. This dissociation is likely to represent an alteration in the type of cognitive operations employed during task performance, where left RPFC is activated during extensive semantic elaboration and right DLPFC is recruited as the monitoring demands, associated with items held in working memory, increase. The function of these separate systems is integrated during the performance of verbal problem-solving tasks although they are differentially sensitive to stimulus degradation.     

Convergence of neural systems processing stimulus associations and coordinating motor responses

A sensory-sensory learning paradigm was used to measure neural changes in humans during acquisition of an association between an auditory and visual stimulus. Three multivariate partial least-squares (PLS) analyses of positron emission tomography data identified distributed neural systems related to (i) processing the significance of the auditory stimulus, (ii) mediating the acquisition of the behavioral response, and (iii) the spatial overlap between these two systems. The system that processed the significance of the tone engaged primarily right hemisphere regions and included dorsolateral prefrontal cortex, putamen, and inferior parietal and temporal cortices. Activity changes in left occipital cortex were also identified, most likely reflecting the learned expectancy of the upcoming visual event. The system related to behavior was similar to that which coded the significance of the tone, including dorsal occipital cortex. The PLS analysis of the concordance between these two systems showed substantial regional overlap, and included occipital, dorsolateral prefrontal, and limbic cortices. However, activity in dorsomedial prefrontal cortex was strictly related to processing the auditory stimulus and not to behavior. Taken together, the PLS analyses identified a system that contained a sensory-motor component (comprised of occipital, temporal association and sensorimotor cortices) and a medial prefrontallimbic component, that as a group simultaneously embodied the learning-related response to the stimuli and the subsequent change in behavior.      

Parieto-frontal interactions in visual-object and visual-spatial working memory: evidence from transcranial magnetic stimulation.

This study aimed to investigate whether transcranial magnetic stimulation (TMS) can induce selective working memory (WM) deficits of visual-object versus visual-spatial information in normal humans. Thirty-five healthy subjects performed two computerized visual n-back tasks, in which they were required to memorize spatial locations or abstract patterns. In a first series of experiments, unilateral or bilateral TMS was delivered on posterior parietal and middle temporal regions of both hemispheres after various delays during the WM task. Bilateral temporal TMS increased reaction times (RTs) in the visual-object, whereas bilateral parietal TMS selectively increased RTs in the visual-spatial WM task. These effects were evident at a delay of 300 ms. Response accuracy was not affected by bilateral or unilateral TMS of either cortical region. In a second group of experiments, bilateral TMS was applied over the superior frontal gyrus (SFG) or the dorsolateral prefrontal cortex (DLPFC). TMS of the SFG selectively increased RTs in the visual-spatial WM task, whereas TMS of the DLPFC interfered with both WM tasks, in terms of both accuracy and RTs. These effects were evident when TMS was applied after a delay of 600 ms, but not one of 300 ms. These findings confirm the segregation of WM buffers for object and spatial information in the posterior cortical regions. In the frontal cortex, the DLPFC appears to be necessary for WM computations regardless of the stimulus material.     

A discrete area within the left dorsolateral prefrontal cortex involved in visual-verbal incongruence judgment

The role of the frontal lobe in cross-modal visual-auditory processing has been documented in experiments using incongruent/congruent paradigms. In this study, 4 patients with left frontal World Health Organization Grade II glioma were assessed during pre-, intra-, and postoperative sessions with picture-naming and verbal-visual task requiring judgment of congruence between pictures and words. During awake brain surgery, the naming and cross-modal tasks were coupled with electrical stimulation inactivating restricted specific regions. For all patients, focal brain stimulation in the dorsolateral prefrontal cortex elicited picture-word matching disturbances but no naming impairment, and the elicited errors exclusively appeared in incongruent and not congruent conditions. The dissociation observed between correct picture naming and disturbed cross-modal judgment shows that electrical stimulation of a discrete cortical area within the left dorsolateral prefrontal cortex can inhibit the simultaneous processing of visual-verbal information without disturbing larger networks involved in the naming process.     

Regional brain activation associated with different performance patterns during learning of a complex motor skill

In understanding the brain's response to extensive practice and development of high-level, expert skill, a key question is whether the same brain structures remain involved throughout the different stages of learning and a form of adaptation occurs, or a new functional circuit is formed with some structures dropping off and others joining. After training subjects on a set of complex motor tasks (tying knots), we utilized fMRI to observe that in subjects who learned the task well new regional activity emerged in posterior medial structures, i.e. the posterior cingulate gyrus. Activation associated with weak learning of the knots involved areas that mediate visual spatial computations. Brain activity associated with no substantive learning indicated involvement of areas dedicated to the declarative aspects learning such as the anterior cingulate and prefrontal cortex. The new activation for the pattern of strong learning has alternate interpretations involving either retrieval during episodic memory or a shift toward non-executive cognitive control of the task. While these interpretations are not resolved, the study makes clear that single time-point images of motor skill can be misleading because the brain structures that implement action can change following practice.     

Dissociable effects of frontal cortical lesions on measures of visuospatial attention and spatial working memory in the rat

Frontal cortex controls voluntary movement through projections to striatum that continue as parallel pallido-thalamic loops. In previous studies we found evidence of a double dissociation in rat striatum between visuospatial response time (RT) and radial maze delayed non-matching (DNM) tasks. Here we compare the effects of frontal cortical lesions on these tasks. We found that lesions involving sensorimotor areas in dorsolateral cortex affect RT for responding to visuospatial stimuli without affecting other measures of response speed or producing signs of attentional or sensory impairment. These deficits were equivalent to impairments observed with lesions in sensorimotor areas of dorsolateral striatum. Dorsal prefrontal lesions produced RT deficits indicative of attentional impairment that have not been observed with striatal or thalamic lesions. This suggests contributions of prefrontal cortex to attention independent of striatum and thalamus. Prefrontal lesions had significant but circumscribed effects on DNM consistent with effects of lesions in anatomically related areas of striatum or thalamus observed in earlier studies. These results are consistent with evidence implicating prefrontal cortex in aspects of spatial memory mediated by anatomically related pathways in the basal ganglia and thalamus.     

Functional dissociation of attentional selection within PFC: response and non-response related aspects of attentional selection as ascertained by fMRI

In this experiment using a color-word Stroop task, we explored whether different regions of prefrontal cortex bias selection of response-related processes as compared with non-response-related processes. To manipulate demands at the level of response selection, we varied the degree of overlap between stimulus-response mappings in a manual Stroop task. To vary demands at a non-response level, we compared activation for incongruent trials (e.g. the word 'purple' in blue ink) that contain two color representations, one in the word and one in the ink color, to neutral trials (e.g. the word 'drawer' in blue ink), which contain only one color representation, that in the ink color. These manipulations had differential effects within prefrontal cortex. Both a region of right inferior frontal cortex and caudal regions of the cingulate were sensitive to the selection demands at the response-level and insensitive to demands at the non-response level. In contrast, a more anterior region of left dorsolateral prefrontal cortex was sensitive to the number of color representations (i.e. incongruent versus neutral trials), but not to the overlap in stimulus-response mappings. Therefore, this study indicates a functional differentiation for implementing attentional control within prefrontal cortex.     

Performance Dip in motor response induced by task-irrelevant weaker coherent visual motion signals

The Performance Dip is a newly characterized behavioral phenomenon, where, paradoxically, a weaker task-irrelevant visual stimulus causes larger disturbances on the accuracy of a main letter identification task than a stronger stimulus does. Understanding mechanisms of the Performance Dip may provide insight into unconsciousness behavior. Here, we investigated the generalization of the Performance Dip. Specifically, we tested whether the Performance Dip occurs in a motion-related Simon task, and if so, whether the Performance Dip involves the same brain region, that is, the dorsolateral prefrontal cortex (DLPFC), previously implicated in the Performance Dip, or the supplementary motor area (SMA) and pre-SMA, implicated in a motion-related Simon Task. Subjects made manual directional responses according to the color of stochastic moving dots while ignoring the global direction of moving dots, which could be either congruent or incongruent to the response appropriate to the main task. We found that weak incongruent task-irrelevant stimuli caused a Performance Dip, in which the SMA and pre-SMA, rather than DLPFC, played critical roles. Our results suggest a possible common brain mechanism across different neural circuits, in which weak, but not strong, task-irrelevant information is free from inhibition and intrudes into neural circuits relevant to the main task.     

Persistent discharges in the prefrontal cortex of monkeys naive to working memory tasks

Neurons in the prefrontal cortex and a network of interconnected brain areas discharge in a persistent fashion after the offset of sensory stimulation. Such persistent discharges are thought to constitute a neuronal correlate of working memory. The information content of neuronal discharges and its anatomical localization across the surface of the prefrontal cortex has been a matter of debate. Discrepant results by different laboratories may be due to the effects of different training regiments and tasks used in memory tasks. In order to address how training in a memory task alters neuronal responses, we performed recordings in monkeys that were never trained in memory tasks, but passively viewed visual stimuli. We have found that a population of prefrontal neurons responded to visual stimuli and also exhibited significantly elevated responses during "delay" intervals of the task. For a population of these neurons, persistent discharges were selective for the location and feature of the preceding stimulus. These discharges were typically disrupted by the appearance of a subsequent stimulus. Our results suggest that some prefrontal neurons represent the location and identity of visual stimuli in a persistent fashion, even when the latter are not behaviorally important or required to be kept in memory.     

Changes in prefrontal neuronal activity after learning to perform a spatial working memory task

The prefrontal cortex is considered essential for learning to perform cognitive tasks though little is known about how the representation of stimulus properties is altered by learning. To address this issue, we recorded neuronal activity in monkeys before and after training on a task that required visual working memory. After the subjects learned to perform the task, we observed activation of more prefrontal neurons and increased activity during working memory maintenance. The working memory-related increase in firing rate was due mostly to regular-spiking putative pyramidal neurons. Unexpectedly, the selectivity of neurons for stimulus properties and the ability of neurons to discriminate between stimuli decreased as the information about stimulus properties was apparently present in neural firing prior to training and neuronal selectivity degraded after training in the task. The effect was robust and could not be accounted for by differences in sampling sites, selection of neurons, level of performance, or merely the elapse of time. The results indicate that, in contrast to the effects of perceptual learning, mastery of a cognitive task degrades the apparent stimulus selectivity as neurons represent more abstract information related to the task. This effect is countered by the recruitment of more neurons after training.     

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.     

Spatial and Temporal Factors in the Role of Prefrontal and Parietal Cortex in Visuomotor Integration

The effects of reversible lesion—by cooling—of dorsolateralprefrontal and posterior parietal cortex were studied in rhesusmonkeys performing a cognitive visuomotor integration task.Correct performance required the use of a learned set of cue-responsecontingencies, some spatial andsome nonspatial; in some cases,the task required the short-term retention, through a delay,of the color of the cue or its implicit response direction.Prefrontal cooling impaired performance of the task regardlessof its spatial demands, an effect that increased with delay.Parietal cooling, on the other hand, only impaired performanceif the task demanded the processing and retention of spatialinformation (i.e., if spatial active memory was required). Parietaleffects were not related to delay. Both prefrontal and, evenmore, parietal cooling increased response time in all task contingencies.Thus, the results dissociate the respective contributions ofthe prefrontal and the posterior parietal cortex to the temporaland spatial aspects of information processing in visuomotorperformance. They indicate that posterior parietal areas participatein spatial processing and in active memory of spatial information,whereas prefrontal areas subserve a broader role of visuomotorprocessing and cross-temporal integration of both spatial andnonspatial information.     

Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands.

We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.     

Prefrontal cortex and dynamic categorization tasks: representational organization and neuromodulatory control

We present a computational model of the intradimensional/ extradimensional (ID/ED) task (a variant of the Wisconsin card sorting task) that simulates the performance of intact and frontally lesioned monkeys on three different kinds of rule changes (Dias et al., 1997, J Neurosci 17:9285-9297). Although Dias et al. interpret the lesion data as supporting a model in which prefrontal cortex is organized into different processing functions, our model suggests an alternative account based on representational content. A key aspect of the model is that prefrontal cortex representations are organized according to different levels of abstraction, with orbital areas encoding more specific featural information and dorsolateral areas encoding more abstract dimensional information. This representational scheme of the model is integrated with two additional key elements: (i) activation-based working memory representations controlled by a dynamic gating mechanism that simulates the hypothesized phasic actions of dopaminergic neuromodulation in prefrontal cortex, which acts to stabilize or destabilize frontal representations based on success in the task; and (ii) a weight-based associative learning system simulating posterior cortex and other subcortical areas, where the stimulus-response mappings are encoded. Frontal cortex contributes to the task via top-down activation-based biasing of task-appropriate features and dimensions in this posterior cortex system - this top-down biasing is specifically important for overcoming prepotent associations after a sorting rule reverses. The ability of the model to capture the double-dissociation observed by Dias et al. with orbital versus dorsolateral lesions supports the validity of these principles, many of which have also been useful in accounting for other frontal phenomena.     

Firing characteristics of deep layer neurons in prefrontal cortex in rats performing spatial working memory tasks

Single cells were recorded with 'tetrodes' in regions of the rat medial prefrontal cortex, including those which are targets of hippocampal afferents, while rats were performing three different behavioral tasks: (i) an eight-arm radial maze, spatial working memory task, (ii) a figure-eight track, delayed spatial alternation task, and (iii) a random food search task in a square chamber. Among 187 recorded units, very few exhibited any evidence of place-specific firing on any of the behavioral tasks, except to the extent that different spatial locations were related to distinct phases of the task. Furthermore, no prefrontal unit showed unambiguous spatially dependent delay activity that might mediate working memory for spatial locations. Rather, the cells exhibited diverse correlates that were generally associated with the behavioral requirements of performing the task. This included firing related to intertrial intervals, onset or end of trials, selection of specific arms on the eight-arm radial maze, delay periods, approach to or departure from goals, and selection of paths on the figure-eight track. Although a small number of cells showed similar behavioral correlates across tasks, the majority of cells showed no consistent correlate when recorded across multiple tasks. Furthermore, some units did not exhibit altered firing patterns in any of the three tasks, while others showed changes in firing that were not consistently related to specific behaviors or task components. These results are in agreement with previous lesion and behavioral studies in rats that suggest a prefrontal cortical role in encoding 'rules' (i.e. structural features) or behavioral sequences within a task but not in encoding allocentric spatial information. Given that the hippocampal projection to this cortical region is capable of undergoing LTP, our data lead to the hypothesis that the role of this projection is not to impose spatial representations upon prefrontal activity, but to provide a mechanism for learning the spatial context in which particular behaviors are appropriate.      

Cortical Metabolic Activation in Humans during a Visual Memory Task

A delayed match-to-sample (DMS) task of abstract, visual memorywas performed during the uptake period of ¹⁸F-fluorodeoxyglucose.The increase in glucose uptake of cortical and subcortical regions("activation") during the DMS task was compared with that duringa control, immediate match-to-sample task using positron emissiontomography. Both discriminant analysis and paired t tests supportedthe observation that the dorsolateral prefrontal area underwentthe greatest activation, while a factor analysis revealed thefunctional correlation matrices of the tasks. Activations inthe ventral premotor cortex and supramarginal and angular gyriwere highly correlated with the change in the dorsolateral prefrontalcortex. The basal forebrain/ventral pole region showed a smallerbut independently significant change. The findings support therole of the dorsal prefrontal region in the nonspatial workingmemory of humans.