Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization.

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD.

The role of visual processing in motor learning and control: Insights from electroencephalography.

Traditionally our understanding of goal-directed action been derived from either behavioral findings or neuroanatomically derived imaging (i.e., fMRI). While both of these approaches have proven valuable, they lack the ability to determine a direct locus of function while concurrently having the necessary temporal precision needed to understand millisecond scale neural interactions respectively. In this review we summarize some seminal behavioral findings across three broad areas (target perturbation, feed-forward control, and feedback processing) and for each discuss the application of electroencephalography (EEG) to the understanding of the temporal nature of visual cue utilization during movement planning, control, and learning using four existing scalp potentials. Specifically, we examine the appropriateness of using the N100 potential as an indicator of corrective behaviors in response to target perturbation, the N200 as an index of movement planning, the P300 potential as a metric of feed-forward processes, and the feedback-related negativity as an index of motor learning. Although these existing components have potential for insight into cognitive contributions and the timing of the neural processes that contribute to motor control further research is needed to expand the control-related potentials and to develop methods to permit their accurate characterization across a wide range of behavioral tasks.

Tactile gating in a reaching and grasping task.

Abstract A multitude of events bombard our sensory systems at every moment of our lives. Thus, it is important for the sensory cortex to gate unimportant events. Tactile suppression is a well-known phenomenon defined as a reduced ability to detect tactile events on the skin before and during movement. Previous experiments found detection rates decrease just prior to and during finger abduction, and decrease according to the proximity of the moving effector. This study examined how tactile detection changes during a reach to grasp. Fourteen human participants used their right hand to reach and grasp a cylinder. Tactors were attached to the index finger, the fifth digit, and the forearm of both the right and left arm and vibrated at various epochs relative to a "go" tone. Results showed that detection rates at the forearm decreased before movement onset; whereas at the right index finger, right fifth digit and at the left index finger, left fifth digit, and forearm sites did not decrease like in the right forearm. These results indicate that the task affects gating dynamics in a temporally- and contextually dependent manner and implies that feed-forward motor planning processes can modify sensory signals.

Facilitating the use of online visual feedback: advance information and the inter-trial interval?

Cheng et al. (2008) showed that when goal-directed reaching movements are performed with a 2.5 s inter-trial interval (ITI) under a randomized visual feedback schedule, individuals use online visual information on trial n to perform efficient online corrections on trial n + 1 (i.e., "reminiscence" effect). These results persisted even when participants were given knowledge of the up-coming vision condition. In this study, the ITI was extended to 5 s in an attempt to negate any effects of the preceding trial. Results from this study revealed that trials with vision were always more accurate than trials performed without vision, suggesting that individuals relied significantly on online information. Furthermore, aiming precision improved when participants knew the vision condition before each trial. It is thus suggested that the reminiscence effects are not longer evident with a 5 s ITI, which in turn allows prior knowledge of visual feedback to influence the use of online vision.

The utility of vision during action: multiple visuomotor processes?

Recently, D. Elliott et al. (2010) asserted that the current control phase of a movement could be segregated in multiple processes, including impulse and limb-target regulation processes. The authors aimed to provide further empirical evidence and determine some of the constraints that govern these visuomotor processes. In 2 experiments, vision was presented or withdrawn when limb velocity was above or below selected velocity criteria. The authors observed that vision provided between 0.8 and 0.9 m/s significantly improved impulse regulation processes while vision provided up to 1.1 m/s significantly increased limb-target regulation processes. These results lend support to D. Elliott et al. and provide evidence that impulse regulation and limb-target regulation can take place at different velocities during a movement.

Explicit knowledge and real-time action control: anticipating a change does not make us respond more quickly.

When the target of a goal-directed reach changes location, people normally respond rapidly and automatically to the target shift. Here, we investigate whether explicit knowledge about a moving target (knowing whether a location change is likely/unlikely) improves responsiveness, with the goal of understanding top-down effects on real-time reaching. In Experiment 1, we presented participants with pre-cues that indicated a 20 or 80% likelihood of a target perturbation on that trial. When participants made pro-pointing responses to the target perturbations, their online response occurred later for 20% trials than for 80% trials, but this effect may have been due to suppression of the online response on 20% trials, rather than enhancement of the response on 80% trials. In Experiment 2, we presented participants with 50 and 100% likelihood pre-cues, and observed no shortening of the latency on 100% trials compared to 50% trials, which suggests that expectation does not enhance the automatic response to a perturbation. However, we did observe more vigorous responses to the perturbation on the 100% trials, and this contributed to shorter movement times relative to the 50% trials. We also examined, in Experiment 2, whether prior knowledge about the direction of the target perturbation would shorten the latency of the online response, but we did not observe any reduction in latency. In sum, the onset of the automatic response appears to be suppressible, but not augmentable by top-down input. The possibility that the forcefulness of the automatic response is modifiable by expectation is examined, but not resolved.

Preceding movement effects on sequential aiming.

In this study, two experiments were devised to examine the control strategy used by individuals when performing sequential aiming movements. Of particular interest was the aiming behavior displayed when task difficulty was changed midway through a sequence of movements. In Experiment 1, target size was manipulated, as the targets were made either larger or smaller, between the 8th and 12th movement of the sequence. In Experiment 2, the amplitude between the two targets was similarly changed while the target size remained constant. Results revealed that in Experiment 1, individuals took two movements following the perturbation to target size, to re-tune their movement times in order to correspond with the new task difficulty. Conversely for Experiment 2, movement time changed immediately and in correspondence with the new target amplitude. These findings demonstrate that participants can use information from the preceding movement to prepare and guide subsequent movements--but only when target size is changed. When response amplitude changes mid-sequence, it seems individuals rely more on immediate, target-derived information. Therefore, counter to some current accounts of visual movement control, it appears that memory representations of the preceding movement can guide subsequent movements; however, this information appears selectively accessed in a context-dependent fashion.

Randomizing visual feedback in manual aiming: reminiscence of the previous trial condition and prior knowledge of feedback availability.

A trial-by-trial analysis was used to systematically examine the influence of switching visual conditions on visual feedback utilization for a manual aiming movement. In experiment one, vision was randomly manipulated from trial to trial with no more than four consecutive trials in the same visual condition. In experiment two, participants were provided with certainty of visual feedback availability prior to every trial. Results of both studies revealed that movement endpoint variability was most associated with visual feedback availability on the previous trial. Furthermore, correlation analyses comparing movement trajectory at 25, 50 and 75% with movement end (i.e. 100%) revealed that the efficiency of online corrections also depends on the availability of visual feedback on the previous trial. These results suggest that the accuracy of an aiming movement is highly dependent on processing of offline visual information from the preceding trial.

The preparation and control of reversal movements as a single unit of action.

Previous research has demonstrated that movement time and kinematic properties of limb trajectories to the first target of a two-target reversal movement differ to that of single-target responses. In the present study we investigated whether two-target reversal movements are organized as a single unit of action or two separate components by perturbing the number of targets prior to and during movement execution. In one experiment, participants performed single-target movements and on one-third of the trials a second target was presented either at target presentation, movement onset or peak velocity. On those trials in which a second target was presented, participants were required to complete their movement to the first target and then move to the second target. In a second experiment, the reverse was the case with participants performing two-target movements that changed to single-target movement on one-third of the trials. A two-target movement time advantage was observed only when the required response was specified prior to movement initiation. Also, participants failed to prevent movement towards the second target when the requirements of the task changed from a two-target to single-target response at movement onset or later. These results indicate that two-target reversal movements were organized as a single unit of action prior to response initiation.