Pilot Study of Acute Behavioral Effects of Pallidal Burst Stimulation in Parkinson's Disease.

BACKGROUND: Burst-patterned pallidal deep brain stimulation (DBS) in an animal model of Parkinson's disease (PD) yields significantly prolonged therapeutic benefit compared to conventional continuous DBS, but its value in patients remains unclear. OBJECTIVES: The aims were to evaluate the safety and tolerability of acute (<2 hours) burst DBS in PD patients and to evaluate preliminary clinical effectiveness relative to conventional DBS. METHODS: Six PD patients were studied with DBS OFF, conventional DBS, and burst DBS. Unified Parkinson's Disease Rating Scale III (UPDRS-III) and proactive inhibition (using stop-signal task) were evaluated for each condition. RESULTS: Burst and conventional DBS were equally tolerated without significant adverse events. Both stimulation patterns provided equivalent significant UPDRS-III reduction and increased proactive inhibition relative to DBS OFF. CONCLUSIONS: This pilot study supports the safety and tolerability of burst DBS, with acute effects similar to conventional DBS. Further larger-scale studies are warranted given the potential benefits of burst DBS due to decreased total energy delivery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Behavior in a visual search task with moving dot stimuli.

Understanding the neuronal mechanisms underlying the processing of visual attention requires a well-designed behavioral task that allows investigators to clearly describe the behavioral effects of attention. Here, we introduce a behavioral paradigm in which one, two or four moving dot stimuli are used in a visual search paradigm that includes two additional attentional conditions. Two animals were trained to make a saccade to a target (a dot patch with net rightward motion) and hold central fixation if no target was present. To implement covert visual attention, we included trials in which a 100% valid spatial cue appeared and trials in which the color of the fixation point indicated, with 100% validity, which of four colored dot patches the animals should attend to. We analyzed the behavior in terms of reaction times and signal detection theory metrics d-prime (representing sensitivity) and criteria. In both animals, we found that reaction times were greater for larger set-sizes and that the introduction of an attentional cue reduced the reaction times substantially. We also found that both animals showed increases in criteria, but no change in sensitivity, as set-size increased and the attentional cues led to an increase in sensitivity, with only some change in criteria. Our results illustrate how the animals perform this task and imply that both animals chose similar strategies. Importantly, this will allow future neurophysiological studies to probe not only the effects of attention, but will give the possibility of seeing whether different neural mechanisms drive changes in criteria and d-prime.

Functional neuroanatomy of cognition in Parkinson's disease.

While cognitive dysfunction in Parkinson's disease (PD) is increasingly recognized as a progressive symptom of the underlying neurodegenerative disease, our understanding of the functional and structural anatomic changes underlying these cognitive changes remains incomplete. Like the motor system, research point to a complex interplay between multiple parallel yet interconnected networks or circuits that are affected in PD and give rise to cognitive symptomatology. These circuits are most often studied in the context of disorders of executive function, and tightly linke to frontal lobe dysfunction. While the tasks employed vary across studies and it is often unclear whether differences in anatomy and function are causal or compensatory, the literature points to several key circuits that seem to be uniquely impaired in PD patients with cognitive dysfunction. This chapter reviews four of these circuits including the frontostriatal, frontoparietal, mesocortical, and noradrenergic circuits. By gaining a better understanding of the functional neuroanatomy of these circuits, we begin to develop a more comprehensive and unifed picture of how they to account for the pathophysiology of cognitive dysfunction in PD.

The roles of the lateral intraparietal area and frontal eye field in guiding eye movements in free viewing search behavior.

The lateral intraparietal area (LIP) and frontal eye field (FEF) have been shown to play significant roles in oculomotor control, yet most studies have found that the two areas behave similarly. To identify the unique roles each area plays in guiding eye movements, we recorded 200 LIP neurons and 231 FEF neurons from four animals performing a free viewing visual foraging task. We analyzed how neuronal responses were modulated by stimulus identity and the animals' choice of where to make a saccade. We additionally analyzed the comodulation of the sensory signals and the choice signal to identify how the sensory signals drove the choice. We found a clearly defined division of labor: LIP provided a stable map integrating task rules and stimulus identity, whereas FEF responses were dynamic, representing more complex information and, just before the saccade, were integrated with task rules and stimulus identity to decide where to move the eye.NEW & NOTEWORTHY The lateral intrapareital area (LIP) and frontal eye field (FEF) are known to contribute to guiding eye movements, but little is known about the unique roles that each area plays. Using a free viewing visual search task, we found that LIP provides a stable map of the visual world, integrating task rules and stimulus identity. FEF activity is consistently modulated by more complex information but, just before the saccade, integrates all the information to make the final decision about where to move.

The functional roles of neural remapping in cortex.

Remapping is a property of some cortical and subcortical neurons that update their responses around the time of an eye movement to account for the shift of stimuli on the retina due to the saccade. Physiologically, remapping is traditionally tested by briefly presenting a single stimulus around the time of the saccade and looking at the onset of the response and the locations in space to which the neuron is responsive. Here we suggest that a better way to understand the functional role of remapping is to look at the time at which the neural signal emerges when saccades are made across a stable scene. Based on data obtained using this approach, we suggest that remapping in the lateral intraparietal area is sufficient to play a role in maintaining visual stability across saccades, whereas in the frontal eye field, remapped activity carries information that affects future saccadic choices and, in a separate subset of neurons, is used to maintain a map of locations in the scene that have been previously fixated.

The neural instantiation of a priority map.

The term priority map is commonly used to describe a map of the visual scene, in which objects and locations are represented by their attentional priority, which itself is a combination of low-level salience and top-down control. The aim of this review is to examine how such a map may be represented at the neuronal level. We propose that there is not a single, common map in the brain, but that a number of cortical areas work together to generate the resultant behavior. Specifically, we suggest that the lateral intraparietal area (LIP) of posterior parietal cortex provides a simple representation of attentional priority, which remaps across saccades, so that there is an apparent allocentric map in a region with retinocentric encoding scheme. We propose that the frontal eye field (FEF) of prefrontal cortex receives the responses from LIP, but can suppress them to control the flow of eye movement behavior, and that the intermediate layers of the superior colliculus (SCi) reflect the final saccade goal. Together, these areas function to guide eye movements and may play a similar role in allocating covert visual attention.

Neurons in FEF Keep Track of Items That Have Been Previously Fixated in Free Viewing Visual Search.

When searching a visual scene for a target, we tend not to look at items or locations we have already searched. It is thought that this behavior is driven by an inhibitory tagging mechanism that inhibits responses on priority maps to the relevant items. We hypothesized that this inhibitory tagging signal should be represented as an elevated response in neurons that keep track of stimuli that have been fixated. We recorded from 231 neurons in the frontal eye field (FEF) of 2 male animals performing a visual foraging task, in which they had to find a reward linked to one of five identical targets (Ts) among five distractors. We identified 38 neurons with activity that was significantly greater when the stimulus in the receptive field had been fixated previously in the trial than when it had not been fixated. The response to a fixated object began before the saccade ended, suggesting that this information is remapped. Unlike most FEF neurons, the activity in these cells was not suppressed during active fixation, had minimal motor responses, and did not change through the trial. Yet using traditional classifications from a memory-guided saccade, they were indistinguishable from the rest of the FEF population. We propose that these neurons keep track of any items that have been fixated within the trial and this signal is propagated by remapping. These neurons could be the source of the inhibitory tagging signal to parietal cortex, where a neuronal instantiation of inhibitory tagging is seen.SIGNIFICANCE STATEMENT When we search a scene for an item, we rarely examine the same location twice. It is thought that this is due to a neural mechanism that keeps track of the items at which we have looked. Here we identified a subset of neurons in the frontal eye field that preferentially responded to items that had been fixated earlier in the trial. These responses were remapped, appearing before the saccade even ended, and were not suppressed during maintained fixation. We propose that these neurons keep track of which items have been examined in search and could be the source of feedback that creates the inhibitory tagging seen in parietal cortex.

Suppression of frontal eye field neuronal responses with maintained fixation.

The decision of where to make an eye movement is thought to be driven primarily by responses to stimuli in neurons' receptive fields (RFs) in oculomotor areas, including the frontal eye field (FEF) of prefrontal cortex. It is also thought that a saccade may be generated when the accumulation of this activity in favor of one location or another reaches a threshold. However, in the reading and scene perception fields, it is well known that the properties of the stimulus at the fovea often affect when the eyes leave that stimulus. We propose that if FEF plays a role in generating eye movements, then the identity of the stimulus at fixation should affect the FEF responses so as to reduce the probability of making a saccade when fixating an item of interest. Using a visual foraging task in which animals could make multiple eye movements within a single trial, we found that responses were strongly modulated by the identity of the stimulus at the fovea. Specifically, responses to the stimulus in the RF were suppressed when the animal maintained fixation for longer durations on a stimulus that could be associated with a reward. We suggest that this suppression, which was predicted by models of eye movement behavior, could be a mechanism by which FEF can modulate the temporal flow of saccades based on the importance of the stimulus at the fovea.

Activity in LIP, But not V4, Matches Performance When Attention is Spread.

The enhancement of neuronal responses in many visual areas while animals perform spatial attention tasks has widely been thought to be the neural correlate of visual attention, but it is unclear whether the presence or absence of this modulation contributes to our striking inability to notice changes in change blindness examples. We asked whether neuronal responses in visual area V4 and the lateral intraparietal area (LIP) in posterior parietal cortex could explain the limited ability of subjects to attend multiple items in a display. We trained animals to perform a change detection task in which they had to compare 2 arrays of stimuli separated briefly in time and found that each animal's performance decreased as function of set-size. Neuronal discriminability in V4 was consistent across set-sizes, but decreased for higher set-sizes in LIP. The introduction of a reward bias produced attentional enhancement in V4, but this could not explain the vast improvement in performance, whereas the enhancement in LIP responses could. We suggest that behavioral set-size effects and the marked improvement in performance with focused attention may not be related to response enhancement in V4 but, instead, may occur in or on the way to LIP.

Object comparison in the lateral intraparietal area.

We can search for and locate specific objects in our environment by looking for objects with similar features. Object recognition involves stimulus similarity responses in ventral visual areas and task-related responses in prefrontal cortex. We tested whether neurons in the lateral intraparietal area (LIP) of posterior parietal cortex could form an intermediary representation, collating information from object-specific similarity map representations to allow general decisions about whether a stimulus matches the object being looked for. We hypothesized that responses to stimuli would correlate with how similar they are to a sample stimulus. When animals compared two peripheral stimuli to a sample at their fovea, the response to the matching stimulus was similar, independent of the sample identity, but the response to the nonmatch depended on how similar it was to the sample: the more similar, the greater the response to the nonmatch stimulus. These results could not be explained by task difficulty or confidence. We propose that LIP uses its known mechanistic properties to integrate incoming visual information, including that from the ventral stream about object identity, to create a dynamic representation that is concise, low dimensional, and task relevant and that signifies the choice priorities in mental matching behavior.NEW & NOTEWORTHY Studies in object recognition have focused on the ventral stream, in which neurons respond as a function of how similar a stimulus is to their preferred stimulus, and on prefrontal cortex, where neurons indicate which stimulus is being looked for. We found that parietal area LIP uses its known mechanistic properties to form an intermediary representation in this process. This creates a perceptual similarity map that can be used to guide decisions in prefrontal areas.

Remapping, Spatial Stability, and Temporal Continuity: From the Pre-Saccadic to Postsaccadic Representation of Visual Space in LIP.

As our eyes move, we have a strong percept that the world is stable in space and time; however, the signals in cortex coming from the retina change with each eye movement. It is not known how this changing input produces the visual percept we experience, although the predictive remapping of receptive fields has been described as a likely candidate. To explain how remapping accounts for perceptual stability, we examined responses of neurons in the lateral intraparietal area while animals performed a visual foraging task. When a stimulus was brought into the response field of a neuron that exhibited remapping, the onset of the postsaccadic representation occurred shortly after the saccade ends. Whenever a stimulus was taken out of the response field, the presaccadic representation abruptly ended shortly after the eyes stopped moving. In the 38% (20/52) of neurons that exhibited remapping, there was no more than 30 ms between the end of the presaccadic representation and the start of the postsaccadic representation and, in some neurons, and the population as a whole, it was continuous. We conclude by describing how this seamless shift from a presaccadic to postsaccadic representation could contribute to spatial stability and temporal continuity.

LIP activity in the interstimulus interval of a change detection task biases the behavioral response.

When looking around at the world, we can only attend to a limited number of locations. The lateral intraparietal area (LIP) is thought to play a role in guiding both covert attention and eye movements. In this study, we tested the involvement of LIP in both mechanisms with a change detection task. In the task, animals had to indicate whether an element changed during a blank in the trial by making a saccade to it. If no element changed, they had to maintain fixation. We examine how the animal's behavior is biased based on LIP activity prior to the presentation of the stimulus the animal must respond to. When the activity was high, the animal was more likely to make an eye movement toward the stimulus, even if there was no change; when the activity was low, the animal either had a slower reaction time or maintained fixation, even if a change occurred. We conclude that LIP activity is involved in both covert and overt attention, but when decisions about eye movements are to be made, this role takes precedence over guiding covert attention.

Evidence for differential top-down and bottom-up suppression in posterior parietal cortex.

When searching for an object, we usually avoid items that are visually different from the target and objects or places that have been searched already. Previous studies have shown that neural activity in the lateral intraparietal area (LIP) can be used to guide this behaviour; responses to task irrelevant stimuli or to stimuli that have been fixated previously in the trial are reduced compared with responses to potential targets. Here, we test the hypothesis that these reduced responses have a different genesis. Two animals were trained on a visual foraging task, in which they had to find a target among a number of physically identical potential targets (T) and task irrelevant distractors. We recorded neural activity and local field potentials (LFPs) in LIP while the animals performed the task. We found that LFP power was similar for potential targets and distractors but was greater in the alpha and low beta bands when a previously fixated T was in the response field. We interpret these data to suggest that the reduced single-unit response to distractors is a bottom-up feed-forward result of processing in earlier areas and the reduced response to previously fixated Ts is a result of active top-down suppression.

Anticipatory remapping of attentional priority across the entire visual field.

It has been suggested that one way we may create a stable percept of the visual world across multiple eye movements is to pass information from one set of neurons to another around the time of each eye movement. Previous studies have shown that some neurons in the lateral intraparietal area (LIP) exhibit anticipatory remapping: these neurons produce a visual response to a stimulus that will enter their receptive field after a saccade but before it actually does so. LIP responses during fixation are thought to represent attentional priority, behavioral relevance, or value. In this study, we test whether the remapped response represents this attentional priority by examining the activity of LIP neurons while animals perform a visual foraging task. We find that the population responds more to a target than to a distractor before the saccade even begins to bring the stimulus into the receptive field. Within 20 ms of the saccade ending, the responses in almost one-third of LIP neurons closely resemble the responses that will emerge during stable fixation. Finally, we show that, in these neurons and in the population as a whole, this remapping occurs for all stimuli in all locations across the visual field and for both long and short saccades. We conclude that this complete remapping of attentional priority across the visual field could underlie spatial stability across saccades.

Dissociating activity in the lateral intraparietal area from value using a visual foraging task.

We make decisions about where to look approximately three times per second in normal viewing. It has been suggested that eye movements may be guided by activity in the lateral intraparietal area (LIP), which is thought to represent the relative value of objects in space. However, it is not clear how values for saccade goal selection are prioritized while free-viewing in a cluttered visual environment. To address this question, we compared the neural responses of LIP neurons in two subjects with their saccadic behavior and three estimates of stimulus value. These measures were extracted from the subjects' performance in a visual foraging task, in which we parametrically controlled the number of objects on the screen. We found that the firing rates of LIP neurons did not correlate well with the animals' behavior or any of our estimated measures of value. However, if the LIP activity was further normalized, it became highly correlated with the animals' decisions. These data suggest that LIP activity does not represent value in complex environments, but that the value can easily be extracted with one further step of processing. We propose that activity in LIP represents attentional priority and that the downstream normalization of this activity is an essential process in guiding action.

Inhibition of return in a visual foraging task in non-human subjects.

Inhibition of return is thought to help guide visual search by inhibiting the orienting of attention to previously attended locations. We have previously shown that, in a foraging visual search task, the neural responses to objects in parietal cortex are reduced after they have been examined. Here we ask whether the animals' reaction times (RTs) in the same task show a psychophysical correlate of inhibition of return: a slowing of reaction time in response to a probe placed at a previously fixated location. We trained three animals to perform an RT version of the visual foraging task. In the foraging task, subjects visually searched through an array of five identical distractors and five identical potential targets; one of which had a reward linked to it. In the RT variant of the task, subjects had to rapidly respond to a probe if it appeared. We found that RTs were slower for probes presented at locations that contained previously fixated objects, faster to potential targets and between the two for behaviorally irrelevant distractors that had not been fixated. These data show behavioral inhibitory tagging of previously fixated objects and suggest that the suppression of activity seen previously in the same task in parietal cortex could be a neural correlate of this mechanism.

The role of the lateral intraparietal area in orienting attention and its implications for visual search.

Orienting visual attention is of fundamental importance when viewing a visual scene. One of the areas thought to play a role in the guidance of this process is the posterior parietal cortex. In this review, we will describe the way the lateral intraparietal area (LIP) of the posterior parietal cortex acts as a priority map to help guide the allocation of covert attention and eye movements (overt attention). We will explain the concept of a priority map and then show that LIP activity is biased by both bottom-up stimulus-driven factors and top-down cognitive influences, and that this activity can be used to predict the locus of covert attention and initial saccadic latencies in simple visual search tasks. We will then describe evidence for how this system acts during covert visual search and how its activity could be used to optimize overt visual search performance.

A pure salience response in posterior parietal cortex.

When exploring a visual scene, some objects perceptually popout because of a difference of color, shape, or size. This bottom-up information is an important part of many models describing the allocation of visual attention. It has been hypothesized that the lateral intraparietal area (LIP) acts as a "priority map," integrating bottom-up and top-down information to guide the allocation of attention. Despite a large literature describing top-down influences in LIP, the presence of a pure salience response to a salient stimulus defined by its static features alone has not been reported. We compared LIP responses with colored salient stimuli and distractors in a passive fixation task. Many LIP neurons responded preferentially to 1 of the 2 colored stimuli, yet the mean responses to the salient stimuli were significantly higher than to distractors, independent of the features of the stimuli. These enhanced responses were significant within 75 ms, and the mean responses to salient and distractor stimuli were tightly correlated, suggesting a simple gain control. We propose that a pure salience signal rapidly appears in LIP by collating salience signals from earlier visual areas. This contributes to the creation of a priority map, which is used to guide attention and saccades.

Microstimulation of posterior parietal cortex biases the selection of eye movement goals during search.

People can find objects in a visual scene fast and effortlessly. It is thought that this may be accomplished by creating a map of the outside world that incorporates bottom-up sensory and top-down cognitive inputs--a priority map. Eye movements are made toward the location represented by the highest activity on the priority map. We hypothesized that the lateral intraparietal area (LIP) of posterior parietal cortex acts as such a map. To test this, we performed low current microstimulation on animals trained to perform a foraging task and asked whether we could bias the animals to make a saccade to a particular stimulus, by creating an artificial peak of activity at the location representing that stimulus on the map. We found that microstimulation slightly biased the animals to make saccades to visual stimuli at the stimulated location, without actively generating saccades. The magnitude of this effect was small, but it appeared to be similar for all visual stimuli. We interpret these results to mean that microstimulation slightly biased saccade goal selection to the object represented at the stimulated location in LIP.

Been there, seen that: a neural mechanism for performing efficient visual search.

In everyday life, we efficiently find objects in the world by moving our gaze from one location to another. The efficiency of this process is brought about by ignoring items that are dissimilar to the target and remembering which target-like items have already been examined. We trained two animals on a visual foraging task in which they had to find a reward-loaded target among five task-irrelevant distractors and five potential targets. We found that both animals performed the task efficiently, ignoring the distractors and rarely examining a particular target twice. We recorded the single unit activity of 54 neurons in the lateral intraparietal area (LIP) while the animals performed the task. The responses of the neurons differentiated between targets and distractors throughout the trial. Further, the responses marked off targets that had been fixated by a reduction in activity. This reduction acted like inhibition of return in saliency map models; items that had been fixated would no longer be represented by high enough activity to draw an eye movement. This reduction could also be seen as a correlate of reward expectancy; after a target had been identified as not containing the reward the activity was reduced. Within a trial, responses to the remaining targets did not increase as they became more likely to yield a result, suggesting that only activity related to an event is updated on a moment-by-moment bases. Together, our data show that all the neural activity required to guide efficient search is present in LIP. Because LIP activity is known to correlate with saccade goal selection, we propose that LIP plays a significant role in the guidance of efficient visual search.