Andrew R. Mitz

Learning-dependent neuronal activity in the premotor cortex: activity during the acquisition of conditional motor associations

It has been proposed that the premotor cortex plays a role in the selection of motor programs based on environmental context. To test this hypothesis, we recorded the activity of single neurons as monkeys learned visuomotor associations. The hypothesis predicts that task- related premotor cortical activity before learning should differ from that afterward. We found that a substantial population of premotor cortex neurons, over half of those adequately tested, showed the predicted learning-dependent changes in activity. The present findings support a role for premotor cortex in motor preparation, generally, and suggest a specific role in the selection of movements on the basis of arbitrary associations.

Changes in motor cortical activity during visuomotor adaptation

Abstract We examined neuronal activity in three motor cortical areas while a rhesus monkey adapted to novel visuomotor transforms. The monkey moved a joystick that controlled a cursor on a video screen. Each trial began with the joystick centered. Next, the cursor appeared in one of eight positions, arranged in a circle around a target stimulus at the center of the screen. To receive reinforcement, the monkey moved the joystick so that the cursor contacted the target continuously for 1s. The video monitor provided continuous visual feedback of both cursor and target position. With those elements of the task constant, we modified the transform between joystick movement and that of the cursor at the beginning of a block of trials. Neuronal activity was studied as the monkey adapted to these novel joystick-cursor transforms. Some novel tasks included spatial transforms such as single-axis inversions, asymmetric double-axis inversions and angular deviations (also known as rotations). Other tasks involved changes in the spatiotemporal pattern and magnitude of joystick movement. As the monkey adapted to various visuomotor tasks, 209 task-related neurons (selected for stable background activity) showed significant changes in their task-related activity: 88 neurons in the primary motor cortex (M1), 32 in the supplementary motor cortex (M2), and 89 in the caudal part of the dorsal premotor cortex (PMdc). Slightly more than half of the sample in each area showed significant changes in the magnitude of activity modulation during adaptation, with the number of increases approximately equaling the number of decreases. These data support the prediction that changes in task-related neuronal activity can be observed in M1 during motor adaptation, but fail to support the hypothesis that M1 and PMdc differ in this regard. When viewed in population averages, motor cortex continued to change its activity for at least dozens of trials after performance reached a plateau. This slow, apparently continuing change in the pattern and magnitude of task-related activity may reflect the initial phases of consolidating the motor memory for preparing and executing visuomotor skills.

Prefrontal Cortex Activity Related to Abstract Response Strategies

Many monkeys adopt abstract response strategies as they learn to map visual symbols to responses by trial and error. According to the repeat-stay strategy, if a symbol repeats from a previous, successful trial, the monkeys should stay with their most recent response choice. According to the change-shift strategy, if the symbol changes, the monkeys should shift to a different choice. We recorded the activity of prefrontal cortex neurons while monkeys chose responses according to these two strategies. Many neurons had activity selective for the strategy used. In a subsequent block of trials, the monkeys learned fixed stimulus-response mappings with the same stimuli. Some neurons had activity selective for choosing responses based on fixed mappings, others for choosing based on abstract strategies. These findings indicate that the prefrontal cortex contributes to the implementation of the abstract response strategies that monkeys use during trial-and-error learning.

A role for primate subgenual cingulate cortex in sustaining autonomic arousal.

Significance Dysregulation of emotion is central to the etiology of mood disorders, such as depression. A causal understanding of how neural structures regulate emotion and arousal could help to improve treatments for these psychiatric disorders. Studies of patients with depression indicate that a particular part of the frontal lobe, the subgenual cingulate cortex, plays an important role in affective processing, though its precise contribution remains unclear. Here we show that, in macaque monkeys, this small part of the frontal cortex is necessary for sustaining elevated arousal in anticipation of positive emotional events. This finding suggests a mechanism for the contribution of this area to affective regulation, including an account for the lack of pleasure and passivity that characterizes mood disorders. The subgenual anterior cingulate cortex (subgenual ACC) plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions. Using Pavlovian conditioning procedures in macaque monkeys, we examined the contribution of the subgenual ACC to autonomic arousal associated with positive emotional events. After such conditioning, autonomic arousal increases in response to cues that predict rewards, and monkeys maintain this heightened state of arousal during an interval before reward delivery. Here we show that although monkeys with lesions of the subgenual ACC show the initial, cue-evoked arousal, they fail to sustain a high level of arousal until the anticipated reward is delivered. Control procedures showed that this impairment did not result from differences in autonomic responses to reward delivery alone, an inability to learn the association between cues and rewards, or to alterations in the light reflex. Our data indicate that the subgenual ACC may contribute to positive affect by sustaining arousal in anticipation of positive emotional events. A failure to maintain positive affect for expected pleasurable events could provide insight into the pathophysiology of psychological disorders in which negative emotions dominate a patient’s affective experience.

Real-Time Dopamine Measurement in Awake Monkeys

Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation.

A liquid-delivery device that provides precise reward control for neurophysiological and behavioral experiments

Behavioral neurophysiology and other kinds of behavioral research often involve the delivery of liquid rewards to experimental subjects performing some kind of operant task. Available systems use gravity or pumps to deliver these fluids, but such methods are poorly suited to moment-to-moment control of the volume, timing, and type of fluid delivered. The design described here overcomes these limitations using an electronic control unit, a pressurized reservoir unit, and an electronically controlled solenoid. The control unit monitors reservoir pressure and provides precisely timed solenoid activation signals. It also stores calibration tables and does on-the-fly interpolation to support computer-controlled delivery calibrated directly in milliliters. The reservoir provides pressurized liquid to a solenoid mounted near the subject. Multiple solenoids, each supplied by a separate reservoir unit and control unit, can be stacked in close proximity to allow instantaneous selection of which liquid reward is delivered. The precision of droplet delivery was verified by weighing discharged droplets on a commercial analytical balance.

A method for recording single-cell activity in the frontal-pole cortex of macaque monkeys.

Neurophysiological research has explored most of the prefrontal cortex of macaque monkeys, but the relatively inaccessible frontal-pole cortex remains unexamined. Here we describe a method for gaining access to the frontal-pole cortex with moveable microelectrodes. The key innovation is a direct approach through the frontal air sinus. In addition, the small size of the frontal-pole cortex in macaques led to the design of a smaller recording chamber than typically used in behavioral neurophysiology. The method has proven successful in two subjects, with no adverse health consequences.

Video based analysis of standing balance in a community center

Postural sway is a well known measure of postural stability in the elderly. Sway measurements, however, are typically made using expensive equipment in a laboratory. We report on efforts to make clinically significant and quantitative measurements of postural sway in a community center with a single un-calibrated video camera. Results indicate that simple tracking technologies can capture some aspects of sway in a community center in a way that is perceptually accurate and capable of distinguishing expert-assigned levels of balance performance in an elderly, balance impaired cohort.

A new technique for measuring muscle fiber conduction velocities in full interference patterns

The motor unit potential shape, mainly its duration and frequency spectra, and the EMG IP crispiness and its frequency spectra are affected by the muscle fiber conduction velocities (MFCVs). Present techniques are somewhat deficient in that they are not adaptable to measure MFCVs continuously and intramuscularly in the presence of interference patterns, and to do so without interfering with the ongoing muscular activity. In this study a cross-correlation with averaging correlograms technique is presented. An EMG needle electrode, with two recording surfaces 1 cm apart, continuously record two channels of EMG activity which is analog-to-digital converted. Contiguous segments of the signals are cross-correlated, the evolved correlograms are averaged together, averaging-out the time-unlocked noise, and averaging-in a peak that represent the average time it takes the EMG signal to propagate from one recording surface to the other. From the distance between these two recording surfaces and the above calculated propagation time the MFCVs can be computed and monitored intramuscularly either in weak or in strong, in isometric or isotonic contractions. But for the fact that a needle is introduced, there is no interference with the muscle electrical activity. It is expected that this technique may add to EMG diagnosis of neuromuscular disorders, will be used to monitor muscular fatigue and applied in normalizing EMG spectra, conditioning them for a better use in diagnostic electromyography.

MatOFF: a tool for analyzing behaviorally complex neurophysiological experiments.

The simple operant conditioning originally used in behavioral neurophysiology 30 years ago has given way to complex and sophisticated behavioral paradigms; so much so, that early general purpose programs for analyzing neurophysiological data are ill-suited for complex experiments. The trend has been to develop custom software for each class of experiment, but custom software can have serious drawbacks. We describe here a general purpose software tool for behavioral and electrophysiological studies, called MatOFF, that is especially suited for processing neurophysiological data gathered during the execution of complex behaviors. Written in the MATLAB programming language, MatOFF solves the problem of handling complex analysis requirements in a unique and powerful way. While other neurophysiological programs are either a loose collection of tools or append MATLAB as a post-processing step, MatOFF is an integrated environment that supports MATLAB scripting within the event search engine safely isolated in a programming sandbox. The results from scripting are stored separately, but in parallel with the raw data, and thus available to all subsequent MatOFF analysis and display processing. An example from a recently published experiment shows how all the features of MatOFF work together to analyze complex experiments and mine neurophysiological data in efficient ways.