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.     

MEG tomography of human cortex and brainstem activity in waking and REM sleep saccades

We recorded the magnetoencephalographic (MEG) signal from three subjects before, during and after eye movements cued to a tone, self-paced, awake and during rapid eye movement (REM) sleep. During sleep we recorded the MEG signal throughout the night together with electroencephalographic (EEG) and electromyographic (EMG) channels to construct a hypnogram. While awake, just prior to and during eye movements, the expected well time-locked physiological activations were imaged in pontine regions, with early 3 s priming. Activity in the frontal eye fields (FEF) was identified in the 300 ms before the saccade onset. Visual cortex activation occurred 200 ms after saccades. During REM, compared to the eyes closed awake condition, activity was higher in supplementary motor area (SMA) and lower in inferior parietal and precuneus cortex. Electro-occulographic (EOG) activity just prior to REM saccades correlated with bilateral pontine and FEF activity some 250-400 ms before REM saccade onset, which in turn was preceded 200 ms earlier by reciprocal activation of the pons and FEF. An orbitofrontal-amygdalo-parahippocampal-pontine sequence, possibly related to emotional activation during REM sleep, was identified in the last 100 ms leading to the REM saccade, but not linked to saccade initiation.     

Functional neuroanatomy of anticipatory behavior: dissociation between sensory-driven and memory-driven systems

The ability to anticipate predictable stimuli allows faster responses. The predictive saccade (PRED) task has been shown to quickly induce such anticipatory behavior in humans. In a PRED task subjects track a visual target jumping back and forth between fixed positions at a fixed time interval. During this task, saccade latencies drop from approximately 200 ms to <80 ms as subjects anticipate target appearance. This change in saccade latency indicates that subjects' behavior shifts from being sensory driven to being memory driven. We conducted functional magnetic resonance imaging studies with 10 healthy adults performing the PRED task using a standard block design. We compared the PRED task with a visually guided saccade (VGS) task using unpredictable targets matched for number, direction and amplitude of required saccades. Our results show greater activation during the PRED task in the prefrontal, pre-supplementary motor and anterior cingulate cortices, hippocampus, mediodorsal thalamus, striatum and cerebellum. The VGS task elicited greater activation in the cortical eye fields and occipital cortex. These results demonstrate the important dissociation between sensory and predictive neural control of similar saccadic eye movements. Anticipatory behavior induced by the PRED task required less sensory-related processing activity and was subserved by a distributed cortico-subcortical memory system including prefronto-striatal circuitry.     

Population vector analysis of primate prefrontal activity during spatial working memory

Population vectors were used to examine information represented by a population of prefrontal activity and its temporal change during spatial working memory processes while monkeys performed ODR and R-ODR tasks. In the ODR task, monkeys made a saccade to the cue location after the delay, whereas in the R-ODR task, they made a saccade 90 degrees clockwise from the cue location. We first constructed population vectors using cue- and response-period activity. The directions of population vectors were similar to the cue directions and the saccade target directions, respectively, indicating that population vectors correctly represented information regarding directions of visual cues and saccade targets. We then calculated population vectors during a 250 ms time-window from the cue presentation to the end of the response period. In the ODR task, all population vectors were directed toward the cue direction. However, in the R-ODR task, the population vector gradually rotated during the delay period from the cue direction to the saccade direction. These results indicate that spatial information represented by a population of prefrontal activity can be shown as the direction of the population vector and that its temporal change during spatial working memory tasks can be depicted as the temporal change of the vector's direction.     

Simultaneous representation of saccade targets and visual onsets in monkey lateral intraparietal area

The monkey's lateral intraparietal area (LIP) has been associated with attention and saccades. LIP neurons have visual on-responses to objects abruptly appearing in their receptive fields (RFs) and sustained activity preceding saccades to the RF. We studied the relationship between the on-responses and delay activity in LIP using a 'stable-array' task. Monkeys viewed eight distinct, continuously illuminated objects, arranged in a circle with at least one object in the RF. A cue flashed instructing the monkey to make a saccade, after a delay, to the stable object physically matching the cue. The location of the cue was fixed in trial blocks, either in or out of the RF. If the cue was outside the RF, neurons developed delay-period activity tuned for the direction of the saccade target at approximately 190 ms after cue onset. If the cue appeared in the RF, neurons initially responded to cue onset and developed tuning for saccade direction only toward the end of the delay period, 390 ms after cue onset. The cue- and saccade-target responses coexisted throughout a significant portion of the delay period. The results show that visual-on responses and delay-period activity in LIP are functionally separable, and that, although highly selective, the salience representation in LIP can contain more than one object at a time.     

Dorsal cortical regions subserving visually guided saccades in humans: an fMRI study

Neurophysiological studies in non-human primates have identified saccade-related neuronal activity in cortical regions including frontal (FEF), supplementary (SEF) and parietal eye fields. Lesion and neuroimaging studies suggest a generally homologous mapping of the oculomotor system in humans; however, a detailed mapping of the precise anatomical location of these functional regions has not yet been achieved. We investigated dorsal frontal and parietal cortex during a saccade task vs. central fixation in 10 adult subjects using functional magnetic resonance imaging (fMRI). The FEF were restricted to the precentral sulcus, and did not extend anteriorly into Brodmann area 8, which has traditionally been viewed as their location in humans. The SEF were located in cortex along the interhemispheric fissure and extended minimally onto the dorsal cortical surface. Parietal activation was seen in precuneus and along the intraparietal sulcus, extending into both superior and inferior parietal lobules. These findings localize areas in frontal and parietal cortex involved in saccade generation in humans, and indicate significant differences from the macaque monkey in both frontal and parietal cortex. These differences may have functional implications for the roles these areas play in visuomotor processes.      

Temporal evolution and strength of neural activity in parietal cortex during eye and hand movements

The role of area 7a in eye-hand movement was studied by recording from individual neurons while monkeys performed 7 different tasks, aimed at assessing the relative influence of retinal, eye, and hand information on neural activity. Parietal cell activity was modulated by visuospatial signals about target location, as well as by information concerning eye and/or hand movement, and position. The highest activity was elicited when the hand moved to the fixation point. The population activities across different memory tasks showed common temporal peaks when aligned to the visual instruction (visuospatial peak) or Go signal (motor peak) for eye, hand, and coordinated eye-hand movement. The motor peak was higher for coordinated eye-hand movement, and it was absent in a No-Go task. Two activation maxima were also observed during visual reaching. They had the same latency of the visuospatial and motor peaks seen in the memory tasks. Therefore, area 7a seems to operate through a common neural mechanism underlying eye, hand, or combined eye-hand movement. This mechanism is revealed by invariant temporal activity profiles and is independent from the effector selected and from the presence or absence of a visible target during movement. For comparative purposes, we have studied the temporal evolution of the population activity in the superior parietal lobule (SPL) during the same reaching tasks and during a saccade task. In SPL, the population activity was characterized by a single peak, time locked to the Go signal for eye, hand, or combined eye-hand movement. As in IPL, the time of occurrence of this peak was effector independent. The population activity remained unchanged when the position of the eye changed, suggesting that SPL is mostly devoted to the hand motor behavior.     

Cortical activity time locked to the shift and maintenance of spatial attention

Attention increases the gain of visual neurons, which improves visual performance. How attention is controlled, however, remains unknown. Clear correlations between attention and saccade planning indicate that the control of attention is mediated through mechanisms housed in the oculomotor network. Here, we used event-related functional magnetic resonance imaging to compare overt and covert attention shifts. Subjects covertly or overtly shifted attention based on an endogenous cue and maintained attention throughout a long and variable delay. To insure continued attention, subjects counted when the attended target dimmed at near-threshold contrast levels. Overt and covert tasks used identical stimuli and required identical motor responses. Additionally, a staircase procedure that adjusted the target-dimming contrast separately for covert and overt trials equated the difficulty between conditions and across subjects. We found that the same regions along the precentral and intraparietal sulci were active during shifts of covert and overt attention. We also found sustained activation in the hemisphere contralateral to the attended visual field. We conclude that maps of prioritized locations are represented in areas classically associated with oculomotor control. The readout of these spatial maps by posterior visual areas directs spatial attention just as the readout by downstream saccade generators directs saccades.     

Oscillatory activity in human parietal and occipital cortex shows hemispheric lateralization and memory effects in a delayed double-step saccade task

We applied magnetoencephalography (MEG) to record oscillatory brain activity from human subjects engaged in planning a double-step saccade. In the experiments, subjects (n = 8) remembered the locations of 2 sequentially flashed targets (each followed by a 2-s delay), presented in either the left or right visual hemifield, and then made saccades to the 2 locations in sequence. We examined changes in spectral power in relation to target location (left or right) and memory load (one or two targets), excluding error trials based on concurrent eye tracking. During the delay period following the first target, power in the alpha (8-12 Hz) and beta (13-25 Hz) bands was significantly suppressed in the hemisphere contralateral to the target. When the second target was presented, there was a further suppression in the alpha- and beta-band power over both hemispheres. In this period, the same sensors also showed contralateral power enhancements in the gamma band (60-90 Hz), most significantly prior to the initiation of the saccades. Adaptive spatial filtering techniques localized the neural sources of the directionally selective power changes in parieto-occipital areas. These results provide further support for a topographic organization for delayed saccades in human parietal and occipital cortex.     

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.     

Dissociating neural correlates of cognitive components in mental calculation

Mental calculation is a complex cognitive operation that is composed of a set of distinct functional processes. Using functional magnetic resonance imaging (fMRI), we mapped brain activity in healthy subjects performing arithmetical tasks and control tasks evoking a comparable load on visuo-constructive, linguistic, attentional and mnemonic functions. During calculation, as well as non-mathematical tasks, similar cortical networks consisting of bilateral prefrontal, premotor and parietal regions were activated, suggesting that most of these cortical areas do not exclusively represent modules for calculation but support more general cognitive operations that are instrumental but not specific to mental arithmetic. Significant differences between calculation and the non-mathematical tasks were found in parietal sub-regions, where non-arithmetic number or letter substitution tasks preferentially activated the superior parietal lobules whereas calculation predominantly elicited activation of the left dorsal angular gyrus and the medial parietal cortices. We interpret the latter activations to reflect sub-processes of mental calculation that are related to the processing of numerical representations during exact calculation and to arithmetical fact retrieval. Finally, we found that more complex calculation tasks involving the application of calculation rules increased activity in left inferior frontal areas that are known to subserve linguistic and working memory functions. Taken together, these findings help to embed the specific cognitive operation of calculation into a neural framework that provides the required set of instrumental components. This result may further inform the cognitive modeling of calculation and adds to the understanding of neuropsychological deficit patterns in patients.     

Human parietal "reach region" primarily encodes intrinsic visual direction, not extrinsic movement direction, in a visual motor dissociation task

Posterior parietal cortex (PPC) participates in the planning of visuospatial behaviors, including reach movements, in gaze-centered coordinates. It is not known if these representations encode the visual goal in retinal coordinates, or the movement direction relative to gaze. Here, by dissociating the intrinsic retinal stimulus from the extrinsic direction of movement, we show that PPC employs a visual code. Using delayed pointing and event-related functional magnetic resonance imaging, we identified a cluster of PPC regions whose activity was topographically (contralaterally) related to the direction of the planned movement. We then switched the normal visual-motor spatial relationship by adapting subjects to optical left/right reversing prisms. With prisms, movement-related PPC topography reversed, remaining tied to the retinal image. Thus, remarkably, the PPC region in each hemisphere now responded more for planned ipsilateral pointing movements. Other non-PPC regions showed the opposite world- or motor-fixed pattern. These findings suggest that PPC primarily encodes not motor commands but movement goals in visual coordinates.     

Canceling planned action: an FMRI study of countermanding saccades

We investigated the voluntary control of motor behavior by studying the process of deciding whether or not to execute a movement. We imaged the human dorsal cortex while subjects performed a countermanding task that allowed us to manipulate the probability that subjects would be able to cancel a planned saccade in response to an imperative stop signal. We modeled the behavioral data as a race between gaze-shifting mechanisms and gaze-holding mechanisms towards a finish line where a saccade is generated or canceled, and estimated that saccade cancelation took approximately 160 ms. The frontal eye fields showed greater activation on stop signal trials regardless of successful cancelation, suggesting coactivation of saccade and fixation mechanisms. The supplementary eye fields, however, distinguished between successful and unsuccessful cancelation, suggesting a role in monitoring performance. These oculomotor regions play distinct roles in the decision processes mediating saccadic choice.     

Cross-modal binding and activated attentional networks during audio-visual speech integration: a functional MRI study

We evaluated the neural substrates of cross-modal binding and divided attention during audio-visual speech integration using functional magnetic resonance imaging. The subjects (n = 17) were exposed to phonemically concordant or discordant auditory and visual speech stimuli. Three different matching tasks were performed: auditory-auditory (AA), visual-visual (VV) and auditory-visual (AV). Subjects were asked whether the prompted pair were congruent or not. We defined the neural substrates for the within-modal matching tasks by VV-AA and AA-VV. We defined the cross-modal area as the intersection of the loci defined by AV-AA and AV-VV. The auditory task activated the bilateral anterior superior temporal gyrus and superior temporal sulcus, the left planum temporale and left lingual gyrus. The visual task activated the bilateral middle and inferior frontal gyrus, right occipito-temporal junction, intraparietal sulcus and left cerebellum. The bilateral dorsal premotor cortex, posterior parietal cortex (including the bilateral superior parietal lobule and the left intraparietal sulcus) and right cerebellum showed more prominent activation during AV compared with AA and VV. Within these areas, the posterior parietal cortex showed more activation during concordant than discordant stimuli, and hence was related to cross-modal binding. Our results indicate a close relationship between cross-modal attentional control and cross-modal binding during speech reading.     

Prefrontal delay-period activity reflects the decision process of a saccade direction during a free-choice ODR task

To examine how delay-period activity participates in the decision of a saccade direction, we analyzed prefrontal activity while monkeys performed 2 tasks: oculomotor delayed-response (ODR) and self-selection ODR (S-ODR) tasks. In the ODR task, monkeys were required to make a memory-guided saccade to the cue location after a 3-s delay. In the S-ODR task, 4 identical visual cues were presented simultaneously during the cue period and monkeys were required to make a saccade in any one direction after the delay. Delay-period activity was observed in both tasks in the same neuron with similar directional preferences. Neurons with delay-period activity were classified into several groups based on the temporal pattern of the activity itself and of the strength of the directional selectivity. Among these, neurons with an increasing type of delay-period activity with persistent directional selectivity throughout the delay period in the ODR task also showed directional delay-period activity in the S-ODR task. These results indicate that an increasing type of delay-period activity, which is thought to represent motor information, plays an important role in generating and enhancing directional bias in the S-ODR task and therefore contributes significantly to the decision process of the saccade direction in the S-ODR task.     

Spatiotemporal analysis of auditory "what" and "where" working memory

Goal-directed attention to sound identity (what) and sound location (where) has been associated with increased neural activity in ventral and dorsal brain regions, respectively. In order to ascertain when such segregation occurs, we measured event-related potentials during an n-back (n = 1, 2) working memory task for sound identity or location, where stimuli selected randomly from 3 semantic categories (human, animal, music) were presented at 3 possible virtual locations. Accuracy and reaction times were comparable in both "what" and "where" tasks, albeit worse for the 2-back than for the 1-back condition. The partial least squares analysis of scalp-recorded and source waveform data revealed domain-specific activity beginning at about 200-ms poststimulus onset, which was best expressed as changes in source activity near Heschl's gyrus, and in central medial, occipital medial, right frontal and right parietal cortex. The effect of working memory load emerged at about 400-ms poststimulus and was expressed maximally over frontocentral scalp region and in sources located in the right temporal, frontal and parietal cortices. The results show that for identical sounds, top-down effects on processing "what" and "where" information is observable at about 200 ms after sound onset and involves a widely distributed neural network.     

Working memory of auditory localization

To investigate brain mechanisms of sound location memory, we studied the distribution of brain activation with functional magnetic resonance imaging (fMRI) in subjects performing an audiospatial n-back task with three memory load levels. Working memory processing of audiospatial information activated areas in the superior, middle and inferior frontal gyri, and in the posterior parietal and middle temporal cortices. In a control experiment, fMRI during audio- and visuospatial 2-back task performances revealed only few differentially activated subregions between the two tasks. These results demonstrate that working memory processing of auditory locations involves a distributed network of brain areas and suggest that mnemonic processing of audio- and visuospatial information is directed along a common neural pathway in the posterior parietal and prefrontal cortices.     

Cortical substrates supporting visual search in humans.

Serial and parallel visual search tasks were presented to patients with focal lesions in dorsolateral frontal, lateral parietal, or temporal-parietal cortex. In the unilateral display conditions, search efficiency in all patient groups was similar to the normal control group for stimuli both on the ipsi- and on the contralesional side of the displays. In contrast, in the bilateral display conditions, all patient groups showed a marked delay in initiating search on the side contralateral to the lesion as compared to normal controls. This delay was more pronounced when attention demands on the ipsilateral side increased, either by making target-distractor discrimination more difficult (serial search task), or by increasing the number of ipsilateral distractor items. The contralateral deficit was evident in all patient groups, supporting the notion that dorsolateral frontal as well as posterior parietal and temporal-parietal cortex plays a critical role in visual spatial attention.     

Cortical Networks for Visual Reaching: Physiological and Anatomical Organization of Frontal and Parietal Lobe Arm Regions

The functional and structural properties of the dorsolateralfrontal lobe and posterior parietal proximal arm representationswere studied in macaque monkeys. Physiological mapping of primarymotor (MI), dorsal premotor (PMd), and posterior parietal (area5) cortices was performed in behaving monkeys trained in aninstructed-delay reaching task. The parietofrontal corticocorticatconnectivities of these same areas were subsequently examinedanatomically by means of retrograde tracing techniques. Signal-, set-, movement-, and position-related directional neuronalactivities were distributed nonuniformly within the task-relatedareas in both frontal and parietal cortices. Within the frontallobe, moving caudally from PMd to the MI, the activity thatsignals for the visuospatial events leading to target localizationdecreased, while the activity more directly linked to movementgeneration increased. Physiological recordings in the superior parietal lobule revealeda gradient-like distribution of functional properties similarto that observed in the frontal lobe. Signal- and set-relatedactivities were encountered more frequently in the intermediateand ventral part of the medial bank of the intraparietal sulcus(IPS), in area MIP. Movement- and position-related activitieswere distributed more uniformly within the superior parietallobule (SPL), in both dorsal area 5 and in MIP. Frontal and parietal regions sharing similar functional propertieswere preferentially connected through their association pathways.As a result of this study, area MIP, and possibly areas MDPand 7m as well, emerge as the parietal nodes by which visualinformation may be relayed to the frontal lobe arm region. Theseparietal and frontal areas, along with their association connections,represent a potential cortical network for visual reaching.The architecture of this network is ideal for coding reachingas the result of a combination between visual and somatic information.     

Population vector analysis of primate mediodorsal thalamic activity during oculomotor delayed-response performance

To understand functional roles of the thalamic mediodorsal nucleus (MD) in sensory-to-motor information transformation during spatial working memory performance and compare with those of the dorsolateral prefrontal cortex (DLPFC), we calculated population vectors using a population of MD activities recorded during 2 tasks. In the oculomotor delayed-response (ODR) task, monkeys needed to make a memory-guided saccade to the cue location, whereas in the rotatory oculomotor delayed-response (R-ODR) task, they needed to make a memory-guided saccade 90 degrees clockwise from the cue direction. The directions of population vectors calculated from populations of cue- and response-period activities were similar to the cue and saccade target directions, respectively, which confirmed that population vectors represent information regarding the directions of the visual cue and the saccade target. We then calculated population vectors of delay-period activity using a sliding 250-ms time window. In the ODR task, population vectors were directed toward the cue direction throughout the delay. However, in the R-ODR task, they gradually rotated from the cue direction to the saccade target direction. Based on a comparison with the results obtained from DLPFC neurons, the rotation of population vectors started earlier in the MD than in the DLPFC, suggesting that the motor information regarding forthcoming saccade is provided from the MD.