Inactivation of parietal and prefrontal cortex reveals interdependence of neural activity during memory-guided saccades

Dorsolateral prefrontal and posterior parietal cortex share reciprocal projections. They also share nearly identical patterns of neuronal activation during performance of memory-guided saccades. To test the hypothesis that the reciprocal projections between parietal and prefrontal neurons may entrain their parallel activation, the present experiments have combined cortical cooling in one cortical area with single-unit recording in the other to more precisely determine the physiological interactions between the two during working memory performance. The activity of 105 cortical neurons during the performance of an oculomotor delayed response (ODR) task (43 parietal neurons during prefrontal cooling, 62 prefrontal neurons during parietal cooling) was compared across two blocks of trials collected while the distant cortical area either was maintained at normal body temperature or cooled. The mean firing rates of 71% of the prefrontal neurons during ODR performance changed significantly when parietal cortex was cooled. Prefrontal neurons the activity of which was modulated during the cue, delay, or saccade periods of the task were equally vulnerable to parietal inactivation. Further, both lower and higher firing rates relative to the precool period were seen with comparable frequency. Similar results were obtained from the converse experiment, in which the mean firing rates of 76% of the parietal neurons were significantly different while prefrontal cortex was cooled, specifically in those task epochs when the activity of each neuron was modulated during ODR performance. These effects again were seen equally in all epochs of the ODR task in the form of augmented or suppressed activity. Significant effects on the latency of neuronal activation during cue and saccade periods of the task were absent irrespective of the area cooled. Cooling was associated in some cases with a shift in the best direction of Gaussian tuning functions fit to neuronal activity, and these shifts were on average larger during parietal than prefrontal cooling. In view of the parallel between the similarity in activity patterns previously reported and the largely symmetrical cooling effects presently obtained, the data suggest that prefrontal and parietal neurons achieve matched activation during ODR performance through a symmetrical exchange of neuronal signals between them; in both cortical areas, neurons activated during the cue, delay, and also saccade epochs of the ODR task participate in reciprocal neurotransmission; and the output of each cortical area produces a mixture of excitatory and inhibitory drives within its target.     

Response of neurons in the lateral intraparietal area to a distractor flashed during the delay period of a memory-guided saccade

Recent experiments raised the possibility that the lateral intraparietal area (LIP) might be specialized for saccade planning. If this was true, one would expect a decreased sensitivity to irrelevant visual stimuli appearing late in the delay period of a memory-guided delayed-saccade task to a target outside the neurons' receptive fields. We trained two monkeys to perform a standard memory-guided delayed-saccade task and a distractor task in which a stimulus flashed for 200 ms at a predictable time 300-100 ms before the end of the delay period. We used two locations, one in the most active part of the receptive field and another well outside the receptive field. We used six kinds of trials randomly intermixed: simple delayed-saccade trials into or away from the receptive field and distractor trials with saccade target and distractor both in the receptive field, both out of the receptive field, or one at each location. This enabled us to study the response to the distractor as a function of the monkey's preparation of a memory-guided delayed-saccade task. We had assumed that the preparation of a saccade away from the receptive field would result in an attenuation of the response to the distractor, i.e., a distractor at the location of the saccade goal would evoke a greater response than when it appeared at a location far from the saccade goal. Instead we found that neurons exhibited either a normal or an enhanced visual response to the distractor during the memory period when the target flashed outside the receptive field. When the distractor flashed at the location of the saccade target, the response to the distractor was either unchanged or diminished. The response to a distractor away from the target location of a memory-guided saccade was even greater than the response to the same target when it was the target for the memory-guided saccade task. Immediate presaccadic activity did not distinguish between a saccade to the receptive field when there was no distractor and a distractor in the receptive field when the monkey made a saccade elsewhere. Nonetheless the distractor had no significant effect on the saccade latency, accuracy, or velocity despite the brisk response it evoked immediately before the saccade. We suggest that these results are inconsistent with a role for LIP in the specific generation of saccades, but they are consistent with a role for LIP in the generation of visual attention.     

Changes in object-oriented arm movements that precede the transition to goal-directed reaching in infancy

The emergence of prehensile skills in infancy is one of the central issues in motor development. The objective of this longitudinal study was to quantitatively describe the changes in the object-oriented arm movements that precede the transition to goal-directed reaching movements in infancy. Arm kinematics in 10 full-term infants were recorded biweekly from the age of 10 to 28 weeks while objects were presented for prehension. The kinematics were analyzed across three progressive phases of object-oriented arm movements (early, before, and after onset of reaching movements). As infant age increased through the stage of object-oriented movements, the distinguishing feature was that there was a decrease in movement jerk (when normalized to a dimensionless quantity), which reflects the increasing ability to adaptively modulate arm movements. This change in the dynamic characteristics of the object-oriented arm movements precedes the onset of goal-directed reaching movements and is hypothesised to reflect a critical variable in the infant developmental process of learning to reach in prehension.     

On the form of the internal model for reaching

We investigated, by using simulations, possible mechanisms responsible for the errors in the direction of arm movements exhibited by deafferented patients. Two aspects of altered feedforward control were evaluated: the inability to sense initial conditions and the degradation of an internal model. A simulation which assumed no compensation for variations in initial arm configuration failed to reproduce the characteristic pattern of errors. In contrast, a simulation that assumed random variability in the generation of joint torque resulted in a distribution of handpaths which resembled some aspects of the pattern of errors exhibited by deafferented patients.     

Processing of retinal and extraretinal signals for memory-guided saccades during smooth pursuit

It is an essential feature for the visual system to keep track of self-motion to maintain space constancy. Therefore the saccadic system uses extraretinal information about previous saccades to update the internal representation of memorized targets, an ability that has been identified in behavioral and electrophysiological studies. However, a smooth eye movement induced in the latency period of a memory-guided saccade yielded contradictory results. Indeed some studies described spatially accurate saccades, whereas others reported retinal coding of saccades. Today, it is still unclear how the saccadic system keeps track of smooth eye movements in the absence of vision. Here, we developed an original two-dimensional behavioral paradigm to further investigate how smooth eye displacements could be compensated to ensure space constancy. Human subjects were required to pursue a moving target and to orient their eyes toward the memorized position of a briefly presented second target (flash) once it appeared. The analysis of the first orientation saccade revealed a bimodal latency distribution related to two different saccade programming strategies. Short-latency (<175 ms) saccades were coded using the only available retinal information, i.e., position error. In addition to position error, longer-latency (>175 ms) saccades used extraretinal information about the smooth eye displacement during the latency period to program spatially more accurate saccades. Sensory parameters at the moment of the flash (retinal position error and eye velocity) influenced the choice between both strategies. We hypothesize that this tradeoff between speed and accuracy of the saccadic response reveals the presence of two coupled neural pathways for saccadic programming. A fast striatal-collicular pathway might only use retinal information about the flash location to program the first saccade. The slower pathway could involve the posterior parietal cortex to update the internal representation of the flash once extraretinal smooth eye displacement information becomes available to the system.     

A genetically engineered live-attenuated simian-human immunodeficiency virus that co-expresses the RANTES gene improves the magnitude of cellular immunity in rhesus macaques

Regulated-on-activation-normal-T-cell-expressed-and-secreted (RANTES), a CC-chemokine, enhances antigen-specific T helper (Th) type-1 responses against HIV-1. To evaluate the adjuvant effects of RANTES against HIV vaccine candidate in SHIV-macaque models, we genetically engineered a live-attenuated SHIV to express the RANTES gene (SHIV-RANTES) and characterized the virus's properties in vivo. After the vaccination, the plasma viral loads were same in the SHIV-RANTES-inoculated monkeys and the parental nef-deleted SHIV (SHIV-NI)-inoculated monkeys. SHIV-RANTES provided some immunity in monkeys by remarkably increasing the antigen-specific CD4⁺ Th cell-proliferative response and by inducing an antigen-specific IFN-γ ELISpot response. The magnitude of the immunity in SHIV-RANTES-immunized animals, however, failed to afford greater protection against a heterologous pathogenic SHIV (SHIV-C2/1) challenge compared to control SHIV-NI-immunized animals. SHIV-RANTES immunized monkeys, elicited robust cellular CD4⁺ Th responses and IFN-γ ELISpot responses after SHIV-C2/1 challenge. These findings suggest that the chemokine RANTES can augment vaccine-elicited, HIV-specific CD4⁺ T cell responses.     

A SacB mutagenesis strategy reveals that the Bartonella quintana variably expressed outer membrane proteins are required for bloodstream infection of the host

Bartonella bacteria adhere to erythrocytes and persistently infect the mammalian bloodstream. We previously identified four highly conserved Bartonella quintana adhesin genes that undergo phase variation during prolonged bloodstream infection. The variably expressed outer membrane proteins (Vomp) encoded by these genes are members of the trimeric autotransporter adhesin family. Each B. quintana Vomp appears to contribute a different adhesion phenotype, likely mediated by the major variable region at the adhesive tip of each Vomp. Although studies document that the Vomp adhesins confer virulence phenotypes in vitro, little is known about in vivo virulence strategies of Bartonella. We sought to determine whether the B. quintana Vomp adhesins are necessary for infection in vivo by using a vomp null mutant. It first was necessary to develop a system to generate in-frame deletions of defined genes by allelic exchange in a wild-type Bartonella background, which had not been achieved previously. We utilized sacB negative selection to generate a targeted, in-frame, markerless deletion of the entire vomp locus in B. quintana. We also recently developed the first animal model for B. quintana infection, and using this model, we demonstrate here that the deletion of the entire vomp locus, but not the deletion of two vomp genes, results in a null mutant strain that is incapable of establishing bloodstream infection in vivo. The Vomp adhesins therefore represent critical virulence factors in vivo, warranting further study. Finally, our allelic exchange strategy provides an important advance in the genetic manipulation of all Bartonella species and, combined with the animal model that recapitulates human disease, will facilitate pathogenesis studies of B. quintana.     

An ERP study of visual change detection: effects of magnitude of spatial frequency changes on the change-related posterior positivity.

In event-related brain potential (ERP) studies using a visual S1-S2 matching task, change stimuli elicit a posterior positivity at around 100-200 ms. In the present study, we investigated the effects of magnitude of spatial frequency changes on change-related positivity. Each trial consisted of two sequentially presented stimuli (S1-S2), where S2 was either (1) the same as S1 (i.e., NO-change, p=.40), (2) different from S1 in spatial frequency only (SF-change, .40), (3) different in orientation only (OR-change, .10), or (4) different in both spatial frequency and orientation (BOTH-change, .10). Further, three magnitude conditions (Large, Medium, and Small) were used to examine the effect of the magnitude of the spatial frequency change. Participant's (N=12) task was to respond to S2 with a change in orientation (from vertical to horizontal, or from horizontal to vertical) regardless of the spatial frequency of the stimulus. Changes in the spatial frequency elicited change-related positivity at a latency range of about 120-180 ms, which was followed by a central negativity (N270) and a late positive component (LPC). The amplitude of the change-related positivity tends to be enhanced as the magnitude of the change is increased. These results support the notion that the change-related positivity reflects memory-based change detection in the human visual system.     

Variability in the magnitude of response of metabolic enzymes reveals patterns of co-ordinated expression following endurance training in women

Skeletal muscles improve their oxidative fatty acid and glucose metabolism following endurance training, but the magnitude of response varies considerably from person to person. In 20 untrained young women we examined interindividual variability in training responses of metabolic enzymes following 6 weeks of endurance training, sufficient to increase maximal oxygen uptake by 10 ± 8% (mean ± SD). Training led to increases in mitochondrial enzymes [succinate dehydrogenase (SDH; 47 ± 78%), cytochrome c oxidase (52 ± 70%) and ATP synthase (63 ± 69%)] and proteins involved in fatty acid metabolism [3-hydroxyacyl CoA dehydrogenase (69 ± 92%) and fatty acid transporter CD36 (86 ± 31%)]. Increases in enzymes of glucose metabolism [phosphofructokinase (29 ± 94%) and glucose transporter 4 (18 ± 65%)] were not significant. There was no relationship between changes in maximal oxygen uptake and the changes in the metabolic proteins. Considerable interindividual variability was seen in the magnitude of responses. The response of each enzyme was proportional to the change in SDH; individuals with a large increase in SDH also showed high gains in all other enzymes, and vice versa. Peroxisome proliferator-activated receptor γ coactivator 1α protein content increased after training, but was not correlated with changes in the metabolic proteins. In conclusion, the results revealed co-ordinated adaptation of several metabolic enzymes following endurance training, despite differences between people in the magnitude of response. Differences between individuals in the magnitude of response might reflect the influence of environmental and genetic factors that govern training adaptations.     

Did I do that? An ERP study of memory for performed and planned actions.

Memory for performed and planned actions was measured on source recognition and source recall tests. Event-related potentials (ERPs) were recorded during the source recognition test to index brain activity during output monitoring. Source identification of performed actions was superior to planned actions and more performed actions were recalled, thereby replicating the enactment effect. Examination of recall errors revealed that more planned than performed actions were omitted. In addition, intrusions and source misattributions were equally likely when recalling planned actions, whereas more misattributions were observed when performed actions were recalled. The ERP data indicated that brain activity elicited by performed actions differed from planned and new actions. Furthermore, activity in the left and right frontal lobes appeared to differ for performed and planned actions indicating that performed actions were evaluated with more heuristic decision processes than both planned and new items. The temporal onset of the frontal ERP differences also suggests that heuristic decision processes begin earlier than systematic processes.     

A refined method for molecular typing reveals that co-occurrence of PrP(Sc) types in Creutzfeldt-Jakob disease is not the rule

Molecular typing in Creutzfeldt-Jakob disease (CJD) relies on the detection of distinct protease-resistant prion protein (PrP(Sc)) core fragments, which differ in molecular mass or glycoform ratio. However, the definition and correct identification of CJD cases with a co-occurrence of PrP(Sc) types remains a challenge. With antibodies recognizing a linear epitope in the octapeptide repeat PrP region, supposed to distinguish between the two major PrP(Sc) isoforms (ie, types 1 and 2), it was recently shown that all type 2 cases display an associated band with a type 1 migration pattern, which led to the conclusion that multiple PrP(Sc) types regularly coexist in CJD. We studied brain samples from 53 sporadic CJD and 4 variant CJD subjects using a high-resolution electrophoresis, a wide range of proteinase K (PK) activities, the 'type 1-selective' antibody 12B2, and several unselective antibodies. We found that the type 1-like band detected by 12B2 in all CJD subtypes associated with PrP(Sc) type 2 is not a PK-resistant PrP(Sc) core but rather matches the physicochemical properties of partially cleaved fragments, which result from the several PK cleavage sites included in the N-terminal portion of PrP(Sc). Furthermore, using gels with high resolution and a relatively high PK activity, we were able to increase the detection sensitivity of either type 1 or 2, when coexisting, to amount corresponding to 3-5% of the total PrP(Sc) signal (ie, weak band of one type/total PrP(Sc)). Our results show that there are many pitfalls associated with the use of 'type 1 selective' antibodies for CJD typing studies and that co-occurrence of PrP(Sc) types in CJD is not the rule. The present results further validate the rationale basis of current CJD classification and the qualitative nature of molecular typing in CJD.     

A simple classification tool for single-trial analysis of ERP components

Event-related potentials (ERPs) were recorded by measuring a dense sensor EEG from eight healthy volunteers in a visual oddball experiment. Single trials were analyzed with an extremely simple high-dimensional version of discriminant analysis. The question was how many of the target trials contribute to the average P3, and to test whether other components in the ERP are sensitive to discriminate between target and non-target trials. One common classification rule for all participants expressing the P3 component correctly classified 88% of the ERPs of all subjects in response to a target or non-target trial. For four of the eight participants, there were strong differences in an early ERP component over the occipital recording sites. Their individual classification rules, obtained from the training data in the time interval up to 200 ms, correctly classified 85% of the trials of the test data.     

The role of the right medial temporal lobe in the control of memory-guided saccades

The role of the hippocampal formation in the control of memory-guided saccades is unclear. We tested two types of memory-guided saccades with short memorization delay in three patients with a lesion affecting the right medial temporal lobe and involving the hippocampal formation. In single memory-guided saccades, testing spatial working memory, the gain of the patient group did not differ from that of an age-matched control group. In contrast, in sequences of memory guided saccades, testing chronological working memory, there was a marked and significant increase in the percentage of erroneous sequences in patients, compared to controls. These results suggest an important role of the hippocampal formation in the memorization of the chronological order of saccade sequences. In contrast, this structure does not appear to be crucial for spatial working memory, used in single memory-guided saccades.     

Turn that frown upside down: ERP effects of thatcherization of misorientated faces

When inverted, thatcherized faces appear normal. This may be due to a decrease in configural and an increase in featural processing. It is not known whether this processing is continuous or reflects two distinct processing systems. Using event-related potentials (ERPs), we investigated the Thatcher effect on thatcherized and normal faces at varying orientations. The ERPs paralleled the perceptual illusion. The effect of thatcherization on upright faces was visible in P1 and N170 ERP components, possibly reflecting attentional engagement due to unpleasantness of thatcherized faces. Effects were also found over two later components, the P250 component, which has been related to configural recognition, and a late parietal component possibly reflecting featural processing. The effect of thatcherization on the two later components decreased gradually (for the P250 component) and abruptly (for the late parietal component) as the faces were rotated away from the upright.     

Directional selectivity of BOLD activity in human posterior parietal cortex for memory-guided double-step saccades

We used functional magnetic resonance imaging (fMRI) to investigate the role of the human posterior parietal cortex (PPC) in storing target locations for delayed double-step saccades. To do so, we exploited the laterality of a subregion of PPC that preferentially responds to the memory of a target location presented in the contralateral visual field. Using an event-related design, we tracked fMRI signal changes in this region while subjects remembered the locations of two sequentially flashed targets, presented in either the same or different visual hemifields, and then saccaded to them in sequence. After presentation of the first target, the fMRI signal was always related to the side of the visual field in which it had been presented. When the second target was added, the cortical activity depended on the respective locations of both targets but was still significantly selective for the target of the first saccade. We conclude that this region within the human posterior parietal cortex not only acts as spatial storage center by retaining target locations for subsequent saccades but is also involved in selecting the target for the first intended saccade.     

Control of neural prostheses for grasping and reaching

In recent years several neural prostheses have been developed and tested as orthoses or as therapeutic systems for hemiplegic and tetraplegic subjects aiming to improve the upper extremities function. The use of neural prostheses demonstrated that the targeted group of subjects could significantly benefit from functional electrical stimulation that is integrated in goal directed movements. In this paper the control for neural prostheses is explained using available systems that apply either surface or implantable interfaces to sensory-motor systems. Further more, a new strategy that has been tested for control of reaching and grasping within a neural prosthesis especially designed for neurorehabilitation is described. This, so-called, coordination strategy was based on mimicking the output space model of natural control determined in reach/grasp/release movements of healthy humans.