Value dynamics affect choice preparation during decision-making.

During decision-making, neurons in the orbitofrontal cortex (OFC) sequentially represent the value of each option in turn, but it is unclear how these dynamics are translated into a choice response. One brain region that may be implicated in this process is the anterior cingulate cortex (ACC), which strongly connects with OFC and contains many neurons that encode the choice response. We investigated how OFC value signals interacted with ACC neurons encoding the choice response by performing simultaneous high-channel count recordings from the two areas in nonhuman primates. ACC neurons encoding the choice response steadily increased their firing rate throughout the decision-making process, peaking shortly before the time of the choice response. Furthermore, the value dynamics in OFC affected ACC ramping-when OFC represented the more valuable option, ACC ramping accelerated. Because OFC tended to represent the more valuable option more frequently and for a longer duration, this interaction could explain how ACC selects the more valuable response.

Fast and slow contributions to decision-making in corticostriatal circuits.

We make complex decisions using both fast judgments and slower, more deliberative reasoning. For example, during value-based decision-making, animals make rapid value-guided orienting eye movements after stimulus presentation that bias the upcoming decision. The neural mechanisms underlying these processes remain unclear. To address this, we recorded from the caudate nucleus and orbitofrontal cortex while animals made value-guided decisions. Using population-level decoding, we found a rapid, phasic signal in caudate that predicted the choice response and closely aligned with animals' initial orienting eye movements. In contrast, the dynamics in orbitofrontal cortex were more consistent with a deliberative system serially representing the value of each available option. The phasic caudate value signal and the deliberative orbitofrontal value signal were largely independent from each other, consistent with value-guided orienting and value-guided decision-making being independent processes.

Taking stock of value in the orbitofrontal cortex.

People with damage to the orbitofrontal cortex (OFC) have specific problems making decisions, whereas their other cognitive functions are spared. Neurophysiological studies have shown that OFC neurons fire in proportion to the value of anticipated outcomes. Thus, a central role of the OFC is to guide optimal decision-making by signalling values associated with different choices. Until recently, this view of OFC function dominated the field. New data, however, suggest that the OFC may have a much broader role in cognition by representing cognitive maps that can be used to guide behaviour and that value is just one of many variables that are important for behavioural control. In this Review, we critically evaluate these two alternative accounts of OFC function and examine how they might be reconciled.

Hippocampal neurons construct a map of an abstract value space.

The hippocampus is thought to encode a "cognitive map," a structural organization of knowledge about relationships in the world. Place cells, spatially selective hippocampal neurons that have been extensively studied in rodents, are one component of this map, describing the relative position of environmental features. However, whether this map extends to abstract, cognitive information remains unknown. Using the relative reward value of cues to define continuous "paths" through an abstract value space, we show that single neurons in primate hippocampus encode this space through value place fields, much like a rodent's place neurons encode paths through physical space. Value place fields remapped when cues changed but also became increasingly correlated across contexts, allowing maps to become generalized. Our findings help explain the critical contribution of the hippocampus to value-based decision-making, providing a mechanism by which knowledge of relationships in the world can be incorporated into reward predictions for guiding decisions.

Closed-Loop Theta Stimulation in the Orbitofrontal Cortex Prevents Reward-Based Learning.

Neuronal oscillations in the frontal cortex have been hypothesized to play a role in the organization of high-level cognition. Within the orbitofrontal cortex (OFC), there is a prominent oscillation in the theta frequency (4-8 Hz) during reward-guided behavior, but it is unclear whether this oscillation has causal significance. One methodological challenge is that it is difficult to manipulate theta without affecting other neural signals, such as single-neuron firing rates. A potential solution is to use closed-loop control to record theta in real time and use this signal to control the application of electrical microstimulation to the OFC. Using this method, we show that theta oscillations in the OFC are critically important for reward-guided learning and that they are driven by theta oscillations in the hippocampus (HPC). The ability to disrupt OFC computations via spatially localized and temporally precise stimulation could lead to novel treatment strategies for neuropsychiatric disorders involving OFC dysfunction.

A model-based approach for targeted neurophysiology in the behaving non-human primate.

Acute neurophysiology in the behaving primate typically relies on traditional manufacturing approaches for the instrumentation necessary for recording. For example, our previous approach consisted of distributing single microelectrodes in a fixed plane situated over a circular patch of frontal cortex using conventionally-milled recording grids. With the advent of robust, multisite linear probes, and the introduction of commercially-available, high-resolution rapid prototyping systems, we have been able to improve upon traditional approaches. Here, we report our methodology for producing flexible, MR-informed recording platforms that allow us to precisely target brain structures of interest, including those that would be unreachable using previous methods. We have increased our single-session recording yields by an order of magnitude and recorded neural activity from widely-distributed regions using only a single recording chamber. This approach both speeds data collection, reduces the damage done to neural tissue over the course of a single experiment, and reduces the number of surgical procedures experienced by the animal.

Restoration of Hindlimb Movements after Complete Spinal Cord Injury Using Brain-Controlled Functional Electrical Stimulation.

Single neuron and local field potential signals recorded in the primary motor cortex have been repeatedly demonstrated as viable control signals for multi-degree-of-freedom actuators. Although the primary source of these signals has been fore/upper limb motor regions, recent evidence suggests that neural adaptation underlying neuroprosthetic control is generalizable across cortex, including hindlimb sensorimotor cortex. Here, adult rats underwent a longitudinal study that included a hindlimb pedal press task in response to cues for specific durations, followed by brain machine interface (BMI) tasks in healthy rats, after rats received a complete spinal transection and after the BMI signal controls epidural stimulation (BMI-FES). Over the course of the transition from learned behavior to BMI task, fewer neurons were responsive after the cue, the proportion of neurons selective for press duration increased and these neurons carried more information. After a complete, mid-thoracic spinal lesion that completely severed both ascending and descending connections to the lower limbs, there was a reduction in task-responsive neurons followed by a reacquisition of task selectivity in recorded populations. This occurred due to a change in pattern of neuronal responses not simple changes in firing rate. Finally, during BMI-FES, additional information about the intended press duration was produced. This information was not dependent on the stimulation, which was the same for short and long duration presses during the early phase of stimulation, but instead was likely due to sensory feedback to sensorimotor cortex in response to movement along the trunk during the restored pedal press. This post-cue signal could be used as an error signal in a continuous decoder providing information about the position of the limb to optimally control a neuroprosthetic device.

Interactive Effects Between Exercise and Serotonergic Pharmacotherapy on Cortical Reorganization After Spinal Cord Injury.

BACKGROUND: In rat models of spinal cord injury, at least 3 different strategies can be used to promote long-term cortical reorganization: (1) active exercise above the level of the lesion; (2) passive exercise below the level of the lesion; and (3) serotonergic pharmacotherapy. Whether and how these potential therapeutic strategies-and their underlying mechanisms of action-interact remains unknown. Methods In spinally transected adult rats, we compared the effects of active exercise above the level of the lesion (treadmill), passive exercise below the level of the lesion (bike), serotonergic pharmacotherapy (quipazine), and combinations of the above therapies (bike+quipazine, treadmill+quipazine, bike+treadmill+quipazine) on long-term cortical reorganization (9 weeks after the spinal transection). Cortical reorganization was measured as the percentage of cells recorded in the deafferented hindlimb cortex that responded to tactile stimulation of the contralateral forelimb. Results Bike and quipazine are "competing" therapies for cortical reorganization, in the sense that quipazine limits the cortical reorganization induced by bike, whereas treadmill and quipazine are "collaborative" therapies, in the sense that the reorganization induced by quipazine combined with treadmill is greater than the reorganization induced by either quipazine or treadmill. CONCLUSIONS: These results uncover the interactive effects between active/passive exercise and serotonergic pharmacotherapy on cortical reorganization after spinal cord injury, emphasizing the importance of understanding the effects of therapeutic strategies in spinal cord injury (and in other forms of deafferentation) from an integrated system-level approach.

Dissociating movement from movement timing in the rat primary motor cortex.

Neural encoding of the passage of time to produce temporally precise movements remains an open question. Neurons in several brain regions across different experimental contexts encode estimates of temporal intervals by scaling their activity in proportion to the interval duration. In motor cortex the degree to which this scaled activity relies upon afferent feedback and is guided by motor output remains unclear. Using a neural reward paradigm to dissociate neural activity from motor output before and after complete spinal transection, we show that temporally scaled activity occurs in the rat hindlimb motor cortex in the absence of motor output and after transection. Context-dependent changes in the encoding are plastic, reversible, and re-established following injury. Therefore, in the absence of motor output and despite a loss of afferent feedback, thought necessary for timed movements, the rat motor cortex displays scaled activity during a broad range of temporally demanding tasks similar to that identified in other brain regions.

Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization.

Physical exercise promotes neural plasticity in the brain of healthy subjects and modulates pathophysiological neural plasticity after sensorimotor loss, but the mechanisms of this action are not fully understood. After spinal cord injury, cortical reorganization can be maximized by exercising the non-affected body or the residual functions of the affected body. However, exercise per se also produces systemic changes - such as increased cardiovascular fitness, improved circulation and neuroendocrine changes - that have a great impact on brain function and plasticity. It is therefore possible that passive exercise therapies typically applied below the level of the lesion in patients with spinal cord injury could put the brain in a more plastic state and promote cortical reorganization. To directly test this hypothesis, we applied passive hindlimb bike exercise after complete thoracic transection of the spinal cord in adult rats. Using western blot analysis, we found that the level of proteins associated with plasticity - specifically ADCY1 and BDNF - increased in the somatosensory cortex of transected animals that received passive bike exercise compared to transected animals that received sham exercise. Using electrophysiological techniques, we then verified that neurons in the deafferented hindlimb cortex increased their responsiveness to tactile stimuli delivered to the forelimb in transected animals that received passive bike exercise compared to transected animals that received sham exercise. Passive exercise below the level of the lesion, therefore, promotes cortical reorganization after spinal cord injury, uncovering a brain-body interaction that does not rely on intact sensorimotor pathways connecting the exercised body parts and the brain.

Serotonergic pharmacotherapy promotes cortical reorganization after spinal cord injury.

Cortical reorganization plays a significant role in recovery of function after injury of the central nervous system. The neural mechanisms that underlie this reorganization may be the same as those normally responsible for skilled behaviors that accompany extended sensory experience and, if better understood, could provide a basis for further promoting recovery of function after injury. The work presented here extends studies of spontaneous cortical reorganization after spinal cord injury to the role of rehabilitative strategies on cortical reorganization. We use a complete spinal transection model to focus on cortical reorganization in response to serotonergic (5-HT) pharmacotherapy without any confounding effects from spared fibers left after partial lesions. 5-HT pharmacotherapy has previously been shown to improve behavioral outcome after SCI but the effect on cortical organization is unknown. After a complete spinal transection in the adult rat, 5-HT pharmacotherapy produced more reorganization in the sensorimotor cortex than would be expected by transection alone. This reorganization was dose dependent, extended into intact (forelimb) motor cortex, and, at least in the hindlimb sensorimotor cortex, followed a somatotopic arrangement. Animals with the greatest behavioral outcome showed the greatest extent of cortical reorganization suggesting that the reorganization is likely to be in response to both direct effects of 5-HT on cortical circuits and indirect effects in response to the behavioral improvement below the level of the lesion.

Encoding of temporal intervals in the rat hindlimb sensorimotor cortex.

The gradual buildup of neural activity over experimentally imposed delay periods, termed climbing activity, is well documented and is a potential mechanism by which interval time is encoded by distributed cortico-thalamico-striatal networks in the brain. Additionally, when multiple delay periods are incorporated, this activity has been shown to scale its rate of climbing proportional to the delay period. However, it remains unclear whether these patterns of activity occur within areas of motor cortex dedicated to hindlimb movement. Moreover, the effects of behavioral training (e.g., motor tasks) under different reward conditions but with similar behavioral output are not well addressed. To address this, we recorded activity from the hindlimb sensorimotor cortex (HLSMC) of two groups of rats performing a skilled hindlimb press task. In one group, rats were trained only to a make a valid press within a finite window after cue presentation for reward (non-interval trained, nIT; n = 5), while rats in the second group were given duration-specific cues in which they had to make presses of either short or long duration to receive reward (interval trained, IT; n = 6). Using perievent time histogram (PETH) analyses, we show that cells recorded from both groups showed climbing activity during the task in similar proportions (35% IT and 47% nIT), however, only climbing activity from IT rats was temporally scaled to press duration. Furthermore, using single trial decoding techniques (Wiener filter), we show that press duration can be inferred using climbing activity from IT animals (R = 0.61) significantly better than nIT animals (R = 0.507, p < 0.01), suggesting IT animals encode press duration through temporally scaled climbing activity. Thus, if temporal intervals are behaviorally relevant then the activity of climbing neurons is temporally scaled to encode the passage of time.

Controlled unilateral isometric force generated by epidural spinal cord stimulation in the rat hindlimb.

Epidural electrical stimulation (EES) has often been used to restore stereotypic locomotor movements after spinal cord injury (SCI). However, restoring freeform movement requires specific force generation and independently controlled limbs for changing environments. Therefore, a second stimulus location would be advantageous, controlling force separately from locomotor movements. In normal and transected rats treated with mineral oil or saline, EES was performed at L1-L6 vertebral levels, caudal to spinal segments typical for locomotion, identifying secondary sites capable of activating hindlimb musculature, producing unilateral force at the paw. Threshold for generating force was identified and stimulation amplitude and duration varied to assess effects on evoked forces. Stimulation at L2 and L3 vertebral levels elicited negative vertical forces from extensor musculature while stimulation at L4 and L5 elicited positive vertical forces from flexion musculature. Thresholds were unchanged with transection or hydration method. Peak force magnitude was significantly correlated to stimulus amplitude, and response duration significantly correlated to stimulus duration in all animals. No differences were found in correlation coefficients or slopes of the regression for force or duration analyses with spinal condition or hydration method. This model demonstrates the ability to induce controlled forces with EES after SCI.

Skilled hindlimb reaching task in rats as a platform for a brain-machine interface to restore motor function after complete spinal cord injury.

Behavioral tasks utilized as models for decoding neural activity for use in brain-machine interfaces are constrained primarily to forelimb tasks or locomotion. We present here our methodology for training adult rats in a novel skilled hindlimb 'reaching' task in which the animal is trained to make different types of hindlimb movements. 6 adult Long-Evans rats were trained to make variable duration (<1 or >1.5 s) hindlimb presses cued by a spatially-independent visual cue. 5 of 6 animals (83.3%) were able to learn the task to proficiency. The training paradigm introduced here serves as a platform to investigate the ability of the animal to transfer motor cortical activity in response to a cue originally generated during normal movments, to a novel context in the absecense of movement and ultimately after complete mid-thoracic spinal cord transection. We also present preliminary results of offline classification of neural activity during trial performance for two trained animals.