Awake Monkeys Research Articles

Photoacoustic detection of functional responses in the motor cortex of awake behaving monkey during forelimb movement

Photoacoustic (PA) imaging was applied to detect the neuronal activity in the motor cortex of an awake, behaving monkey during forelimb movement. An adult macaque monkey was trained to perform a reach-to-grasp task while PA images were acquired through a 30-mm diameter implanted cranial chamber. Increased PA signal amplitude results from an increase in regional blood volume and is interpreted as increased neuronal activity. Additionally, depth-resolved PA signals enabled the study of functional responses in deep cortical areas. The results demonstrate the feasibility of utilizing PA imaging for studies of functional activation of cerebral cortex in awake monkeys performing behavioral tasks.

P.3.d.010 Effects of chronic exposure of cariprazine on dopamine receptor subtypes

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3 mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [3H]TAK-063 significantly accumulated in the caudate—putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [3H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3 mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3 mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2 mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3 mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

Journal-related Activities and Other Special Activities at the 2012 American Society of Anesthesiologists Annual Meeting

P1-5: Effect of Luminance Contrast on the Color Selective Responses in the Inferior Temporal Cortex Neurons of the Macaque Monkey

Although the relationship between color signal and luminance signal is an important problem in visual perception, relatively little is known about how the luminance contrast affects the responses of color selective neurons in the visual cortex. In this study, we examined this problem in the inferior temporal (IT) of the awake monkey performing a visual fixation task. Single neuron activities were recorded from the anterior and posterior color selective regions in IT cortex (AITC and PITC) identified in previous studies where color selective neurons are accumulated. Color stimuli consisted of 28 stimuli that evenly distribute across the gamut of the CRT display defined on the CIE- xychromaticity diagram at two different luminance levels (5 cd/m 2or 20 cd/m 2) and 2 stimuli at white points. The background was maintained at 10 cd/m 2gray. We found that the effect of luminance contrast on the color selectivity was markedly different between AITC and PITC. When we examined the correlation between the responses...

Suppressive Surrounds of Receptive Fields In Monkey Frontal Eye Field

A critical step in determining how a neuron contributes to visual processing is determining its visual receptive field (RF). While recording from neurons in frontal eye field (FEF) of awake monkeys (Macaca mulatta), we probed the visual field with small spots of light and found excitatory RFs that decreased in strength from RF center to periphery. However, presenting stimuli with different diameters centered on the RF revealed suppressive surrounds that overlapped the previously determined excitatory RF and reduced responses by 84%, on average. Consequently, in that overlap area, stimulation produced excitation or suppression, depending on the stimulus. Strong stimulation of the RF periphery with annular stimuli allowed us to quantify this effect. A modified difference of gaussians model that independently varied center and surround activation accounted for the nonlinear activity in the overlap area. Our results suggest that (1) the suppressive surrounds found in FEF are fundamentally the same as those in V1 except for the size and strength of excitatory and suppressive mechanisms, (2) methodically assaying suppressive surrounds in FEF is essential for correctly interpreting responses to large and/or peripheral stimuli and therefore understanding the effects of stimulus context, and (3) regulating the relative strength of the surround clearly changes neuronal responses and may therefore play a significant part in the neuronal changes resulting from visual attention and stimulus salience.

Layer-specific BOLD activation in awake monkey V1 revealed by ultra-high spatial resolution functional magnetic resonance imaging

The laminar structure of the cortex has previously been explored both in non-human primates and human subjects using high-resolution functional magnetic resonance imaging (fMRI). However, whether the spatial specificity of the blood-oxygenation-level-dependent (BOLD) fMRI is sufficiently high to reveal lamina specific organization in the cortex reliably is still unclear. In this study we demonstrate for the first time the detection of such layer-specific activation in awake monkeys at the spatial resolution of 200 × 200 × 1000 μm(3) in a vertical 4.7 T scanner. Results collected in trained monkeys are high in contrast-to-noise ratio and low in motion artifacts. Isolation of laminar activation was aided by choosing the optimal slice orientation and thickness using a novel pial vein pattern analysis derived from optical imaging. We found that the percent change of GE-BOLD signal is the highest at a depth corresponding to layer IV. Changes in the middle layers (layer IV) were 30% greater than changes in the top layers (layers I-III), and 32% greater than the bottom layers (layers V/VI). The laminar distribution of BOLD signal correlates well with neural activity reported in the literature. Our results suggest that the high intrinsic spatial resolution of GE-BOLD signal is sufficient for mapping sub-millimeter functional structures in awake monkeys. This degree of spatial specificity will be useful for mapping both laminar activations and columnar structures in the cerebral cortex.

Motion boundary response domains in awake monkey V2

Motion boundary response domains in awake monkey V2

Shape encoding consistency across colors in primate V4

Neurons in primate cortical area V4 are sensitive to the form and color of visual stimuli. To determine whether form selectivity remains consistent across colors, we studied the responses of single V4 neurons in awake monkeys to a set of two-dimensional shapes presented in two different colors. For each neuron, we chose two colors that were visually distinct and that evoked reliable and different responses. Across neurons, the correlation coefficient between responses in the two colors ranged from -0.03 to 0.93 (median 0.54). Neurons with highly consistent shape responses, i.e., high correlation coefficients, showed greater dispersion in their responses to the different shapes, i.e., greater shape selectivity, and also tended to have less eccentric receptive field locations; among shape-selective neurons, shape consistency ranged from 0.16 to 0.93 (median 0.63). Consistency of shape responses was independent of the physical difference between the stimulus colors used and the strength of neuronal color tuning. Finally, we found that our measurement of shape response consistency was strongly influenced by the number of stimulus repeats: consistency estimates based on fewer than 10 repeats were substantially underestimated. In conclusion, our results suggest that neurons that are likely to contribute to shape perception and discrimination exhibit shape responses that are largely consistent across colors, facilitating the use of simpler algorithms for decoding shape information from V4 neuronal populations.

Spontaneous High-Gamma Band Activity Reflects Functional Organization of Auditory Cortex in the Awake Macaque

In the absence of sensory stimuli, spontaneous activity in the brain has been shown to exhibit organization at multiple spatiotemporal scales. In the macaque auditory cortex, responses to acoustic stimuli are tonotopically organized within multiple, adjacent frequency maps aligned in a caudorostral direction on the supratemporal plane (STP) of the lateral sulcus. Here, we used chronic microelectrocorticography to investigate the correspondence between sensory maps and spontaneous neural fluctuations in the auditory cortex. We first mapped tonotopic organization across 96 electrodes spanning approximately two centimeters along the primary and higher auditory cortex. In separate sessions, we then observed that spontaneous activity at the same sites exhibited spatial covariation that reflected the tonotopic map of the STP. This observation demonstrates a close relationship between functional organization and spontaneous neural activity in the sensory cortex of the awake monkey.

Nonlinear analysis of macaque V1 color tuning reveals cardinal directions for cortical color processing.

Understanding color vision requires knowing how signals from the three classes of cone photoreceptor are combined in the cortex. We recorded from single V1 neurons in awake monkeys while an automated, closed-loop system identified stimuli that differed in cone contrast but evoked the same response. We found that isoresponse surfaces for about half the neurons were planar, consistent with linear processing. The remaining isoresponse surfaces were nonplanar. Some were cup-shaped, indicating sensitivity to a narrow region of color space. Others were ellipsoidal, indicating sensitivity to all color directions. The major and minor axes of these nonlinear surfaces were often aligned to a set of three color directions that were previously identified in perceptual experiments. These results demonstrate that many V1 neurons combine cone signals nonlinearly and provide a new framework within which to decipher color processing in V1.

State-Space Analysis of Time-Varying Higher-Order Spike Correlation for Multiple Neural Spike Train Data

Precise spike coordination between the spiking activities of multiple neurons is suggested as an indication of coordinated network activity in active cell assemblies. Spike correlation analysis aims to identify such cooperative network activity by detecting excess spike synchrony in simultaneously recorded multiple neural spike sequences. Cooperative activity is expected to organize dynamically during behavior and cognition; therefore currently available analysis techniques must be extended to enable the estimation of multiple time-varying spike interactions between neurons simultaneously. In particular, new methods must take advantage of the simultaneous observations of multiple neurons by addressing their higher-order dependencies, which cannot be revealed by pairwise analyses alone. In this paper, we develop a method for estimating time-varying spike interactions by means of a state-space analysis. Discretized parallel spike sequences are modeled as multi-variate binary processes using a log-linear model that provides a well-defined measure of higher-order spike correlation in an information geometry framework. We construct a recursive Bayesian filter/smoother for the extraction of spike interaction parameters. This method can simultaneously estimate the dynamic pairwise spike interactions of multiple single neurons, thereby extending the Ising/spin-glass model analysis of multiple neural spike train data to a nonstationary analysis. Furthermore, the method can estimate dynamic higher-order spike interactions. To validate the inclusion of the higher-order terms in the model, we construct an approximation method to assess the goodness-of-fit to spike data. In addition, we formulate a test method for the presence of higher-order spike correlation even in nonstationary spike data, e.g., data from awake behaving animals. The utility of the proposed methods is tested using simulated spike data with known underlying correlation dynamics. Finally, we apply the methods to neural spike data simultaneously recorded from the motor cortex of an awake monkey and demonstrate that the higher-order spike correlation organizes dynamically in relation to a behavioral demand.

Orientation selectivity and noise correlation in awake monkey area V1 are modulated by the gamma cycle

Gamma-band synchronization adjusts the timing of excitatory and inhibitory inputs to a neuron. Neurons in the visual cortex are selective for stimulus orientation because of dynamic interactions between excitatory and inhibitory inputs. We hypothesized that these interactions and hence also orientation selectivity vary during the gamma cycle. We determined for each spike its phase relative to the gamma cycle. As a function of gamma phase, we then determined spike rates and their orientation selectivity. Orientation selectivity was modulated by gamma phase. The firing rate of spiking activity that occurred close to a neuron's mean gamma phase of firing was most orientation selective. This stimulus-selective signal could best be conveyed to postsynaptic neurons if it were not corrupted by noise correlations. Noise correlations between firing rates were modulated by gamma phase such that they were not statistically detectable for the spiking activity occurring close to a neuron's mean gamma phase of firing. Thus, gamma-band synchronization produces spiking activity that carries maximal stimulus selectivity and minimal noise correlation in its firing rate, and at the same time synchronizes this spiking activity for maximal impact on postsynaptic targets.

Spontaneous neural activity predicts individual differences in performance

We each have particular strengths—some of us are good at math and others are good at language—that vary from one person to another. Less appreciated is the fact that individual differences also extend to performing what appear on the surface to be simple perceptual tasks, like learning to detect one visual form among an array of visually similar forms (1, 2). Neurophysiological studies in awake monkeys and functional MRI (fMRI) studies in humans have provided considerable information about the neural changes that accompany visual perceptual learning—including that learning is highly specific to the retinotopic location of the trained stimulus—making it an ideal model system for studying cortical plasticity (3). Typically, there is also a large amount of intersubject performance variability, making it an ideal model for exploring the neural correlates of individual differences. However, other than good learners showing greater neural activity during the first learning trials than poor learners (2), little is known about the neural underpinnings of individual differences in perceptual learning. In PNAS, Baldassarre et al. (4) present a unique approach to this topic by evaluating the relationship between visual perceptual learning and slowly (<0.1 Hz) fluctuating, spontaneous neural activity recorded during an fMRI resting-state scan 1–2 days before learning.

Neural mechanisms of rhythmic masking release in monkey primary auditory cortex: implications for models of auditory scene analysis

The ability to detect and track relevant acoustic signals embedded in a background of other sounds is crucial for hearing in complex acoustic environments. This ability is exemplified by a perceptual phenomenon known as "rhythmic masking release" (RMR). To demonstrate RMR, a sequence of tones forming a target rhythm is intermingled with physically identical "Distracter" sounds that perceptually mask the rhythm. The rhythm can be "released from masking" by adding "Flanker" tones in adjacent frequency channels that are synchronous with the Distracters. RMR represents a special case of auditory stream segregation, whereby the target rhythm is perceptually segregated from the background of Distracters when they are accompanied by the synchronous Flankers. The neural basis of RMR is unknown. Previous studies suggest the involvement of primary auditory cortex (A1) in the perceptual organization of sound patterns. Here, we recorded neural responses to RMR sequences in A1 of awake monkeys in order to identify neural correlates and potential mechanisms of RMR. We also tested whether two current models of stream segregation, when applied to these responses, could account for the perceptual organization of RMR sequences. Results suggest a key role for suppression of Distracter-evoked responses by the simultaneous Flankers in the perceptual restoration of the target rhythm in RMR. Furthermore, predictions of stream segregation models paralleled the psychoacoustics of RMR in humans. These findings reinforce the view that preattentive or "primitive" aspects of auditory scene analysis may be explained by relatively basic neural mechanisms at the cortical level.

Response to comment on: Exp Brain Res. 2011 May 5th. Transcranial magnetic stimulation of macaque frontal eye fields decreases saccadic reaction time. Pierre Pouget PhD, Nicolas Wattiez MSc and Antoni Valero-Cabre MDPhD

We welcome the chance to respond to the comments of Pouget and Valero-Cabre about our recent study (Gerits et al. 2011, Experimental Brain Research), which showed an impact of continuous theta burst (cTBS) transcranial magnetic stimulation (TMS) over monkey frontal eye Welds (FEF) on prosaccade latency. No such eVect was observed when applying TBS over M1 instead, at a site 10–11 mm away from the eVective FEF site. We note that Pouget and Valero-Cabre acknowledge “the utmost importance” of extending TBS and other TMS protocols to animal models, as done in Gerits et al. (2011). They also state that “there is little doubt that Gerits et al. demonstrate for the Wrst time the feasibility of applying cTBS patterns to the awake monkey brain and record saccade behaviour immediately thereafter”. We share their enthusiasm for extending this approach with other TMS protocols, and in other behavioural and cognitive paradigms. Like them, we anticipate that larger eVects are there to be found and that TBS/TMS work in non-human primates may ultimately go well beyond what is known from human studies. Pouget and Valero-Cabre comment several times on the small absolute size of the observed cTBS eVect in Gerits et al. (mean 7 ms speeding of prosaccades after FEF cTBS, but not after M1 cTBS). Although small, this eVect was highly reliable (p < .0001 within each monkey, p < .000001 when pooling over monkeys). Moreover, it was highly systematic, as it was found in 8/8 comparisons after FEF cTBS, but in 0/8 after M1 cTBS. Although 7ms is small in absolute terms, it should be recalled that prosaccading is a simple task performed very quickly, with a mean diVerence of 7 ms representing a »5% change. In Gerits et al. (2011), this change could be produced by just 40 s of FEF cTBS, yet the observed eVect was comparable in size to that found on memory-guided saccades after much more drastic and invasive interventions (e.g. muscimol injection into area LIP, see Liu et al. 2010; Fig 1b and 1c). Finally, Pouget and Valero-Cabre query the sampling rate of Gerit et al.’s eyetracker (120 Hz, one sample every 8.3 ms) relative to the highly signiWcant mean eVect of 7 ms that was found, corresponding approximately to (just below) one sample. But it is well known that with a large number of repeated samples, one can reliably measure a mean eVect at or even below the measurement unit, and in Gerits et al. (2011), we had sampled 44,465 saccades in total. Pouget and Valero-Cabre comment on our comparison of the eVective FEF TBS site with the control M1 site that Jon Driver: Deceased

Integration of shape and motion cues in biological motion processing in the monkey STS

To correctly perceive biological actions, the movement pattern generated in the course of the action has to be linked to the configuration of the actor. Recently, we showed that in humans, motion and configuration cues are processed separately in occipito-temporal cortex, and that both cues are integrated in the extrastriate (EBA) and fusiform (FBA) body areas (Jastorff and Orban, 2009). Using the same factorial design as in our human study, we performed fMRI experiments in awake monkeys to compare biological motion processing in the two species. Point-light displays of monkeys engaged in various actions were presented in a 2×2 factorial design. One factor manipulated the configuration of the stimuli, the other, the kinematics. As in humans, the two factors were anatomically segregated in the superior temporal sulcus (STS) rostral to the MT/V5 complex, with the effect of configuration significant along the lower bank and that of kinematics significant in the fundus and the upper bank of the STS. Moreover, voxels showing a significant interaction between the two factors were mainly confined to body-selective patches within the STS, mimicking our human findings. Importantly, this study reports for the first time differential activation for biological actions presented as point-light displays in the monkey. Moreover, our results suggest that the processing mechanisms of biological actions are remarkably similar in humans and macaque monkeys, and provide the basis for linking existing and future single-cell physiology in the monkey with human functional imaging.

An Analysis Approach for High-Field fMRI Data from Awake Non-Human Primates

fMRI experiments with awake non-human primates (NHP) have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1) Trial-based experimental design. 2) Careful control of subject movement. 3) Computer-assisted selection of trials devoid of artefacts and animal motion. 4) Nonrigid between-trial and rigid within-trial realignment of concatenated data from temporally separated trials and sessions. 5) Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6) Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri-sandbox/), for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan.

High resolution 3 T fMRI in anesthetized monkeys

Although there are numerous 3T MRI research devices all over the world, only a few functional studies at 3T have been done in anesthetized monkeys. In the past, anesthetized preparations were reported to be misleading when exploring cortical brain regions outside the primary sensory areas. Nonetheless, a great improvement has been achieved in the limited effect of anesthetic agents on the reactivity of the brain.Here, we re-address the feasibility and potential applications of the brain oxygen level dependent (BOLD) fMRI signal in Macaca mulatta monkeys that have been lightly anesthetized with sevoflurane and curarized. The monkeys were studied with commercially available coils and sequences using a 3T clinical magnet. We obtained sagittal T1 scout images, gray matter double inversion recovery, standard gradient echo sequences and gradient echo functional imaging sequences. Given that fMRI signals are most readily identified in the cerebral cortices, we optimized Echo Planar Imaging sequences to reproduce significant changes in the BOLD signal subsequent to a visual stimulation paradigm.Our results provide a satisfactory signal to noise ratio with a limited standard deviation range, when compared with studies on alert macaques.We suggest that the 3T magnet remains a valuable tool to analyze neural pathways in the macaque brain under light anesthesia and report the use of spatially resolved fMRI in higher visual areas of anesthetized monkeys. This methodology avoids the need for time-consuming training of awake monkeys, is stable over many hours, provides reproducible data and could be applied successfully to future functional studies.

Human hand function: the limitations of brain and brawn

Human hand function: the limitations of brain and brawn

Functional magnetic resonance imaging of awake monkeys: some approaches for improving imaging quality

Functional magnetic resonance imaging (fMRI) at high magnetic field strength can suffer from serious degradation of image quality because of motion and physiological noise, as well as spatial distortions and signal losses due to susceptibility effects. Overcoming such limitations is essential for sensitive detection and reliable interpretation of fMRI data. These issues are particularly problematic in studies of awake animals. As part of our initial efforts to study functional brain activations in awake, behaving monkeys using fMRI at 4.7 T, we have developed acquisition and analysis procedures to improve image quality with encouraging results. We evaluated the influence of two main variables on image quality. First, we show how important the level of behavioral training is for obtaining good data stability and high temporal signal-to-noise ratios. In initial sessions, our typical scan session lasted 1.5 h, partitioned into short (<10 min) runs. During reward periods and breaks between runs, the monkey exhibited movements resulting in considerable image misregistrations. After a few months of extensive behavioral training, we were able to increase the length of individual runs and the total length of each session. The monkey learned to wait until the end of a block for fluid reward, resulting in longer periods of continuous acquisition. Each additional 60 training sessions extended the duration of each session by 60 min, culminating, after about 140 training sessions, in sessions that last about 4 h. As a result, the average translational movement decreased from over 500 μm to less than 80 μm, a displacement close to that observed in anesthetized monkeys scanned in a 7-T horizontal scanner. Another major source of distortion at high fields arises from susceptibility variations. To reduce such artifacts, we used segmented gradient-echo echo-planar imaging (EPI) sequences. Increasing the number of segments significantly decreased susceptibility artifacts and image distortion. Comparisons of images from functional runs using four segments with those using a single-shot EPI sequence revealed a roughly twofold improvement in functional signal-to-noise-ratio and 50% decrease in distortion. These methods enabled reliable detection of neural activation and permitted blood-oxygenation-level-dependent-based mapping of early visual areas in monkeys using a volume coil. In summary, both extensive behavioral training of monkeys and application of segmented gradient-echo EPI sequence improved signal-to-noise ratio and image quality. Understanding the effects these factors have is important for the application of high field imaging methods to the detection of submillimeter functional structures in the awake monkey brain.