A machine learning toolbox for the analysis of sharp-wave ripples reveals common waveform features across species.

The study of sharp-wave ripples has advanced our understanding of memory function, and their alteration in neurological conditions such as epilepsy is considered a biomarker of dysfunction. Sharp-wave ripples exhibit diverse waveforms and properties that cannot be fully characterized by spectral methods alone. Here, we describe a toolbox of machine-learning models for automatic detection and analysis of these events. The machine-learning architectures, which resulted from a crowdsourced hackathon, are able to capture a wealth of ripple features recorded in the dorsal hippocampus of mice across awake and sleep conditions. When applied to data from the macaque hippocampus, these models are able to generalize detection and reveal shared properties across species. We hereby provide a user-friendly open-source toolbox for model use and extension, which can help to accelerate and standardize analysis of sharp-wave ripples, lowering the threshold for its adoption in biomedical applications.

A machine learning toolbox for the analysis of sharp-wave ripples reveal common features across species.

The study of sharp-wave ripples (SWRs) has advanced our understanding of memory function, and their alteration in neurological conditions such as epilepsy and Alzheimer's disease is considered a biomarker of dysfunction. SWRs exhibit diverse waveforms and properties that cannot be fully characterized by spectral methods alone. Here, we describe a toolbox of machine learning (ML) models for automatic detection and analysis of SWRs. The ML architectures, which resulted from a crowdsourced hackathon, are able to capture a wealth of SWR features recorded in the dorsal hippocampus of mice. When applied to data from the macaque hippocampus, these models were able to generalize detection and revealed shared SWR properties across species. We hereby provide a user-friendly open-source toolbox for model use and extension, which can help to accelerate and standardize SWR research, lowering the threshold for its adoption in biomedical applications.

Theta- and gamma-band oscillatory uncoupling in the macaque hippocampus.

Nested hippocampal oscillations in the rodent give rise to temporal dynamics that may underlie learning, memory, and decision making. Although theta/gamma coupling in rodent CA1 occurs during exploration and sharp-wave ripples emerge in quiescence, it is less clear that these oscillatory regimes extend to primates. We therefore sought to identify correspondences in frequency bands, nesting, and behavioral coupling of oscillations taken from macaque hippocampus. We found that, in contrast to rodent oscillations, theta and gamma frequency bands in macaque CA1 were segregated by behavioral states. In both stationary and freely moving designs, beta2/gamma (15-70 Hz) had greater power during visual search whereas the theta band (3-10 Hz; peak ~8 Hz) dominated during quiescence and early sleep. Moreover, theta-band amplitude was strongest when beta2/slow gamma (20-35 Hz) amplitude was weakest, instead occurring along with higher frequencies (60-150 Hz). Spike-field coherence was most frequently seen in these three bands (3-10 Hz, 20-35 Hz, and 60-150 Hz); however, the theta-band coherence was largely due to spurious coupling during sharp-wave ripples. Accordingly, no intrinsic theta spiking rhythmicity was apparent. These results support a role for beta2/slow gamma modulation in CA1 during active exploration in the primate that is decoupled from theta oscillations. The apparent difference to the rodent oscillatory canon calls for a shift in focus of frequency when considering the primate hippocampus.

Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys.

Background: Donepezil exerts pro-cognitive effects by nonselectively enhancing acetylcholine (ACh) across multiple brain systems. Two brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum, which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose ranges for donepezil to enhance the cognitive domains of attention and flexible learning. Methods: To test for dose-specific effects of donepezil on different cognitive domains, we devised a multitask paradigm for nonhuman primates that assessed attention and cognitive flexibility. The nonhuman primates received either vehicle or variable doses of donepezil before task performance. We measured intracerebral donepezil and its strength in preventing the breakdown of ACh within the prefrontal cortex and anterior striatum using solid phase microextraction neurochemistry. Results: The highest administered donepezil dose improved attention and made the subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. Conclusions: The donepezil dose for maximally improving attention differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in two major brain systems supporting these functions. These results suggest that in our cohort of adult monkeys, donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Retrosplenial and Hippocampal Synchrony during Retrieval of Old Memories in Macaques.

Memory for events from the distant past relies on multiple brain regions, but little is known about the underlying neural dynamics that give rise to such abilities. We recorded neural activity in the hippocampus and retrosplenial cortex of two female rhesus macaques as they visually selected targets in year-old and newly acquired object-scene associations. Whereas hippocampal activity was unchanging with memory age, the retrosplenial cortex responded with greater magnitude alpha oscillations (10-15 Hz) and greater phase locking to memory-guided eye movements during retrieval of old events. A similar old-memory enhancement was observed in the anterior cingulate cortex but in a beta2/gamma band (28-35 Hz). In contrast, remote retrieval was associated with decreased gamma-band synchrony between the hippocampus and each neocortical area. The increasing retrosplenial alpha oscillation and decreasing hippocampocortical synchrony with memory age may signify a shift in frank memory allocation or, alternatively, changes in selection among distributed memory representations in the primate brain.SIGNIFICANCE STATEMENT Memory depends on multiple brain regions, whose involvement is thought to change with time. Here, we recorded neuronal population activity from the hippocampus and retrosplenial cortex as nonhuman primates searched for objects embedded in scenes. These memoranda were either newly presented or a year old. Remembering old material drove stronger oscillations in the retrosplenial cortex and led to a greater locking of neural activity to search movements. Remembering new material revealed stronger oscillatory synchrony between the hippocampus and retrosplenial cortex. These results suggest that with age, memories may come to rely more exclusively on neocortical oscillations for retrieval and search guidance and less on long-range coupling with the hippocampus.

A corollary discharge mediates saccade-related inhibition of single units in mnemonic structures of the human brain.

Despite the critical link between visual exploration and memory, little is known about how neuronal activity in the human mesial temporal lobe (MTL) is modulated by saccades. Here, we characterize saccade-associated neuronal modulations, unit-by-unit, and contrast them to image onset and to occipital lobe neurons. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies saccades, inhibiting/exciting a unique population of broad-/narrow-spiking units, respectively, before and during saccades and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking neuronal activity to event-related potentials (ERPs), which are directionally modulated following saccades, we recontextualize the ERP associated with saccades as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded saccade-related ERP in the human brain.

A Kiosk Station for the Assessment of Multiple Cognitive Domains and Cognitive Enrichment of Monkeys.

Nonhuman primates (NHP's) are self-motivated to perform cognitive tasks on touchscreens in their animal housing setting. To leverage this ability, fully integrated hardware and software solutions are needed that work within housing and husbandry routines while also spanning cognitive task constructs of the Research Domain Criteria (RDoC). Here, we detail such an integrated robust hardware and software solution for running cognitive tasks in cage-housed NHP's with a cage-mounted Kiosk Station (KS-1). KS-1 consists of a frame for mounting flexibly on housing cages, a touchscreen animal interface with mounts for receptables, reward pumps, and cameras, and a compact computer cabinet with an interface for controlling behavior. Behavioral control is achieved with a Unity3D program that is virtual-reality capable, allowing semi-naturalistic visual tasks to assess multiple cognitive domains.KS-1 is fully integrated into the regular housing routines of monkeys. A single person can operate multiple KS-1's. Monkeys engage with KS-1 at high motivation and cognitive performance levels at high intra-individual consistency. KS-1 is optimized for flexible mounting onto standard apartment cage systems and provides a new design variation complementing existing cage-mounted touchscreen systems. KS-1 has a robust animal interface with options for gaze/reach monitoring. It has an integrated user interface for controlling multiple cognitive tasks using a common naturalistic object space designed to enhance task engagement. All custom KS-1 components are open-sourced.In summary, KS-1 is a versatile new tool for cognitive profiling and cognitive enrichment of cage-housed monkeys. It reliably measures multiple cognitive domains which promises to advance our understanding of animal cognition, inter-individual differences, and underlying neurobiology in refined, ethologically meaningful behavioral foraging contexts.

Long-term memory and hippocampal function support predictive gaze control during goal-directed search.

Eye movements during visual search change with prior experience for search stimuli. Previous studies measured these gaze effects shortly after initial viewing, typically during free viewing; it remains open whether the effects are preserved across long delays and for goal-directed search, and which memory system guides gaze. In Experiment 1, we analyzed eye movements of healthy adults viewing novel and repeated scenes while searching for a scene-embedded target. The task was performed across different time points to examine the repetition effects in long-term memory, and memory types were grouped based on explicit recall of targets. In Experiment 2, an amnesic person with bilateral extended hippocampal damage and the age-matched control group performed the same task with shorter intervals to determine whether or not the repetition effects depend on hippocampal function. When healthy adults explicitly remembered repeated target-scene pairs, search time and fixation duration decreased, and gaze was directed closer to the target region, than when they forgot targets. These effects were seen even after a one-month delay from their initial viewing, suggesting the effects are associated with long-term, explicit memory. Saccadic amplitude was not strongly modulated by scene repetition or explicit recall of targets. The amnesic person did not show explicit recall or implicit repetition effects, whereas his control group showed similar patterns to those seen in Experiment 1. The results reveal several aspects of gaze control that are influenced by long-term memory. The dependence of gaze effects on medial temporal lobe integrity support a role for this region in predictive gaze control.

Sharp-wave ripple features in macaques depend on behavioral state and cell-type specific firing.

Sharp-wave ripples (SWRs) are spontaneous, synchronized neural population events in the hippocampus widely thought to play a role in memory consolidation and retrieval. They occur predominantly in sleep and quiet immobility, and in primates, they also appear during active visual exploration. Typical measures of SWRs in behaving rats include changes in the rate of occurrence, or in the incidence of specific neural ensemble activity contained within the categorical SWR event. Much less is known about the relevance of spatiotemporal SWR features, though they may index underlying activity of specific cell types including ensemble-specific internally generated sequences. Furthermore, changes in SWR features during active exploratory states are unknown. In this study, we recorded hippocampal local-field potentials and single-units during periods of quiescence and as macaques performed a memory-guided visual search task. We observed that (a) ripples during quiescence have greater amplitudes and larger postripple waves (PRW) compared to those in task epochs, and (b) during "remembered" trials, ripples have larger amplitudes than during "forgotten" trials, with no change in duration or PRWs. We further found that spiking activity influences SWR features as a function of cell type and ripple timing. As expected, larger ripple amplitudes were associated with putative pyramidal or putative basket interneuron (IN) activity, even when the spikes in question exceed the duration of the ripple. In contrast, the PRW was attenuated with activity from low firing rate cells and enhanced with activity from high firing rate cells, with putative IN spikes during ripples leading to the most prominent PRW peaks. The selective changes in SWR features as a function of time window, cell type, and cognitive/vigilance states suggest that this mesoscopic field event can offer additional information about the local network and animal's state than would be appreciated from SWR event rates alone.

The Contribution of Different Cortical Regions to the Control of Spatially Decoupled Eye-Hand Coordination.

Our brain's ability to flexibly control the communication between the eyes and the hand allows for our successful interaction with the objects located within our environment. This flexibility has been observed in the pattern of neural responses within key regions of the frontoparietal reach network. More specifically, our group has shown how single-unit and oscillatory activity within the dorsal premotor cortex (PMd) and the superior parietal lobule (SPL) change contingent on the level of visuomotor compatibility between the eyes and hand. Reaches that involve a coupling between the eyes and hand toward a common spatial target display a pattern of neural responses that differ from reaches that require eye-hand decoupling. Although previous work examined the altered spiking and oscillatory activity that occurs during different types of eye-hand compatibilities, they did not address how each of these measures of neurological activity interacts with one another. Thus, in an effort to fully characterize the relationship between oscillatory and single-unit activity during different types of eye-hand coordination, we measured the spike-field coherence (SFC) within regions of macaque SPL and PMd. We observed stronger SFC within PMdr and superficial regions of SPL (areas 5/PEc) during decoupled reaches, whereas PMdc and regions within SPL surrounding medial intrapareital sulcus had stronger SFC during coupled reaches. These results were supported by meta-analysis on human fMRI data. Our results support the proposal of altered cortical control during complex eye-hand coordination and highlight the necessity to account for the different eye-hand compatibilities in motor control research.

Sharp-Wave Ripples in Primates Are Enhanced near Remembered Visual Objects.

The hippocampus plays an important role in memory for events that are distinct in space and time. One of the strongest, most synchronous neural signals produced by the hippocampus is the sharp-wave ripple (SWR), observed in a variety of mammalian species during offline behaviors, such as slow-wave sleep [1-3] and quiescent waking and pauses in exploration [4-8], leading to long-standing and widespread theories of its contribution to plasticity and memory during these inactive or immobile states [9-14]. Indeed, during sleep and waking inactivity, hippocampal SWRs in rodents appear to support spatial long-term and working memory [4, 15-23], but so far, they have not been linked to memory in primates. More recently, SWRs have been observed during active, visual scene exploration in macaques [24], opening up the possibility that these active-state ripples in the primate hippocampus are linked to memory for objects embedded in scenes. By measuring hippocampal SWRs in macaques during search for scene-contextualized objects, we found that SWR rate increased with repeated presentations. Furthermore, gaze during SWRs was more likely to be near the target object on repeated than on novel presentations, even after accounting for overall differences in gaze location with scene repetition. This proximity bias with repetition occurred near the time of target object detection for remembered targets. The increase in ripple likelihood near remembered visual objects suggests a link between ripples and memory in primates; specifically, SWRs may reflect part of a mechanism supporting the guidance of search based on past experience.

Hippocampal gamma-band Synchrony and pupillary responses index memory during visual search.

Memory for scenes is supported by the hippocampus, among other interconnected structures, but the neural mechanisms related to this process are not well understood. To assess the role of the hippocampus in memory-guided scene search, we recorded local field potentials and multiunit activity from the hippocampus of macaques as they performed goal-directed search tasks using natural scenes. We additionally measured pupil size during scene presentation, which in humans is modulated by recognition memory. We found that both pupil dilation and search efficiency accompanied scene repetition, thereby indicating memory for scenes. Neural correlates included a brief increase in hippocampal multiunit activity and a sustained synchronization of unit activity to gamma band oscillations (50-70 Hz). The repetition effects on hippocampal gamma synchronization occurred when pupils were most dilated, suggesting an interaction between aroused, attentive processing and hippocampal correlates of recognition memory. These results suggest that the hippocampus may support memory-guided visual search through enhanced local gamma synchrony. © 2016 Wiley Periodicals, Inc.

Pupillary responses and memory-guided visual search reveal age-related and Alzheimer's-related memory decline.

Episodic memory - composed of memory for unique spatiotemporal experiences - is known to decline with aging, and even more severely in Alzheimer 's disease (AD). Memory for trial-unique objects in spatial scenes depends on the integrity of the hippocampus and interconnected structures that are among the first areas affected in AD. We reasoned that memory for objects-in-scenes would be impaired with aging, and that further impairments would be observed in AD. We asked younger adults, healthy older adults, older adults at-risk for developing cognitive impairments, and older adults with probable early AD to find changing items ('targets') within images of natural scenes, measuring repeated-trial changes in search efficiency and pupil diameter. Compared to younger adults, older adults took longer to detect target objects in repeated scenes, they required more fixations and those fixations were more dispersed. Whereas individuals with AD showed some benefit of memory in this task, they had substantially longer detection times, and more numerous, dispersed fixations on repeated scenes compared to age-matched older adults. Correspondingly, pupillary responses to novel and repeated scenes were diminished with aging and further in AD, and the memory-related changes were weaker with aging and absent in AD. Our results suggest that several nonverbal measures from memory-guided visual search tasks can index aging and Alzheimer's disease status, including pupillary dynamics. The task measurements are sensitive to the integrity of brain structures that are associated with Alzheimer's-related neurodegeneration, the task is well tolerated across a range of abilities, and thus, it may prove useful in early diagnostics and longitudinal tracking of memory decline.

Selective scanpath repetition during memory-guided visual search.

Visual search efficiency improves with repetition of a search display, yet the mechanisms behind these processing gains remain unclear. According to Scanpath Theory, memory retrieval is mediated by repetition of the pattern of eye movements or "scanpath" elicited during stimulus encoding. Using this framework, we tested the prediction that scanpath recapitulation reflects relational memory guidance during repeated search events. Younger and older subjects were instructed to find changing targets within flickering naturalistic scenes. Search efficiency (search time, number of fixations, fixation duration) and scanpath similarity (repetition) were compared across age groups for novel (V1) and repeated (V2) search events. Younger adults outperformed older adults on all efficiency measures at both V1 and V2, while the search time benefit for repeated viewing (V1-V2) did not differ by age. Fixation-binned scanpath similarity analyses revealed repetition of initial and final (but not middle) V1 fixations at V2, with older adults repeating more initial V1 fixations than young adults. In young adults only, early scanpath similarity correlated negatively with search time at test, indicating increased efficiency, whereas the similarity of V2 fixations to middle V1 fixations predicted poor search performance. We conclude that scanpath compression mediates increased search efficiency by selectively recapitulating encoding fixations that provide goal-relevant input. Extending Scanpath Theory, results suggest that scanpath repetition varies as a function of time and memory integrity.

Closed-Loop Interruption of Hippocampal Ripples through Fornix Stimulation in the Non-Human Primate.

BACKGROUND: Hippocampal sharp-wave ripples (SWRs) arising from synchronous bursting in CA3 pyramidal cells and propagating to CA1 are thought to facilitate memory consolidation. Stimulation of the CA3 axon collaterals comprising the hippocampal commissure in rats interrupts sharp-wave ripples and leads to memory impairment. In primates, however, these commissural collaterals are limited. Other hippocampal fiber pathways, like the fornix, may be potential targets for modulating ongoing hippocampal activity, with the short latencies necessary to interrupt ripples. OBJECTIVE: The aim of this study is to determine the efficacy of closed-loop stimulation adjacent to the fornix for interrupting hippocampal ripples. METHOD: Stimulating electrodes were implanted bilaterally alongside the fornix in the macaque, together with microelectrodes targeting the hippocampus for recording SWRs. We first verified that fornix stimulation reliably and selectively evoked a response in the hippocampus. We then implemented online detection and stimulation as hippocampal ripples occurred. RESULTS: The closed-loop interruption method was effective in interrupting ripples as well as the associated hippocampal multi-unit activity, demonstrating the feasibility of ripple interruption using fornix stimulation in primates. CONCLUSION: Analogous to murine research, such an approach will likely be useful in understanding the role of SWRs in memory formation in macaques and other primates sharing these pathways, such as humans. More generally, closed-loop stimulation of the fornix may prove effective in interrogating hippocampal-dependent memory processes. Finally, this rapid, contingent-DBS approach may be a means for modifying pathological high-frequency events within the hippocampus, and potentially throughout the extended hippocampal circuit.

Sharp Wave Ripples during Visual Exploration in the Primate Hippocampus.

Hippocampal sharp-wave ripples (SWRs) are highly synchronous oscillatory field potentials that are thought to facilitate memory consolidation. SWRs typically occur during quiescent states, when neural activity reflecting recent experience is replayed. In rodents, SWRs also occur during brief locomotor pauses in maze exploration, where they appear to support learning during experience. In this study, we detected SWRs that occurred during quiescent states, but also during goal-directed visual exploration in nonhuman primates (Macaca mulatta). The exploratory SWRs showed peak frequency bands similar to those of quiescent SWRs, and both types were inhibited at the onset of their respective behavioral epochs. In apparent contrast to rodent SWRs, these exploratory SWRs occurred during active periods of exploration, e.g., while animals searched for a target object in a scene. SWRs were associated with smaller saccades and longer fixations. Also, when they coincided with target-object fixations during search, detection was more likely than when these events were decoupled. Although we observed high gamma-band field potentials of similar frequency to SWRs, only the SWRs accompanied greater spiking synchrony in neural populations. These results reveal that SWRs are not limited to off-line states as conventionally defined; rather, they occur during active and informative performance windows. The exploratory SWR in primates is an infrequent occurrence associated with active, attentive performance, which may indicate a new, extended role of SWRs during exploration in primates. SIGNIFICANCE STATEMENT: Sharp-wave ripples (SWRs) are high-frequency oscillations that generate highly synchronized activity in neural populations. Their prevalence in sleep and quiet wakefulness, and the memory deficits that result from their interruption, suggest that SWRs contribute to memory consolidation during rest. Here, we report that SWRs from the monkey hippocampus occur not only during behavioral inactivity but also during successful visual exploration. SWRs were associated with attentive, focal search and appeared to enhance perception of locations viewed around the time of their occurrence. SWRs occurring in rest are noteworthy for their relation to heightened neural population activity, temporally precise and widespread synchronization, and memory consolidation; therefore, the SWRs reported here may have a similar effect on neural populations, even as experiences unfold.

Decoupling the actions of the eyes from the hand alters beta and gamma synchrony within SPL.

Eye-hand coordination is crucial for our ability to interact with the world around us. However, much of the visually guided reaches that we perform require a spatial decoupling between gaze direction and hand orientation. These complex decoupled reaching movements are in contrast to more standard eye and hand reaching movements in which the eyes and the hand are coupled. The superior parietal lobule (SPL) receives converging eye and hand signals; however, what is yet to be understood is how the activity within this region is modulated during decoupled eye and hand reaches. To address this, we recorded local field potentials within SPL from two rhesus macaques during coupled vs. decoupled eye and hand movements. Overall we observed a distinct separation in synchrony within the lower 10- to 20-Hz beta range from that in the higher 30- to 40-Hz gamma range. Specifically, within the early planning phase, beta synchrony dominated; however, the onset of this sustained beta oscillation occurred later during eye-hand decoupled vs. coupled reaches. As the task progressed, there was a switch to low-frequency and gamma-dominated responses, specifically for decoupled reaches. More importantly, we observed local field potential activity to be a stronger task (coupled vs. decoupled) and state (planning vs. execution) predictor than that of single units alone. Our results provide further insight into the computations of SPL for visuomotor transformations and highlight the necessity of accounting for the decoupled eye-hand nature of a motor task when interpreting movement control research data.

Saccades during visual exploration align hippocampal 3-8 Hz rhythms in human and non-human primates.

Visual exploration in primates depends on saccadic eye movements (SEMs) that cause alternations of neural suppression and enhancement. This modulation extends beyond retinotopic areas, and is thought to facilitate perception; yet saccades may also influence brain regions critical for forming memories of these exploratory episodes. The hippocampus, for example, shows oscillatory activity that is generally associated with encoding of information. Whether or how hippocampal oscillations are influenced by eye movements is unknown. We recorded the neural activity in the human and macaque hippocampus during visual scene search. Across species, SEMs were associated with a time-limited alignment of a low-frequency (3-8 Hz) rhythm. The phase alignment depended on the task and not only on eye movements per se, and the frequency band was not a direct consequence of saccade rate. Hippocampal theta-frequency oscillations are produced by other mammals during repetitive exploratory behaviors, including whisking, sniffing, echolocation, and locomotion. The present results may reflect a similar yet distinct primate homologue supporting active perception during exploration.

Differences in spectral profiles between rostral and caudal premotor cortex when hand-eye actions are decoupled.

The aim of this research was to understand how the brain controls voluntary movement when not directly interacting with the object of interest. In the present study, we examined the role of premotor cortex in this behavior. The goal of this study was to characterize the oscillatory activity within the caudal and rostral subdivisions of dorsal premotor cortex (PMdc and PMdr) with a change from the most basic reaching movement to one that involves a simple dissociation between the actions of the eyes and hand. We were specifically interested in how PMdr and PMdc respond when the eyes and hand are decoupled by moving along different spatial planes. We recorded single-unit activity and local field potentials within PMdr and PMdc from two rhesus macaques during performance of two types of visually guided reaches. During the standard condition, a visually guided reach was performed whereby the visual stimulus guiding the movement was the target of the reach itself. During the nonstandard condition, the visual stimulus provided information about the direction of the required movement but was not the target of the motor output. We observed distinct task-related and topographical differences between PMdr and PMdc. Our results support functional differences between PMdr and PMdc during visually guided reaching. PMdr activity appears more involved in integrating the rule-based aspects of a visually guided reach, whereas PMdc is more involved in the online updating of the decoupled reach. More broadly, our results highlight the necessity of accounting for the nonstandard nature of a motor task when interpreting movement control research data.