Long term study of motivational and cognitive effects of low-intensity focused ultrasound neuromodulation in the dorsal striatum of nonhuman primates.

Noninvasive brain stimulation using transcranial focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2-0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

[Microtitration of anti-RH1 antibodies: interest in the follow-up of pregnant women]. / Intérêt de la technique de microtitrage des anticorps anti-RH1 dans le suivi immunohématologique des femmes enceintes.

UNLABELLED: The proposal for a 300 microg anti-RH1 injection at 28 GW by RH:-1 pregnant women complicates the interpretation of the screening for alloantibodies during pregnancy; to distinguish an alloantibody from a passive one is nevertheless important for the care of the patients. Testing a technique allowing this distinction seems thus necessary. MATERIAL AND METHODS: The technique of microtitration of anti- RH1 antibodies is an indirect antiglobulin test. Two hundred specimens were tested in comparison with a standard prepared from a national anti- RH1 standard. If the anti- RH1 concentration measured is lower or equal to the expected concentration, there is a passive antibody. If the concentration is largely higher, we can suspect an allo-immunization. RESULTS: With this technique, 38 alloanti- RH1 and 112 passive anti- RH1 antibodies were confirmed. Twenty-five diagnosis were modified: seven alloanti- RH1 initially labeled passive and 18 passive anti- RH1 previously considered as alloantibodies. 15 cases can not be concluded, because the blood sample was taking away too early after the injection, and 10 cases are on standby, waiting for a control. DISCUSSION: The microtitration is an important exam in the follow-up of the RH:-1 pregnant women when an anti-RH1 antibody is found. This exam should be offered each time we have no information about the anti-D injection, or when an incoherent reaction compared to the presumed date of injection is observed.

Activity of prefrontal neurons during location and color delayed matching tasks.

Many cells in prefrontal cortex show enhanced activity prior to movement onset in delayed or memory-guided saccade tasks. This activity is a possible neural correlate of spatial attention and working memory. The goal of this study was to determine whether delay activity is evoked when non-spatial cues such as color are used to guide saccades. Monkeys were trained on a saccade target selection task in which they were cued for either the location or color of the rewarded target. When the location of the target was specified explicitly, many cells showed visual responses and delay activity that were spatially selective. Color selective visual responses or delay activity were both rare and weak. However, for many cells, spatially selective delay activity could be evoked when color was used to specify the location of the target. These results indicate that color is capable of eliciting spatially selective activity from cells that have no overt color selectivity.

Perceived speed of moving two-dimensional patterns.

When two cosine gratings drifting in different directions are superimposed they can form a coherently moving two-dimensional pattern (plaid) whose resultant speed is related to the component velocities by a geometric construction known as the intersection-of-constraints (IOC). When measured against a standard which has the same spatial frequency as its components, a plaid always appears to move slower than the IOC prediction. However, the perceived speed is generally faster than would be predicted if speed were judged based on the temporal frequency of either the components or the nodes of the plaid. On the other hand, when the standard has the same spatial period as the nodes, the plaid appears to move at the same rate as the predicted IOC resultant. Furthermore, a grating with the same spatial period as the nodes appears to move slower than a grating at the component spatial frequency, just the plaid does. It is therefore likely that speed is encoded similarly for both gratings and plaids, and that the perceived speed of both is determined by the spatial periodicity of the pattern. We have previously classified 2D moving patterns as either type I (resultant lies between component directions) or type II (resultant outside of components). We find that the perceived speed of both types can be accounted for on the basis of the nodal spatial period. Finally we present a model for velocity coding which is based on the responses of spatio-temporal mechanisms.

Direction specific masking and the analysis of motion in two dimensions.

We measured the effects of moving two-component cosine grating masks on the detectability of a moving spatially localized test pattern with a 1.0 octave spatial frequency bandwidth. Masking was used to distinguish between two-component patterns with fluid motion (blobs) and those with rigid motion (plaids). The two gratings which made up the two-dimensional masking patterns were always of the same spatial frequency and contrast, but moved in different directions. We find that plaid masks consistently produced threshold elevations that are 2.0-4.0 times greater than are produced by a single component mask at twice the contrast. Furthermore, this effect is nearly independent of the angle between the two mask components. For fluid motion, however, masking is determined by the mask component whose direction of motion is closest to that of the test. The results obtained with moving two-dimensional patterns demonstrate that, for blobs, the motion of the pattern as a whole has no effect on the degree of masking, whereas, for plaids, the signals arising from the two components interact in a nonlinear manner, thus producing a substantial enhancement of masking, which is clearly related to the coherent motion of the entire pattern. These data shed light on the properties of higher order motion units (possibly in MT cortex) that respond to the direction of two-dimensional pattern motion, suggesting that they combine, in a nonlinear manner, the outputs of units which respond independently to the direction of each mask component.

Perceived direction of moving two-dimensional patterns.

When two drifting cosine gratings are superimposed, they will, under appropriate conditions, form a coherently moving two-dimensional pattern whose resultant direction of motion may either be between (type I), or outside (type II) the directions of the two components. We have previously shown that type I patterns produce much stronger masking than either of their components, while type II patterns do not. In this study, we measured perceived direction of motion and thresholds for discrimination of motion direction. We found that type II patterns had a perceived bias of about 7.5 deg toward the direction of their components, and had discrimination thresholds around 6.5 deg, whereas type I patterns had discrimination thresholds around 1.0 deg and no significant bias. We conclude that the neural mechanisms which compute two-dimensional image motion do not strictly implement the intersection-of-constraints construction proposed by Adelson and Movshon (1982).

Detection thresholds for spiral Glass patterns.

We measured thresholds for the detection of spiral Glass patterns in the presence of random noise. The patterns were constructed so that the orientation content did not vary as a function of spiral angle or signal level. We found that spiral patterns had higher thresholds than either radial or concentric Glass patterns. The results support the idea that the human visual system is specialized to detect radial and concentric patterns.

Spatial frequency tuning of transient non-oriented units.

Thresholds for a vertical test stimulus with a 1.0 octave bandwidth were measured as a function of the spatial frequency of a horizontal flickering cosine mask. Both test and mask were temporally modulated at 8.0 Hz, as low temporal frequencies were found to produce very little masking. Separate experiments were run at each of 10 test frequencies from 0.25 to 8.0 cycles per degree (c/deg) at 0.5 octave intervals. Masking curves thus obtained for each of three subjects were used to compute the spatial frequency sensitivities of three non-oriented mechanisms. Compared to previous masking studies of orientation selective units, non-oriented units have somewhat broader spatial frequency sensitivity curves, in agreement with primate neurophysiology.

A reduction in the number of directionally selective neurons extends the spatial limit for global motion perception.

Dynamic random-dot targets were used to study neural mechanisms underlying motion perception. Performance of cats with severely reduced numbers of cortical directionally selective neurons (reduced DS) was compared to that of normal animals. We assessed the spatial properties of the residual motion mechanism by measuring direction discriminations at various dot displacements. At small displacements, reduced DS cats' motion integration thresholds for opposite direction discrimination were nearly normal. At larger displacements, their thresholds surpassed those of normal cats and their upper displacement limit (dmax) was increased by 0.35 deg. The accuracy of direction discrimination was reduced at small displacements, but at larger displacements direction difference thresholds of reduced DS cats approached or surpassed those of normals. These data were compared to the performance of humans who showed an extension of dmax for peripherally viewed targets. The data support the hypothesis that expansion in spatial scale of the motion mechanism may contribute to extension of dmax. Additional support for this hypothesis is provided by a modified direction discriminating line-element model. The model also suggests that changes in sampling of motion mechanisms in the reduced DS system may play a role.

Spatial frequency and orientation tuning of spatial visual mechanisms in human albinos.

A masking paradigm was used to measure the spatial frequency and orientation tuning of spatial mechanisms in the albino visual system. Threshold elevation curves obtained in this manner at test spatial frequencies of 0.25 cycles/deg (cpd), 0.50 cpd, and 1 cpd have the same shape as curves obtained from normal subjects at test frequencies two octaves higher. Additional masking studies showed that contrast processing in albinos obeys the same compressive power law as in normals. Thus, spatial mechanisms in albino central vision have normal spatial frequency and orientation bandwidths. As central cones in the albino are spaced 3-4 times further apart than in the normal fovea, these results support the hypothesis that monocular spatial vision in albinos is primarily limited by this increased receptor spacing. It is hypothesized that this, in turn, is the result of arrested development of the albino retina.

Serum and synovial fluid osteocalcin in rheumatic diseases.

The mechanisms involved in juxta-articular bone destruction are poorly understood. Osteocalcin or gamma-carboxyglutamic acid (GLA) protein is a small non-collagenous bone protein. It is a sensitive marker of osteoblastic bone formation. Its seric variations in the serum in such rheumatisms as rheumatoid arthritis remain unclear. Further information on local osteoblastic activity may be obtained by assaying the level of osteocalcin in the synovium. Its serum level can be evaluated by radioimmunoassay. The same method can be used in the synovial fluid. Paired serum and synovial fluid samples have been assayed from 63 patients, 33 patients with inflammatory arthritis (rheumatoid arthritis, psoriasis, chondrocalcinosis, pyogenic arthritis) and 30 patients with mechanical joint effusion (osteoarthritis, meniscal lesions). Serum levels of osteocalcin were the same in the inflammatory group (m: 8.69 +/- 0.68 ng/ml) and in the mechanical group (m: 10.2 +/- 0.67 ng/ml). In the synovial fluid, the levels of osteocalcin were significantly lower in the inflammatory group (m: 3.27 +/- 0.40 ng/ml) than in the mechanical group (m: 6.91 +/- 0.47 ng/ml). The same results were obtained with the ratio of synovial fluid osteocalcin on serum osteocalcin. There was a significant correlation between serum and synovial fluid osteocalcin and an inverse correlation between synovial fluid osteocalcin and the number of synovial fluid cells. The present study suggests that periarticular osteoblastic depression, among patients with inflammatory arthritis, is likely.

[From quality assurance to quality management in a blood transfusion center]. / De l'assurance qualité au management qualité au sein d'un établissement de transfusion sanguine.

Quality assurance favours transfusion safety and quality, and plays a role in restoring the confidence in the agents of the blood transfusion system. To perpetuate such quality processes, the approach should develop toward quality management based on a quality policy, which means staff's involvement and motivation, and continuous evaluation and improvement. Referring to a daily experience, this papers underlines how it is important that the policy be clearly expressed in the quality manual; it also permits to identify some factors that take part in the evolution toward improvement and anticipation of quality.

[Methodology for the development of a program for following and maintaining the competency of human resources]. / Méthodologie de développement d'un programme de suivi et maintien des compétences des ressources humaines.

The progressive introduction of a management program for the maintenance and assessment of staff competence has also focussed attention on the human factor, a major consideration in risk management and quality control. This article has examined the relevant tools and practical means of application, and proposes a methodology combining a methodical analysis of processes with the determination of the minimal knowledge required for participation in the practical and theoretical training programs that provide a means of objective evaluation. The results obtained in terms of technical, organizational and cultural impact have also been analyzed.

[Data interchange in blood transfusion: the impact of a new standard on the evolution of health electronic data exchange in France]. / Echange de données en transfusion sanguine: impact d'une nouvelle norme sur l'évolution de l'EDI santé en France.

The sanitary and social data interchange within care establishments or networks is today the subject of many national or international considerations. Electronic data interchange in the health field has characteristics linked to ethical and deontological principles of care staff. Used daily, this tool contributes to the quality of care, to the optimization of patient treatment and to the organization of the system care. In the transfusion field, the standardization of messages related to the traceability of blood products in now required by the No. 2 instruction of French Blood Agency, which rules the using of national norms elaborated by the French Agency of Normalization. If the technicality is the greater part of these regulated and formalized messages, this standardization systematizes and justifies the nominative and ciphered data interchange in an open environment, opening a new dimension in the interoperability of data system between care establishments. This article analyzes the characteristics and the potential impact of this normalization on the evolution of the electronic data interchange in the health field.

[Cold agglutinins, clinical presentation and significance; retrospective analysis of 58 patients]. / Agglutinines froides, circonstances de découverte chez l'adulte et signification en pratique clinique: analyse rétrospective à propos de 58 patients.

PURPOSE: To describe clinical, biological characteristics and associated diseases of cold agglutinins in adults. METHODS: Retrospective study in a single department of internal medicine from 1997 to 2002. The inclusion criteria were a positive direct Coombs test and a positive research for cold-reactive autoantibodies. We recorded for each patient: clinical presentation at onset and during follow-up, biological parameters of haemolysis, biological characteristics of the cold agglutinin and associated diseases. RESULTS: Fifty-eight patients (34 females, 24 males), with medium age of 58.8 were included in the study. Clinical presentation was highly variable between acute life-threatening haemolysis and absence of symptoms. Results of direct antiglobulin test were C3 (74%), IgG + C3 (22.4%), IgG (3.4%). Titer, thermal amplitude, strength and specificity of Coombs test were correlated, in all cases except 6, with cold agglutinin haemolytic activity. In 77.6% of cases cold agglutinin was secondary; related to: autoimmune disorders (n = 19), lymphoproliferative disorders (n = 11) and infections (n = 10). CONCLUSION: Clinical presentation of cold agglutinin is highly variable and not always related to the biological characteristics of the bound antibody (titer, thermal amplitude, specificity). In our single center study, diseases associated with cold agglutinin were various with the highest frequency of auto-immune disorders. Our study underlined also the high frequency of lymphoproliferative disorders and justifies a close follow-up of these patients. Finally, we reported a high frequency of hepatitis C virus infection among the infectious aetiologies.

Task-dependent modulation of the sensorimotor transformation for smooth pursuit eye movements.

To investigate the transformation of retinal image velocity into smooth pursuit eye velocity, eye movements were measured in the presence of two moving targets. In the first experiment, the targets were identical in all respects except for direction of motion, and the monkey was not cued to attend to either target. In this experiment, smooth pursuit eye velocity elicited by two targets was the vector average of the response evoked by each target alone. In subsequent experiments, we examined the effects of stimulus and task parameters on the selectivity of pursuit. When the targets were made different colors and monkeys were cued for the color of the rewarded target, their pursuit eye movements were biased in the direction of the rewarded target, but still showed a substantial influence of the nonrewarded target (distractor). It did not matter whether the same target color was used for an entire session or whether the color was randomized from trial to trial. Reducing uncertainty about the axis of motion of the rewarded target also had little effect. However, the pattern of image motion appeared to have a substantial effect; radial image motion favored averaging, and winner-take-all pursuit was found only with nonradial image motion. We conclude that the sensorimotor interface for pursuit uses a flexible decision rule that can vary continuously from vector averaging to winner-take-all. We present a simple recurrent network model that reflects this range of behavior. The model has allowed us to identify three computational elements (selection bias, competitive inhibition, and response normalization) that should be taken into consideration in future models of smooth pursuit.

Vector averaging for smooth pursuit eye movements initiated by two moving targets in monkeys.

The visual input for pursuit eye movements is represented in the cerebral cortex as the distributed activity of neurons that are tuned for both the direction and speed of target motion. To probe how the motor system uses this distributed code to compute a command for smooth eye movements, we have recorded the initiation of pursuit for 150 msec presentations of two spots moving at different speeds and/or in different directions. With equal probability, one of the two spots continued to move at the same speed and in the same direction and became the tracking target, whereas the other disappeared and served as a distractor. We measured eye acceleration in the interval from 110 to 206 msec after the onset of spot motion, within both the open-loop interval for pursuit and the interval during which eye motion was affected by the two spots. Our results demonstrate that weighted vector averaging is used to combine the responses to two moving spots. We found only a minute number of responses that were consistent with either vector summation or winner-take-all computations. In addition, our data show that it is difficult for the monkey to defeat vector averaging without extended training on the use of an explicit cue about which spot will become the target. We argue that our experiment reveals the computations done by the pursuit system in the absence of attentional bias and that vector averaging is normally used to read the distributed code of image motion when there is only one target.

Neuronal responses in visual areas MT and MST during smooth pursuit target selection.

We recorded the activity of single neurons in the middle temporal (MT) and middle superior temporal (MST) visual areas in two macaque monkeys while the animals performed a smooth pursuit target selection task. The monkeys were presented with two moving stimuli of different colors and were trained to initiate smooth pursuit to the stimulus that matched the color of a previously given cue. We designed these experiments so that we could separate the component of the neuronal response that was driven by the visual stimulus from an extraretinal component that predicted the color or direction of the selected target. We found that for all cells in MT and MST the response was primarily determined by the visual stimulus. However, 14% (8 of 58) of MT neurons and 26% (22 of 84) of MST neurons had a small predictive component that was significant at the P < or = 0.05 level. In some cells, the predictive component was clearly related to the color of the intended target, but more often it was correlated with the direction of the target. We have previously documented a systematic shift in the latency of smooth pursuit that depends on the relative direction of motion of the two stimuli. We found that neither the latency nor the amplitude of neuronal responses in MT or MST was correlated with behavioral latency. These results are consistent with a model for target selection in which a weak selection bias for the intended target is amplified by a competitive network that suppresses motion signals related to the nonintended stimulus. It is possible that the predictive component of neuronal responses in MT and MST contributes to the selection bias. However, the strength of the selection bias in MT and MST is not sufficient to account for the high degree of selectivity shown by pursuit behavior.

Attention and target selection for smooth pursuit eye movements.

Two rhesus monkeys were trained to track a small moving target in the presence of a moving distractor. The target and distractor were distinguished by their color. Smooth pursuit eye movements were quantified in terms of the latency of the eye movement and the open-loop eye acceleration profile. Smooth pursuit latencies for single targets were on the order of 100 msec. When the target was paired with a distractor moving in the same direction as the target, pursuit latencies decreased to roughly 85 msec. When the target was paired with a distractor moving in the opposite direction, pursuit latencies increased to roughly 150 msec. The motion of the distractor had no significant effect on the eye acceleration profile. Experiments were performed to dissociate visual search for the target from pursuit initiation by providing a spatial cue rather than the color cue. These experiments showed that visual search necessarily preceded pursuit initiation only when the distractor moved in the opposite direction relative to the target. In this case, visual search contributed about 25 msec to the overall latency of pursuit. Control experiments showed that the monkey need not attend to the distractor in order for it to influence the latency of pursuit. A network model was developed in which units that represent the motions of the target and distractor compete against one another. Attention serves to bias the outcome of this competition toward the direction of the selected target. The performance of this network exhibits a striking parallel to the effect of the distractor on smooth pursuit latency.