Neural activity during a simple reaching task in macaques is counter to gating and rebound in basal ganglia-thalamic communication.

Task-related activity in the ventral thalamus, a major target of basal ganglia output, is often assumed to be permitted or triggered by changes in basal ganglia activity through gating- or rebound-like mechanisms. To test those hypotheses, we sampled single-unit activity from connected basal ganglia output and thalamic nuclei (globus pallidus-internus [GPi] and ventrolateral anterior nucleus [VLa]) in monkeys performing a reaching task. Rate increases were the most common peri-movement change in both nuclei. Moreover, peri-movement changes generally began earlier in VLa than in GPi. Simultaneously recorded GPi-VLa pairs rarely showed short-time-scale spike-to-spike correlations or slow across-trials covariations, and both were equally positive and negative. Finally, spontaneous GPi bursts and pauses were both followed by small, slow reductions in VLa rate. These results appear incompatible with standard gating and rebound models. Still, gating or rebound may be possible in other physiological situations: simulations show how GPi-VLa communication can scale with GPi synchrony and GPi-to-VLa convergence, illuminating how synchrony of basal ganglia output during motor learning or in pathological conditions may render this pathway effective. Thus, in the healthy state, basal ganglia-thalamic communication during learned movement is more subtle than expected, with changes in firing rates possibly being dominated by a common external source.

Perturbation of Macaque Supplementary Motor Area Produces Context-Independent Changes in the Probability of Movement Initiation.

The contribution of the supplementary motor area (SMA) to movement initiation remains unclear. SMA exhibits premovement activity across a variety of contexts, including externally cued and self-initiated movements. Yet SMA lesions impair initiation primarily for self-initiated movements. Does SMA influence initiation across contexts or does it play a more specialized role, perhaps contributing only when initiation is less dependent on external cues? To address this question, we perturbed SMA activity via microstimulation at variable times before movement onset. Experiments used two adult male rhesus monkeys trained on a reaching task. We used three contexts that differed regarding how tightly movement initiation was linked to external cues. Movement kinematics were not altered by microstimulation. Instead, microstimulation induced a variety of changes in the timing of movement initiation, with different effects dominating for different contexts. Despite their diversity, these changes could be explained by a simple model where microstimulation has a stereotyped impact on the probability of initiation. Surprisingly, a unified model accounted for effects across all three contexts, regardless of whether initiation was determined more by external cues versus internal considerations. All effects were present for stimulation both contralateral and ipsilateral to the moving arm. Thus, the probability of initiating a pending movement is altered by perturbation of SMA activity. However, changes in initiation probability are independent of the balance of internal and external factors that establish the baseline initiation probability.SIGNIFICANCE STATEMENT The role of the supplementary motor area (SMA) in initiating movement remains unclear. Lesion experiments suggest that SMA makes a critical contribution only for self-initiated movements. Yet SMA is active before movements made under a range of contexts, suggesting a less-specialized role in movement initiation. Here, we use microstimulation to probe the role of SMA across a range of behavioral contexts that vary in the degree to which movement onset is influenced by external cues. We demonstrate that microstimulation produces a temporally stereotyped change in the probability of initiation that is independent of context. These results argue that SMA participates in the computations that lead to movement initiation and does so across a variety of contexts.

Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.

Axonal and synaptic failure suppress the transfer of firing rate oscillations, synchrony and information during high frequency deep brain stimulation.

High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian ß oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.

Identifying Interpretable Latent Factors with Sparse Component Analysis.

In many neural populations, the computationally relevant signals are posited to be a set of 'latent factors' - signals shared across many individual neurons. Understanding the relationship between neural activity and behavior requires the identification of factors that reflect distinct computational roles. Methods for identifying such factors typically require supervision, which can be suboptimal if one is unsure how (or whether) factors can be grouped into distinct, meaningful sets. Here, we introduce Sparse Component Analysis (SCA), an unsupervised method that identifies interpretable latent factors. SCA seeks factors that are sparse in time and occupy orthogonal dimensions. With these simple constraints, SCA facilitates surprisingly clear parcellations of neural activity across a range of behaviors. We applied SCA to motor cortex activity from reaching and cycling monkeys, single-trial imaging data from C. elegans, and activity from a multitask artificial network. SCA consistently identified sets of factors that were useful in describing network computations.

Large-scale high-density brain-wide neural recording in nonhuman primates.

High-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmatically select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.

Independent generation of sequence elements by motor cortex.

Rapid execution of motor sequences is believed to depend on fusing movement elements into cohesive units that are executed holistically. We sought to determine the contribution of primary motor and dorsal premotor cortex to this ability. Monkeys performed highly practiced two-reach sequences, interleaved with matched reaches performed alone or separated by a delay. We partitioned neural population activity into components pertaining to preparation, initiation and execution. The hypothesis that movement elements fuse makes specific predictions regarding all three forms of activity. We observed none of these predicted effects. Rapid two-reach sequences involved the same set of neural events as individual reaches but with preparation for the second reach occurring as the first was in flight. Thus, at the level of dorsal premotor and primary motor cortex, skillfully executing a rapid sequence depends not on fusing elements, but on the ability to perform two key processes at the same time.

Postural control of arm and fingers through integration of movement commands.

Every movement ends in a period of stillness. Current models assume that commands that hold the limb at a target location do not depend on the commands that moved the limb to that location. Here, we report a surprising relationship between movement and posture in primates: on a within-trial basis, the commands that hold the arm and finger at a target location depend on the mathematical integration of the commands that moved the limb to that location. Following damage to the corticospinal tract, both the move and hold period commands become more variable. However, the hold period commands retain their dependence on the integral of the move period commands. Thus, our data suggest that the postural controller possesses a feedforward module that uses move commands to calculate a component of hold commands. This computation may arise within an unknown subcortical system that integrates cortical commands to stabilize limb posture.

Moving an arm requires the brain to send electrical signals to the arm's muscles, causing them to contract. Neuroscientists call these types of brain signals "move signals". The brain also sends so-called hold signals, which hold the arm still in a desired position. Part of the brain known as the primary motor cortex helps to calculate the move signals for the arm, but it was unclear how the brain produces the corresponding hold signals. Fortunately, the fact that the brain moves other things besides arms may help answer this question. Previous research has shown, for example, that a brain area called the "neural integrator" calculates the hold signals needed to hold the eye in a specific position. The neural integrator does this by using basic principles of physics, and details of the speed and duration of the eye's movements. Now, Albert et al. show a similar mechanism appears to control hold signals for arm movements. In one set of experiments, muscle activity was measured as monkeys moved their arms or fingers to different target positions. In other experiments, human volunteers held a robot arm, and Albert et al. measured the forces they produced while reaching and holding still. Both the human and monkey experiments revealed a relationship between move signals and hold signals. Like for eye movements, hold signals for the arm could be calculated from the move signals. In further experiments with stroke patients where the brain had been damaged, the move signals were found to be deteriorated, but the way hold signals were calculated stayed the same. This suggests that there is an unknown structure within the brain that calculates hold signals based on move signals. Investigating how the brain holds the arm still may help scientists understand why some neurological conditions like stroke or dystonia cause unwanted movements or unusual postures. This might also lead scientists to develop new ways to treat these conditions.

Conservation of preparatory neural events in monkey motor cortex regardless of how movement is initiated.

A time-consuming preparatory stage is hypothesized to precede voluntary movement. A putative neural substrate of motor preparation occurs when a delay separates instruction and execution cues. When readiness is sustained during the delay, sustained neural activity is observed in motor and premotor areas. Yet whether delay-period activity reflects an essential preparatory stage is controversial. In particular, it has remained ambiguous whether delay-period-like activity appears before non-delayed movements. To overcome that ambiguity, we leveraged a recently developed analysis method that parses population responses into putatively preparatory and movement-related components. We examined cortical responses when reaches were initiated after an imposed delay, at a self-chosen time, or reactively with low latency and no delay. Putatively preparatory events were conserved across all contexts. Our findings support the hypothesis that an appropriate preparatory state is consistently achieved before movement onset. However, our results reveal that this process can consume surprisingly little time.

c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells: Implications for cystic fibrosis treatment.

CFTR is a PKA activated Cl(-) channel expressed in the apical membrane of fluid transporting epithelia. We previously demonstrated that c-Cbl decreases CFTR stability in the plasma membrane by facilitating its endocytosis and lysosomal degradation in human airway epithelium. The most common mutation associated with cystic fibrosis, deletion of Phe508 (∆F508), leads to a temperature sensitive biosynthetic processing defect in the CFTR protein. Mature ∆F508-CFTR that has been rescued by low temperature or chemical chaperones is partially functional as a Cl(-) channel but has decreased plasma membrane stability due to altered post-maturational trafficking. Our present data demonstrate that c-Cbl controls the post-maturational trafficking of rescued ∆F508-CFTR. Partial depletion of c-Cbl increased stability of the plasma membrane associated mature ∆F508-CFTR and the ∆F508-CFTR mediated Cl(-) secretion. These data indicate that correcting the post-maturational trafficking of ∆F508-CFTR may represent a therapeutic approach complementary to the biosynthetic rescue. Because c-Cbl functions as an adaptor and scaffolding protein during CFTR endocytosis, we propose that interfering with the c-Cbl mediated endocytic recruitment of ∆F508-CFTR may increase stability of ∆508-CFTR in the plasma membrane after its biosynthetic rescue.