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Background: Vagus nerve stimulation (VNS) is regularly used to treat a variety of neurological disorders that impact the central nervous system (CNS). There are, however, few large animal models that allow for detailed mechanistic studies of the effects of VNS on the CNS during behavior. Methods: To that end, we describe the anatomical organization, surgical methodology to implant VNS electrodes and characterization of target engagement/neural interface properties in a non-human primate (NHP) model of VNS that permits chronic stimulation over long periods of time. Furthermore, we demonstrate the utility of this preparation in low n, proof of concept behavioral and imaging experiments investigating the effects of VNS on the CNS. Results: VNS electrode impedance remained constant over months suggesting a stable interface. VNS elicited robust activation of the vagus nerve which resulted in decreases of respiration rate and/or partial pressure of carbon dioxide in expired air, but not changes in heart rate in both awake and anesthetized NHPs. Conclusions: We anticipate that this preparation will be very useful to study the mechanisms underlying the effects of VNS for the treatment of conditions such as epilepsy and depression, for which VNS is extensively used, as well as for the study of the neurobiological basis underlying higher order functions such as learning and memory.

The gut immune system in the healthy intestine is anti‐inflammatory, but can move to a pro‐inflammatory state when the gut is challenged by pathogens or in disease. The nervous system influences the level of inflammation through enteric neurons and extrinsic neural connections, particularly vagal and sympathetic innervation of the gastrointestinal tract, each of which exerts anti‐inflammatory effects. Within the enteric nervous system (ENS), three neuron types that influence gut immune cells have been identified, intrinsic primary afferent neurons (IPANs), vasoactive intestinal peptide (VIP) neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers. The enteric neuropeptides, calcitonin gene‐related peptide (CGRP), tachykinins, and neuromedin U (NMU), which are contained in IPANs, and VIP produced by the mucosa innervating neurons, all influence immune cells, notably innate lymphoid cells (ILCs). ILC2 are stimulated by VIP to release IL‐22, which promotes microbial defense and tissue repair. Enteric neurons are innervated by the vagus, and, in the large intestine, by the pelvic nerves. Vagal nerve stimulation reduces gut inflammation, which may be both by stimulation of efferent (motor) pathways to the ENS, and stimulation of afferent pathways that connect to integrating centers in the CNS. Efferent pathways from the CNS have their anti‐inflammatory effects through either or both vagal efferent neurons and sympathetic pathways. The final neurons in sympathetic pathways reduce gut inflammation by the action of noradrenaline on β2 adrenergic receptors expressed by immune cells. Activation of neural anti‐inflammatory pathways is an attractive option to treat inflammatory bowel disease that is refractory to other treatments. Further investigation of the ways in which enteric reflexes, vagal pathways and sympathetic pathways integrate their effects to modulate the gut immune system and gut inflammation is needed to optimize neuromodulation therapy.

The purpose of this study was to develop a non-invasive restraint helmet integrated with an radio frequency (RF) coil for awake-behaving non-human primate MR imaging. To prevent image-corrupting motion, the head needs to be immobilized, which is currently achieved via invasive surgical headpost implants. In this work, an RF coil holder was integrated into the design of a subject-specific helmet to place the coil in closest distance to the head for improved signal-to-noise ratio (SNR). Additive manufacturing was used to print the helmet based upon computed tomography images of the subject. A single channel transmit/receive loop coil was designed using electromagnetic simulations loaded with a voxel-based monkey head model. The Rhesus macaque used in this study underwent behavioral training based on positive reinforcement before engaging in MR imaging. Imaging was performed using the helmet coil, which was successful in immobilizing the macaque head in an awake, unanesthetized subject. Results showed improved SNR by approximately 30% compared to a loop coil used with an implanted head post, and minimal motion artifact in structural imaging. The non-invasive helmet coil eliminates the need for permanently implanting monkeys with a headpost, provides the necessary head immobilization, and allows the use of more subjects for neuroimaging studies.

This study is the physiological complement to previous behavioral work that demonstrated that rhesus monkeys are able to allocate attention about the surrounding space based on brief, broadband auditory cues. Single-unit recordings were taken from the intermediate layers of the superior colliculus (iSC) while the subjects oriented to visual and auditory targets in the context of a cuing task with their heads unrestrained. The results show a correlation between behavioral manifestations of attention allocation, attention capture and inhibition of return, and modulation of target-evoked responses in single iSC neurons. NEW & NOTEWORTHY These results show for the first time a neural correlate of attention capture and inhibition of return in response to auditory stimuli in the superior colliculus of the head-unrestrained monkey.

Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or ‘vagotopy’ that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

INTRODUCTION The spatial and temporal resolution limits of functional MRI (fMRI) brain mapping provide primarily correlative information on brain connectivity. Determining how one region causally modulates and mediates activity in other regions remains difficult with fMRI. We demonstrate a simple means to add causality in resting state functional connectivity MRI (rs-fcMRI) using techniques developed first for convection-enhanced delivery (CED) of therapeutics. Here we use CED to guide and monitor pharmacologic alteration of a local brain region in anaesthetized Rhesus monkeys while monitoring rs-fcMRI signal changes. METHODS Pre-surgical MRI was used to determine skull locations for craniotomies for installation of NavigusTMbrain ports in two untrained monkeys slated for euthanasia. The ports were aligned in real–time to provide trajectories aimed at the central nucleus of the amygdala (CeA). Fused silica catheters were then inserted into the CeA where 24 mg of muscimol (inhibitory agent) was infused in 24 ml of buffered solution under pressure over 12 minutes, first on the right side and then on the left side. rs-fcMRI studies were done for 45 minutes before and after the unilateral infusion and then after the bilateral infusion. RESULTS Catheters were successfully aligned and inserted into the CeA targets with sub-mm accuracy. T2-weighted imaging detected the enhanced T2 from the infusion’s buffer. Pre-infusion rs-fcMRI provides results consistent with prior studies, which have shown that the CeA is most strongly connected to the contralateral CeA. This connectivity was significantly reduced following both unilateral and bilateral injections of muscimol into the CeA, demonstrating the effectiveness of the muscimol infusions. Conditional Grainger Causality (CGC) analysis shows unexpected new connectivity after the unilateral infusion. Upon the bilateral infusion, global effective connectivity in the region is reduced. CONCLUSION Expected and unexpected changes in resting state functional connectivity resulted from unilateral and bilateral infusions of inhibitory agents.

RATIONALE: Low doses of psychostimulants such as methylphenidate (MPH), which increase extracellular dopamine and norepinephrine by inhibiting their reuptake, are the most commonly used treatment for Attention Deficit Hyperactivity Disorder (ADHD). Therapeutic doses of these drugs may improve focused attention at the expense of hindering other cognitive functions, including the ability to adapt behavior in response to changing circumstances - cognitive flexibility. Cognitive flexibility is thought to depend on proper operation of the prefrontal cortex (PFC) and is also linked to reward processing, which is dopamine-dependent. Additionally, reward outcome signals have been recorded from the PFC. OBJECTIVES: This study tested the hypothesis that therapeutic doses of MPH impair cognitive flexibility and that this impairment in performance resulted from interference in reward signals within the PFC. METHODS: Four rhesus monkeys were given therapeutically relevant doses of oral MPH (0, 3, and 6mg/kg) while performing an oculomotor switching task to evaluate its effect on task performance. Single unit recordings in the PFC of two monkeys were taken before and after MPH administration during task performance. RESULTS. The results show that MPH does hinder switching task performance, an effect that was correlated with a reduction in the amplitude of outcome signals found in the discharges of some neurons in the PFC. CONCLUSIONS: Methylphenidate impaired task switching performance, which can be used as a measure of cognitive flexibility. This detriment may result from degraded outcome signaling within the PFC. This study has implications for the use of MPH in the treatment of ADHD.

Dopamine (DA) levels in the striatum are increased by many therapeutic drugs, such as methylphenidate (MPH), which also alters behavioral and cognitive functions thought to be controlled by the PFC dose-dependently. We linked DA changes and functional connectivity (FC) using simultaneous [18F]fallypride PET and resting-state fMRI in awake male rhesus monkeys after oral administration of various doses of MPH. We found a negative correlation between [18F]fallypride nondisplaceable binding potential (BPND) and MPH dose in the head of the caudate (hCd), demonstrating increased extracellular DA resulting from MPH administration. The decreased BPNDwas negatively correlated with FC between the hCd and the PFC. Subsequent voxelwise analyses revealed negative correlations with FC between the hCd and the dorsolateral PFC, hippocampus, and precuneus. These results, showing that MPH-induced changes in DA levels in the hCd predict resting-state FC, shed light on a mechanism by which changes in striatal DA could influence function in the PFC.SIGNIFICANCE STATEMENTDopamine transmission is thought to play an essential role in shaping large scale-neural networks that underlie cognitive functions. It is the target of therapeutic drugs, such as methylphenidate (Ritalin), which blocks the dopamine transporter, thereby increasing extracellular dopamine levels. Methylphenidate is used extensively to treat attention deficit hyperactivity disorder, even though its effects on cognitive functions and their underlying neural mechanisms are not well understood. To date, little is known about the link between changes in dopamine levels and changes in functional brain organization. Using simultaneous PET/MR imaging, we show that methylphenidate-induced changes in endogenous dopamine levels in the head of the caudate predict changes in resting-state functional connectivity between this structure and the prefrontal cortex, precuneus, and hippocampus.

In non-human primate [NHP] neuroimaging, the head needs to be immobilized. This is currently achieved via surgical implants; however, this method is invasive with risks of medical complications and limits the number of subjects that can enroll in a study due to the long waiting time after surgery for the implant area to heal and high cost. The purpose of this study is to demonstrate a non-invasive, subject-specific, restraint helmet with an integrated MRI RF coil. This system removes the need for invasive head post implantation and can be designed and implemented quickly at a low cost. Low dose computed tomography (CT) images were processed to create a subject-specific restraint helmet and structure of an RF coil. The helmet coil was 3D-printed from polylactic acid (PLA) plastic. The measured S 11 of the fabricated coil is −32 dB indicating a good match at 127.8 MHz (the frequency corresponding to 3T MRI). Imaging was performed on a MR spherical phantom, and a high signal- to- noise ratio of 924 in the region of interest was measured.

Decisions are often made based on which option will result in the largest reward. When given a choice between a smaller but immediate reward and a larger delayed reward, however, humans and animals often choose the smaller, an effect known as temporal discounting. Dopamine (DA) neurotransmission is central to reward processing and encodes delayed reward value. Impulsivity, the tendency to act without forethought, is associated with excessive discounting of rewards, which has been documented in patients with attention deficit hyperactivity disorder (ADHD). Both impulsivity and temporal discounting are linked to the dopaminergic system. Methylphenidate (MPH), which blocks the DA transporter and increases extracellular levels of DA in the basal ganglia and prefrontal cortex, is a primary treatment for ADHD and, at low doses, ameliorates impulsivity in both humans and animals. This study tested the hypothesis that low doses of MPH would decrease the discounting rate of rhesus monkeys performing an intertemporal choice task, suggesting a reduction in impulsivity. The results support this hypothesis and provide further evidence for the role of DA in temporal discounting and impulsive behavior.

Low doses of methylphenidate reduce hyperactivity and improve attention in individuals with attention deficit hyperactivity disorder (ADHD) as well as in healthy humans and animals. Despite its extensive use, relatively little is known about its mechanisms of action. This study investigated the effects of methylphenidate on working memory performance, impulsivity, response accuracy and precision, and the ability to stay on task in rhesus monkeys using an oculomotor delayed response task. Methylphenidate affected task performance in an inverted-U manner in all three subjects tested. The improvements resulted from a reduction in premature responses and, importantly, not from improvement in the memory of target location. The length of time subjects participated in each session was also affected dose dependently. However, the dose at which the length of participation was maximally increased significantly impaired performance on the working memory task. This dissociation of effects has implications for the treatment of ADHD, for the nonprescription use of methylphenidate for cognitive enhancement, and for furthering the basic understanding of the neural substrate underlying these processes.

Spatial attention mediates the selection of information from different parts of space. When a brief cue is presented shortly before a target [cue to target onset asynchrony (CTOA)] in the same location, behavioral responses are facilitated, a process called attention capture. At longer CTOAs, responses to targets presented in the same location are inhibited; this is called inhibition of return (IOR). In the visual modality, these processes have been demonstrated in both humans and non-human primates, the latter allowing for the study of the underlying neural mechanisms. In audition, the effects of attention have only been shown in humans when the experimental task requires sound localization. Studies in monkeys with the use of similar cues but without a sound localization requirement have produced negative results. We have studied the effects of predictive acoustic cues on the latency of gaze shifts to visual and auditory targets in monkeys experienced in localizing sound sources in the laboratory with the head unrestrained. Both attention capture and IOR were demonstrated with acoustic cues, although with a faster time course than with visual cues. Additionally, the effect was observed across sensory modalities (acoustic cue to visual target), suggesting that the underlying neural mechanisms of these effects may be mediated within the superior colliculus, a center where inputs from both vision and audition converge.

Studies of sound localization in humans have used various behavioral measures to quantify the observers’ perceptions; a non-comprehensive list includes verbal reports, head pointing, gun pointing, stylus pointing, and laser aiming. Comparison of localization performance reveals that in humans, just as in animals, different results are obtained with different experimental tasks. Accordingly, to circumvent problems associated with task selection and training, this study used gaze, an ethologically valid behavior for spatial pointing in species with a specialized area of the fovea, to measure sound localization perception of human subjects. Orienting using gaze as a pointer does not require training, preserves the natural link between perception and action, and allows for direct behavioral comparisons across species. The results revealed, unexpectedly, a large degree of variability across subjects in both accuracy and precision. The magnitude of the average angular localization errors for the most eccentric horizontal targets, however, were very similar to those documented in studies that used head pointing, whereas the magnitude of the localization errors for the frontal targets were considerably larger. In addition, an overall improvement in sound localization in the context of the memory-saccade task, as well as a lack of effect of initial eye and head position on perceived sound location were documented.

The sound localization abilities of three rhesus monkeys were tested under head-restrained and head-unrestrained conditions. Operant conditioning and the magnetic search coil technique were used to measure eye and head movements to sound sources. Whereas the results support previous findings that monkeys localize sounds very poorly with their heads restrained, the data also reveal for the first time that monkeys localize sounds much more accurately and with less variability when their heads are allowed to move. Control experiments using acoustic stimuli known to produce spatial auditory illusions such as summing localization confirmed that the monkeys based their orienting on localizing the sound sources and not on remembering spatial locations that resulted in rewards. Overall, the importance of using ecologically valid behaviors for studies of sensory processes is confirmed, and the potential of the rhesus monkey, the model closest to human, for studies of spatial auditory function, is established.

Several auditory spatial illusions, collectively called the precedence effect (PE), occur when transient sounds are presented from two different spatial locations but separated in time by an interstimulus delay (ISD). For ISDs in the range of localization dominance (

Impulsivity, the predisposition to act without regard for negative consequences, is a characteristic of several psychiatric disorders and is thought to result in part from genetic variation in the untranslated region of the dopamine transporter (DAT) gene. As the exact link between genetic mutations and impulsivity has not been established, we used oculomotor behavior to characterize rhesus monkeys as impulsive or calm and genetic/epigenetic analysis and positron emission tomography (PET) to correlate phenotype to DAT genotype, DAT gene methylation, and DAT availability. We found three single nucleotide polymorphisms (SNPs) in the 3′-UTR of the DAT gene, one of which provided a potential site for methylation in the impulsive group. Bisulfite analysis showed that the DNA of the impulsive but not the calm subjects was methylated at one SNP. Because genetic/epigenetic modifications could lead to differences in protein expression, we measured DAT availability using [18F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([18F]FECNT) PET and found higher DAT availability in the internal globus pallidus, an output nucleus of the basal ganglia, of the impulsive group. Higher DAT availability lowers dopamine levels, potentially altering neuronal circuits involved in the initiation of action, thus contributing to the impulsive phenotype. The association between increased methylation in the DAT gene and greater DAT availability suggests that mutations to the regulatory portion of the DAT gene lead to a susceptibility to epigenetic modification resulting in a discrete behavioral phenotype.

Operant conditioning was used to train cats with their heads immobilized to localize sound by directing their eyes to the location of the sources. The kinematics of those eye movements were studied and compared with eye movements to visual targets at the same locations. The main finding of this study is that eye movements to broadband long-duration acoustic targets have two components: an initial slow phase of variable duration and a fast, normal saccade. The slow component is characterized by a persistent, shallow velocity ramp, while the saccadic component of the response falls on the main sequence computed from eye movements to visual targets. The slow component was shorter before saccades to long-duration stimuli performed under the delayed-saccade task and practically absent before saccades to transient acoustic stimuli. The results suggest that the initial slow component is used by cats to deal with uncertainty associated with the location of long-duration broadband targets and that the input to the saccade integrator(s) is similar under both visual and acoustic conditions.

Illusions are effective tools for the study of the neural mechanisms underlying perception because neural responses can be correlated to the physical properties of stimuli and the subject's perceptions. The Franssen illusion (FI) is an auditory spatial illusion evoked by presenting a transient, abrupt tone and a slowly rising, sustained tone of the same frequency simultaneously on opposite sides of the subject. Perception of the FI consists of hearing a single sound, the sustained tone, on the side that the transient was presented. Both subcortical and cortical mechanisms for the FI have been proposed, but, to date, there is no direct evidence for either. The data show that humans and rhesus monkeys perceive the FI similarly. Recordings were taken from single units of the inferior colliculus in the monkey while they indicated the perceived location of sound sources with their gaze. The results show that the transient component of the Franssen stimulus, with a shorter first spike latency and higher discharge rate than the sustained tone, encodes the perception of sound location. Furthermore, the persistent erroneous perception of the sustained stimulus location is due to continued excitation of the same neurons, first activated by the transient, by the sustained stimulus without location information. These results demonstrate for the first time, on a trial-by-trial basis, a correlation between perception of an auditory spatial illusion and a subcortical physiological substrate.

The topographical organization of the 22 motoneuron pools that innervate the pinna muscles of the cat was examined by injecting the B-subunit of cholera toxin conjugated to horseradish peroxidase into individual muscles. All 22 pools are found in the facial nucleus, organized as rostro-caudally oriented columns, and arranged according to the action of the muscles they innervate. Pools innervating muscles that pull the pinna dorsally are located in the dorsal two thirds of the medio-dorsal subdivision, and those innervating muscles that pull the pinna ventrally are located in the ventral one half of the nucleus. Motoneurons innervating muscles that pull the pinna cranially are located laterally, those that pull the pinna caudally are located medio-ventrally, and those that change the shape of the pinna are located along the entire dorso-ventral extent in the center of the medio-dorsal subdivision. This topographical layout is consistent with the somatotopic organization of the entire facial nucleus as demonstrated in a variety of species.

We have studied eye-head coordination in nonhuman primates with acoustic targets after finding that they are unable to make accurate saccadic eye movements to targets of this type with the head restrained. Three male macaque monkeys with experience in localizing sounds for rewards by pointing their gaze to the perceived location of sources served as subjects. Visual targets were used as controls. The experimental sessions were configured to minimize the chances that the subject would be able to predict the modality of the target as well as its location and time of presentation. The data show that eye and head movements are coordinated differently to generate gaze shifts to acoustic targets. Chiefly, the head invariably started to move before the eye and contributed more to the gaze shift. These differences were more striking for gaze shifts of

Self-recognition in front of a mirror is used as an indicator of self-awareness. Along with humans, some chimpanzees and orangutans have been shown to be self-aware using the mark test. Monkeys are conspicuously absent from this list because they fail the mark test and show persistent signs of social responses to mirrors despite prolonged exposure, which has been interpreted as evidence of a cognitive divide between hominoids and other species. In stark contrast with those reports, the rhesus monkeys in this study, who had been prepared for electrophysiological recordings with a head implant, showed consistent self-directed behaviors in front of the mirror and showed social responses that subsided quickly during the first experimental session. The self-directed behaviors, which were performed in front of the mirror and did not take place in its absence, included extensive observation of the implant and genital areas that cannot be observed directly without a mirror. We hypothesize that the head implant, a most salient mark, prompted the monkeys to overcome gaze aversion inhibition or lack of interest in order to look and examine themselves in front of the mirror. The results of this study demonstrate that rhesus monkeys do recognize themselves in the mirror and, therefore, have some form of self-awareness. Accordingly, instead of a cognitive divide, they support the notion of an evolutionary continuity of mental functions.

In young and elderly subjects, push and pull arm movements were executed during sitting or standing, under both simple reaction (SR) and choice reaction (CR) conditions. The combined reaction time (RT) results showed that CRT was larger than SRT in both groups. While sitting, the young group exhibited only slight change in RT, whereas the elderly group showed sizeable RT decrease. During standing, for the SR condition, the elderly's RTs were slightly slower than the young's; in contrast, for the CR condition, the elderly's RTs were substantially slower. Further, when the activation of ankle-stabilizer muscles was examined, it was found that postural muscle onset was essentially the same under both conditions. Focal-muscle onset and reaction time, under the choice condition, however, was sensitive to age-related differences. When these data are taken together, they suggest that the elderly may have an impaired postural system which is slow to stabilize the body prior to movement initiation.

The superior colliculus (SC) is a midbrain structure that plays a central role in the integration of information from different sensory modalities and the generation of orienting responses. Its normal function is thought to be governed by a strictly held balance between excitation and inhibition. This hypothesis was tested by recording from the same single units in the SC of cats before the injection of anesthetics, while anesthetics took effect, and after the injections during recovery. Sodium pentobarbital and ketamine, two agents commonly used in sensory physiology, were used. The results show a plethora of dose-dependent and nonlinear effects: the magnitude of evoked responses, receptive field properties, first spike latency, and bimodal integration were affected by both anesthetics in all units tested. Notably, prominent facilitation was observed at low levels of anesthesia, and inhibitory responses were changed into excitatory. Overall, the results challenge a fundamental tenet of sensory physiology: anesthesia, while decreasing single-unit responsiveness, leaves unaltered basic physiological properties.

In oculomotor research, there are two common methods by which the apparent location of visual and/or auditory targets are measured, saccadic eye movements with the head restrained and gaze shifts (combined saccades and head movements) with the head unrestrained. Because cats have a small oculomotor range (approximately ±25°), head movements are necessary when orienting to targets at the extremes of or outside this range. Here we tested the hypothesis that the accuracy of localizing auditory and visual targets using more ethologically natural head-unrestrained gaze shifts would be superior to head-restrained eye saccades. The effect of stimulus duration on localization accuracy was also investigated. Three cats were trained using operant conditioning with their heads initially restrained to indicate the location of auditory and visual targets via eye position. Long-duration visual targets were localized accurately with little error, but the locations of short-duration visual and both long- and short-duration auditory targets were markedly underestimated. With the head unrestrained, localization accuracy improved substantially for all stimuli and all durations. While the improvement for long-duration stimuli with the head unrestrained might be expected given that dynamic sensory cues were available during the gaze shifts and the lack of a memory component, surprisingly, the improvement was greatest for the auditory and visual stimuli with the shortest durations, where the stimuli were extinguished prior to the onset of the eye or head movement. The underestimation of auditory targets with the head restrained is explained in terms of the unnatural sensorimotor conditions that likely result during head restraint.

We examined the motor error hypothesis of visual and auditory interaction in the superior colliculus (SC), first tested by Jay and Sparks in the monkey. We trained cats to direct their eyes to the location of acoustic sources and studied the effects of eye position on both the ability of cats to localize sounds and the auditory responses of SC neurons with the head restrained. Sound localization accuracy was generally not affected by initial eye position, i.e., accuracy was not proportionally affected by the deviation of the eyes from the primary position at the time of stimulus presentation, showing that eye position is taken into account when orienting to acoustic targets. The responses of most single SC neurons to acoustic stimuli in the intact cat were modulated by eye position in the direction consistent with the predictions of the “motor error” hypothesis, but the shift accounted for only two-thirds of the initial deviation of the eyes. However, when the average horizontal sound localization error, which was ∼35% of the target amplitude, was taken into account, the magnitude of the horizontal shifts in the SC auditory receptive fields matched the observed behavior. The modulation by eye position was not due to concomitant movements of the external ears, as confirmed by recordings carried out after immobilizing the pinnae of one cat. However, the pattern of modulation after pinnae immobilization was inconsistent with the observations in the intact cat, suggesting that, in the intact animal, information about the position of the pinnae may be taken into account.

Bimodal enhancement, a form of nonlinear summation of physiological responses from two sensory modalities, has been demonstrated in the intermediate layers of the superior colliculus (SCi) and is thought to be a manifestation of a neural mechanism underlying behavioral facilitation to such stimuli. Most physiological studies, however, have been performed in anesthetized animals. We tested for bimodal enhancement in the SCi of behaving cats trained to orient to acoustic, visual, and bimodal stimuli. Surprisingly, we never observed the large enhanced responses reported in anesthetized animals, even when we varied the time between presentation of the visual and acoustic stimuli and/or decreased the level of the stimuli. Using three different behavioral paradigms, we found no support for enhanced interactions between auditory and visual modalities. Prominent depressive effects were seen, however, particularly when the cats were required to fixate a visual target during presentation of an acoustic stimulus.

In visual and somatosensory cortices of several species, spiny stellate cells in layer 4 are the first elements in signal processing where thalamic information is integrated and emergent receptive field properties are generated and sent on to more superficial cortical layers. In vivo and in vitro experiments have provided important information about how the anatomy and physiology of these cells and this layer fit into the functional cortical circuitry. No such data exist for the auditory cortex but are requisite if we are to understand whether ideas about information processing in one sensory cortical area can be generalized to another. Accordingly, we used in vitro slices from which to record and labeled cells in the middle layers of the cat auditory and visual cortices to compare basic anatomical and physiological features of cells recovered in similar layers using the same methods. Our results demonstrate a striking difference in a basic characteristic of two primary sensory cortical areas. In the visual cortex, spiny stellate cells predominate, receive short-latency synaptic inputs, and project to supergranular layers. No such spiny stellate population is encountered in the middle layers of the auditory cortex. Spiny cells that are not stellate or pyramidal are occasionally encountered but, as a group, do not display consistent anatomical or physiological features that might allow them to function as auditory cortical versions of the visual spiny stellates. Rather, pyramidal cells in the lower half of layer 3 and layer 4 appear to have assumed this role. J. Comp. Neurol. 436:508–519, 2001. © 2001 Wiley-Liss, Inc.

We measured the movements of the external ear, or pinna, using the magnetic search coil technique in cats trained to look at auditory and visual targets for a food reward. No behavioral contingencies were placed on pinna movements. Prominent pinna movements accompany eye movements when the animal orients to either auditory or visual stimuli. In visual trials the pinna movements are coordinated with eye movements, suggesting that they are part of the general orientation response of the animal. In auditory trials the pinna response was composed of two movements: short- and long-latency components. Whereas the long-latency component seemed to occur with the eye movement to the target, the short-latency component was coupled to the onset of the stimulus. The short-latency component (∼25 msec) was highly asymmetrical, being largest in the pinna ipsilateral to the stimuli. In one animal it persisted after >105trials.

Physiological studies of the auditory system have traditionally focussed on understanding the mechanisms of action in the peripheral auditory system, from observations of the traveling wave down the basilar membrane (von Bekesy, 1960) to the transduction of vibrations by the inner hair cells (Russell and Sellick, 1978) and the subsequent coding of sound stimuli by auditory nerve fibers (Sachs and Young, 1979). The neuronal processing in the central auditory system has not received as much attention as in the visual system, with the possible exception of studies in the auditory cortex of the echolocating bat (Suga et al., this volume). Moreover, while there have been a large number of studies of the visual system using behaving animals, very few studies in the auditory system have exploited the benefits of this preparation.

We are studying the relationship between single‐unit responses in the inferior colliculus (IC) of behaving cats and their perception of spatial location using stimuli evoking the precedence effect (PE), an illusion where the perceived location of two similar sounds delivered from different locations but separated by a time delay approximates the perceived location of only the leading sound. Psychophysically, our cats experienced the PE: for 1–15‐ms delays, they localized paired transients to nearly the same location as the leading sound alone. For delays greater than 15–20 ms, they often localized the leading and/or lagging location, an indication of echo threshold. Physiologically, for the delays that the cats experienced the PE the IC responses to the lag were reduced relative to the responses to the lag presented alone but with little effect on the response to the lead. The responses of these cells correlate with the behavioral perception of location: for delays encompassing the PE the cats’ spatial pe...