We evaluated the feasibility of using human, whole-head MEG instrumentation for nonhuman primate investigations, recording the first neuromagnetic responses of rhesus monkey during mechanoreceptive processing. Most importantly, the results establish that existing whole-head MEG instruments can be used for studies in slightly smaller model organisms, such as adult rhesus monkeys. Of course, smaller MEG helmets and sensor radii would improve the spatial resolution of the measurements and more broadly optimize the recording process (e.g., head placement). Beyond feasibility, the results indicated that tactile stimulation of the second digit pad elicits a cortical response peaking ~16 ms after stimulus onset. The results suggest the same stimulation applied to the right fifth digit peaks in the cortex slightly earlier, a finding that will need further study using higher sampling rates. Finally, we localized the neural generators of these tactile responses to an area posterior to the central sulcus. These source localization results are consistent with somatotopic maps attained invasively in the same species (Pons et al., 1985
). Conclusions in regard to the minuscule spatial differences we observed between the fifth and second digit are withheld as this spatial resolution is beyond what is possible using currently available equipment.
The response to tactile stimulation in rhesus monkey has a much more rapid onset than in humans. This was partially expected given earlier work that used electrical stimulation of the median nerve in monkeys (Allison et al., 1989
). These studies suggested the human ~20ms response detected with EEG had roughly a 10 ms peak latency when measured invasively in monkeys, assuming the two responses were in fact cross-species homologues (Allison et al., 1989
). Previous human MEG studies have used tactile stimulation devices, identical to that employed in the current work, in healthy adults (Hoechstetter et al., 2001
; Reite et al., 2003
) and children (Wilson et al., 2007
). The earliest response in humans peaks ~50 ms after stimulus onset and is generated in the somatotopically organized primary somatosensory cortex (S1) of the contralateral hemisphere. The relationship of the human M50 and the monkey M16 is unknown, but the magnetic flux patterns suggest both responses are generated by intraneuronal current flow in the same direction (see field map in (Reite et al., 2003
) and present data). In the early 7-channel MEG study of auditory responses, Teale and colleagues (1994)
suggested that a M46 response in monkey may correspond to the M100 response in humans (which normally peaks at ~110ms) based on similar criteria and the source location. The M16 reported here is about 3-times faster than the M50 response, which suggests that the relative conduction speeds in the somatosensory and auditory systems differ between the two species. The weaker somatosensory response observed at 96 ms may not have a previously described human homologue. Assuming it was generated in the monkey's left (contralateral) hemisphere, it may be related to the human 85 ms response which is the second and final response in the hemisphere contralateral to stimulation (Hoechstetter et al., 2001
Our study has particular significance as a bridge between methodologies that allow the use of invasive experimental variables in nonhuman primate models and methodologies that monitor brain activity in human subjects. Studies using non-invasive imaging in animals have typically taken one of two forms. A large body of work has used imaging to understand disease progression or the effects of drug use/abuse. A smaller number of studies have used animal preparations to more clearly identify the biological processes these tools measure. Accordingly, most knowledge concerning the physiological basis of the physical signals quantified by these imaging tools has been derived from work in animals, in which the imaging modality of interest has been combined with invasive electrophysiological recordings. In what is likely the most well-known and thorough example, Logothetis and colleagues (2001)
examined the neuronal bases of the blood-oxygen-level-dependent (BOLD) signal that is measured in fMRI studies. They found significant correlations between local-field potential (LFP) measures, multi-unit spiking activity, and the BOLD signal in occipital cortices of anaesthetized rhesus monkeys. Logothetis et al. (2001)
reported that LFP measures were the best estimate of spatially coincident BOLD responses, which suggests fMRI activation reflects the intracortical processing and synaptic activity of a neural area rather than its spiking output (Logothetis et al., 2001
). Interestingly, a similar visual contrast paradigm was used by Hall and colleagues (2005)
in a human MEG study. Consistent with LFP data from the monkey (Logothetis et al., 2001
), they reported occipital gamma oscillations increased in amplitude as a linear function of stimulus contrast (Hall et al. 2005
). Furthermore, the MEG gamma power response function in human and the analogous LFP function in monkey occipital cortices correlated strongly (Logothetis et al., 2001
; Hall et al., 2005
). However, more broadly, human MEG studies have benefited relatively less from physiological data derived through animal studies, at least partially due to the absence of simultaneously acquired invasive recordings and MEG in monkeys. Early studies using custom-made micro-SQUID (superconducting quantum interference devices) technology and guinea pig hippocampal slices showed that primary currents in parallel-oriented pyramidal cells were the dominant source of MEG signals (Okada et al., 1997
). Using micro-SQUID technology and an elegant porcine preparation, this group also provided the first empirical evidence that EEG signals, but not MEG signals, are strongly affected by intervening tissues (e.g., skull and scalp; (Okada et al., 1999a
; Okada et al., 1999b
). More recently, Okada and colleagues have provided single-cell simulation data suggesting action potentials may contribute substantially to MEG signals (Murakami and Okada, 2006
), which of course contradicts conventional views of action potentials having a negligible role in the genesis of MEG signals. The capacity to do whole-head recordings in monkeys, as demonstrated here, should expand our understanding of the physiological processes that underlie the MEG signal. For example, whole-head monkey MEG will eventually allow important questions, such as MEG's capacity to resolve temporally coincident sources in nearby but distinct sections of tissue as distinct patches of activity, to be thoroughly addressed using a relatively human-like in vivo model. Likewise, the number of cells and perhaps even the type of cells (e.g., Murakami and Okada, 2006
) involved in generating stereotypic human MEG responses could be more fully understood through MEG in monkeys.
Beyond the potential to further understand the biological basis of the methods, perhaps the most important application of non-invasive imaging in animals is that it provides a means to gain a longitudinal understanding of how drugs, diseases, development, and even social situations affect neural structure and function. An example of such a longitudinal analysis is a previous PET imaging study that demonstrated striatal dopamine D2 receptor availability was higher in socially dominant versus subordinate cynomolgus monkeys (Grant et al., 1998
; Morgan et al., 2002
); these changes in receptor availability had profound influences on behavior as demonstrated by the subsequent findings that cocaine functioned as a reinforcer in subordinate but not dominant monkeys (Morgan et al., 2002
). With the addition of MEG, similar studies would provide insight into how dopamine receptor variations modulate local circuit physiology as well as activity in larger-scale neurocognitive systems.
This is the first study to demonstrate the effective use of whole-head MEG in a nonhuman primate. Using MEG, somatosensory responses were mapped to the predicted cortical region, and a marked latency difference was determined in the response to somatosensory stimulation between rhesus monkeys and the reports from human subjects. The implementation of a MEG sensor array designed specially for rhesus monkeys, and the capacity to study behaving monkeys are other longer-term goals. Despite these limitations, the present study demonstrates the feasibility of whole head MEG in nonhuman primates, which should allow for imaging studies that combine the advantages of MEG-derived neurophysiological imaging with the important capability of experimental manipulations that are possible with nonhuman primate models.