Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials.

Every institution that is involved in research with animals is expected to have in place policies and procedures for the management of allegations of noncompliance with the Animal Welfare Act and the U.S. Public Health Service Policy on the Humane Care and Use of Laboratory Animals. We present here a model set of recommendations for institutional animal care and use committees and institutional officials to ensure appropriate consideration of allegations of noncompliance with federal Animal Welfare Act regulations that carry a significant risk or specific threat to animal welfare. This guidance has 3 overarching aims: 1) protecting the welfare of research animals; 2) according fair treatment and due process to an individual accused of noncompliance; and 3) ensuring compliance with federal regulations. Through this guidance, the present work seeks to advance the cause of scientific integrity, animal welfare, and the public trust while recognizing and supporting the critical importance of animal research for the betterment of the health of both humans and animals.-Hansen, B. C., Gografe, S., Pritt, S., Jen, K.-L. C., McWhirter, C. A., Barman, S. M., Comuzzie, A., Greene, M., McNulty, J. A., Michele, D. E., Moaddab, N., Nelson, R. J., Norris, K., Uray, K. D., Banks, R., Westlund, K. N., Yates, B. J., Silverman, J., Hansen, K. D., Redman, B. Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials.

Monkey primary somatosensory cortical activity during the early reaction time period differs with cues that guide movements.

Vibration-related neurons in monkey primary somatosensory cortex (SI) discharge rhythmically when vibratory stimuli are presented. It remains unclear how functional information carried by vibratory inputs is coded in rhythmic neuronal activity. In the present study, we compared neuronal activity during wrist movements in response to two sets of cues. In the first, movements were guided by vibratory cue only (VIB trials). In the second, movements were guided by simultaneous presentation of both vibratory and visual cues (COM trials). SI neurons were recorded extracellularly during both wrist extensions and flexions. Neuronal activity during the instructed delay period (IDP) and the early reaction time period (RTP) were analyzed. A total of 96 cases from 48 neurons (each neuron contributed two cases, one each for extension and flexion) showed significant vibration entrainment during the early RTPs, as determined by circular statistics (Rayleigh test). Of these, 50 cases had cutaneous (CUTA) and 46 had deep (DEEP) receptive fields. The CUTA neurons showed lower firing rates during the IDPs and greater firing rate changes during the early RTPs when compared with the DEEP neurons. The CUTA neurons also demonstrated decreases in activity entrainment during VIB trials when compared with COM trials. For the DEEP neurons, the difference of entrainment between VIB and COM trials was not statistically significant. The results suggest that somatic vibratory input is coded by both the firing rate and the activity entrainment of the CUTA neurons in SI. The results also suggest that when vibratory inputs are required for successful task completion, the activity of the CUTA neurons increases but the entrainment degrades. The DEEP neurons may be tuned before movement initiation for processing information encoded by proprioceptive afferents.

Detecting neuronal activity changes using an interspike interval algorithm compared with using visual inspection.

A universally accepted method for efficiently detecting neuronal activity changes (NACs) in neurophysiological studies has not been established. Visual inspection is still considered to be one of the most reliable methods, although it is limited when it is used for analyzing large quantities of data. In this study, an algorithm that considers interspike intervals (ISIs) was developed to define the onset of NACs. Two criteria, involving the mean and the standard deviation (S.D.) of the ISIs during a control period, were used in the ISI algorithm to evaluate the NACs that occurred during a detection period. The first, an ISI decrease of more than 1 S.D. from the mean ISI of the control period, proved to be an effective criterion for qualifying the increased NACs (firing rate increases). The second, an ISI increase greater than 3 S.D.s, efficiently demarcated periods of decreased NACs (firing rate decreases). Statistically significant correlations between the detection of NAC onset times by the ISI algorithm and the detection of those times by visual inspections were observed after offline analyses of recorded neuronal activity. The present results suggest that this ISI algorithm is a reliable and efficient way of defining the onset of NACs.

Neostriatal Neuronal Activity Correlates Better with Movement Kinematics under Certain Rewards.

This study investigated how the activity of neostriatal neurons is related to the kinematics of movement when monkeys performed visually and vibratory cued wrist extensions and flexions. Single-unit recordings of 142/236 neostriatal neurons showed pre-movement activity (PMA) in a reaction time task with unpredictable reward. Monkeys were pseudo-randomly (75%) rewarded for correct performance. A regression model was used to determine whether the correlation between neostriatal neuronal activity and the kinematic variables (position, velocity, and acceleration) of wrist movement changes as a function of reward contingency, sensory cues, and movement direction. The coefficients of determination (CoD) representing the proportion of the variance in neuronal activity explained by the regression model on a trial by trial basis, together with their temporal occurrences (time of best regression/correlation, ToC) were compared across sensory modality, movement direction, and reward contingency. The best relationship (correlation) between neuronal activity and movement kinematic variables, given by the average coefficient of determination (CoD), was: (a) greater during trials in which rewards were certain, called "A" trials, as compared with those in which reward was uncertain called ("R") trials, (b) greater during flexion (Flex) trials as compared with extension (Ext) trials, and (c) greater during visual (VIS) cued trials than during vibratory (VIB) cued trials, for the same type of trial and the same movement direction. These results are consistent with the hypothesis that predictability of reward for correct performance is accompanied by faster linkage between neostriatal PMA and the vigor of wrist movement kinematics. Furthermore, the results provide valuable insights for building an upper-limb neuroprosthesis.

Enrichment and nonhuman primates: "first, do no harm".

Since the 1998 publication of The Psychological Well-Being of Nonhuman Primates by the National Research Council, and the 1991 implementation of the 1985 Animal Welfare Act Amendment, many formal and informal nonhuman primate enrichment programs have been put into practice. Reports of their successes and failures, however, are few. All programs have at least two things in common: (1) They are best when designed and maintained by teams of individuals with species-specific expertise; (2) the members of those teams, the stakeholders, usually include principal investigators, animal care and use committee members, veterinarians, and animal care staff. Discussions in this article address general principles about enrichment, goals of such programs from the perspective of each of the major stakeholders, and recently published sources of related information. These discussions follow the central premise that enrichment should benefit all involved and "First, do no harm."

Motor Planning under Unpredictable Reward: Modulations of Movement Vigor and Primate Striatum Activity.

Although reward probability is an important factor that shapes animal's behavior, it is not well understood how the brain translates reward expectation into the vigor of movement [reaction time (RT) and speed]. To address this question, we trained two monkeys in a RT task that required wrist movements in response to vibrotactile and visual stimuli, with a variable reward schedule. Correct performance was rewarded in 75% of the trials. Monkeys were certain that they would be rewarded only in the trials immediately following withheld rewards. In these trials, the animals responded sooner and moved faster. Single-unit recordings from the dorsal striatum revealed modulations in neural firing that reflected changes in movement vigor. First, in the trials with certain rewards, striatal neurons modulated their firing rates earlier. Second, magnitudes of changes in neuronal firing rates depended on whether or not monkeys were certain about the reward. Third, these modulations depended on the sensory modality of the cue (visual vs. vibratory) and/or movement direction (flexions vs. extensions). We conclude that dorsal striatum may be a part of the mechanism responsible for the modulation of movement vigor in response to changes of reward predictability.

Neuronal activity in monkey primary somatosensory cortex is related to expectation of somatosensory and visual go-cues.

The present study was to investigate whether neuronal activity in primary somatosensory cortical areas (SI) differs when monkeys expect go-cues of different sensory modalities. Two monkeys made wrist extensions and flexions after steadily holding wrist at a center position. Movements were guided by increases in vibration to the monkey's palm (VIB), visual targets (VIS), or both in combination (COM). Neuronal activity recorded in SI during the early and late phases (i.e., the first and last 250 ms) of the instructed delay periods (IDP) were analyzed. Of 406 neurons recorded during all three paradigms, 263 (64.8%) showed significant changes in firing rates (FR) between the early and late IDP phases during either VIB or VIS trials and were selected for further analyses. The selected neurons were classified as VIB- or VIS-biased, depending on the paradigm (VIB or VIS) in which the greater FR changes occurred. Both increases and decreases in FRs were observed during the analyzed epochs. Most VIB-biased neurons showed the biggest FR changes during VIB trials and the least during VIS trials. Conversely, most VIS-biased neurons had the biggest FR changes during VIS trials and the least during VIB trials. For both VIB- and VIS-biased neurons, however, the FR changes were intermediate during COM trials. These results suggest that SI neurons play an important role in initiating/executing wrist movements. Neurons involved in wrist movements showed biases to the modality of cueing signals. Most SI neurons were biased to only one sensory modality. The expectation-related FR changes suggest different involvement by SI in movement initiation when tasks are guided by vibratory and visual signals.

Neuronal activity in primary motor cortex differs when monkeys perform somatosensory and visually guided wrist movements.

This study was designed to investigate how activity patterns of primary motor cortical (MI) neurons change when monkeys perform the same movements guided by somatosensory and/or visual cues. Two adult male rhesus monkeys were trained to make wrist extensions and flexions after holding a steady position during an instructed delay period lasting 0.5-2.0 s. Monkeys held against a 0.07 Nm load that opposed flexion movements. Wrist movements were guided by vibratory cues (VIB-trials), visual cues (VIS-trials), or both in combination (COM-trials). Extracellular recordings of 188 MI neurons were made during all three paradigms. Individual neurons were counted twice, once for each movement direction, yielding 376 cases. All neurons had significant task-related activity (TRA) changes relative to delay period activity during at least one of the three paradigms. TRA was analyzed to determine if it was different as a function of the sensory cue(s) that initiated movement and that specified movement endpoints. Cases were grouped by whether the TRA changes were greater in VIB- or VIS-trials; this defined their "bias". One hundred and eighteen cases (31.4%) had greater TRA changes in VIB-trials (Vb-neurons), whereas 185 (49.2%) showed greater TRA changes in VIS-trials (Vs-neurons). The remaining 73 cases (19.4%) had similar TRA changes in VIB- and VIS-trials (Nb-neurons). For Vb- and Vs-neurons, earlier TRA onsets and greater TRA changes were observed in the trials for which these neurons were biased. During the COM-trials, the TRA was intermediate. During the trials for which the activity was not biased, the TRA was the least. For Nb-neurons, no significant TRA differences were observed across paradigms. TRA changes of MI neurons may represent movement planning-related inputs from other central, presumably cortical, sources as well as contribute to motor outflow from the cortex. These data suggest that Vb- and Vs-neurons are affected differently by somatosensory- and visually related central inputs, resulting in different TRAs, even for essentially identical movements. Such differences may depend not only on the type of sensory information that initiates movement but also whether that information specifies movement endpoints or might interfere with movement monitoring.