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Before 1900 most of biology was primarily concerned with description. By detailing and classifying the relationships between organisms a taxonomy o f the natural world slowly took shape. Darwin’s theory o f evolution by natural selection (1859) was one of the first attempts to begin to explain why such diversity existed. Without the taxonomists who preceded him, Darwin would not have possessed the rich fund of data that allowed him to make his conclusions. This pattern is common in science - descriptive explanations are typically superseded by theories with predictive power.

Although experimental neuroimaging is a new science, it is already sufficiently mature for there to exist a number of attempts at proceeding beyond an initial taxonomic level of description. Methodological advances have allowed investigators to show that brain regions can be involved in a number of roles depending on their connectivity and the task being performed (e.g. Macintosh and Gonzalez-Lima, 1994; Friston et al., 1995d). However, like Darwin’s theory, these advances relied upon earlier, simpler studies to describe the form of the systems under investigation (e.g. to form the structural anatomical models essential for structural equation models). Furthermore, current levels of knowledge are not sufficient to allow these kinds o f analyses to be performed in all sensory systems - as described in Chapter one, there is still much to be learned about even the basic connectivity and number of cortical areas involved in human somesthetic processing. My objective was to form and address simple hypotheses initially, with a view to addressing more involved questions subsequently. The experiments presented in this chapter focus on two aims: i) the construction of an ‘MR friendly’ somatosensory stimulator, and ii) an evaluation o f the stimulator’s ability to produce statistically significant changes in BOLD signal in cortical somatosensory areas.

3.1.1 Somatosensory Stimuli Used in Experimental Studies

Choosing one stimulation technique over another in neuroimaging experiments should be primarily informed by the researcher’s experimental hypothesis. In studies of the visual system this is usually easy to ensure, as there are few appreciable differences between delivering a visual stimulus during a psychophysical experiment and a neuroimaging experiment (as long as one can project images into the scanning environment). The situation is very different for other sensory modalities. While auditory studies can be easily performed in PET, the presence of periodic wide-frequency noise during fMRI studies can present serious problems (see Eden et al., 1999; Hall et al., 1999). Somatosensory stimulation paradigms are arguably even worse off. Although presenting somesthetic stimuli during PET scanning is of a comparable difficulty to using the stimuli in behavioural experiments, the magnetic environment of the MR scanner presents serious problems for somatosensory activation studies in fMRI. These problems hinge upon the submodality of stimulation employed.

At present there are a number of techniques used in experimental studies of the somatosensory system. Early behavioural studies of touch were constrained by the technology available to investigators (Weber’s early studies used coins and compasses; later investigators employed horse hairs [Von Frey hairs] calibrated to bend under known pressures). Similarly, initial attempts at mapping the spatial organisation of somatosensory cortex were far cruder than current non-invasive methods. Penfield and Boldrey (1937) were first to describe the somatosensory homunculus in human subjects using direct stimulation of the exposed cortical surface. This paper represents the beginning of ‘cartographic’ electrophysiology in the somatosensory system, in which the primary aim was to examine the spatial layout of receptive fields - how the body’s surface was mapped or represented in the brain. These early studies tend to be quoted extensively, and are frequently referred to as ‘gold standards’ with which to compare the efficacy of novel techniques for non-invasive mapping of human somatosensory cortex.

Most of subsequent research extending Penfield’s work was carried out in non­ human primates: e.g. the initial single cell somatosensory studies carried out by Mountcastle (1957); the work of Werner and Whitsel on transforming the three­

dimensional representation of the body onto a 2D plane (reviewed in Dykes and Ruest, 1986); and finally the first demonstration that the cytoarchitectonie areas of primary somatosensory cortex in monkeys each contain a map of the body surface (Merzenich et al., 1978). Human neurophysiological studies have necessarily lagged behind. Until the advent of somatosensory evoked magnetic fields (SEFs), somatosensory evoked potentials (SEPs) and PET and fMRI, most human data was acquired during invasive procedures on patients in a similar manner to Penfield’s original study. Early fMRI studies used simple yet hard to quantify stimulation methods such as rubbing the subject’s hand with the investigator’s hand (Yetkin et al., 1995). More sophisticated stimuli followed (textured surfaces, Lin et al., 1996; median nerve stimulation. Puce et al., 1995; peripheral electrical stimulation, Kurth et al., 1998), but few systematic studies of which stimuli optimally cause SI ‘activation’ were carried out. One of the few studies to do this compared two manual stimulation paradigms (air blowing over the palm vs. brushing the fingers) to median nerve stimulation (Puce et al., 1995). Median nerve simulation was found to be less reliable than other methods of stimulation, but the authors’ sample size was low. Certainly activation of SI is inconsistent in neuroimaging studies, and even a detailed examination of the parameters of each study do not greatly assist the choice of new stimulation methods.

While a number of early neuroimaging studies used somatosensory stimulation (e.g. Ingvar, 1975) it was apparent even at this stage that it was more difficult to elicit significant rCBF changes in the primary somatosensory cortex (SI) than, for example, in the primary motor cortex (M l). Ingvar’s early work showed that somatosensory stimulation produced more robust changes in frontal areas than parietal areas, contrary to evidence from human and non-human primate studies. He coined the term ‘sensory-motor paradox’ to describe his findings. A number of investigators have referred to this finding (e.g. Paulesu et al., 1997) as a reason why PET and fMRI studies of the somatosensory system (and SI in particular) are rarely as informative as those from other modalities (e.g. MEG, Yang et al., 1993; Nakamura et al., 1998). This is not to say that there have been no successful neurovascular neuroimaging studies of the somatosensory system - merely that it is tacitly accepted that somatosensory fMRI studies are difficult.

In clinical situations, it is common for investigators to use peripheral nerve stimulation: in particular, median nerve stimulation is used in both SEP and SEE studies (for reviews see McLaughlin et al., 1993 (SEPs) and Kakigi et al., 2000 (SEFs)). While this technique is a reliable test of peripheral nerve function, it is an inherently non-physiological method of stimulation - analogous to attempting to study the normal functioning of the visual system by direct stimulation o f the optic nerve. Although microneurography and microstimulation allow (careful) investigators to stimulate and record from single primary afferent fibres in unanaesthetised humans, and this has both clinical and experimental value, it is an invasive procedure with some morbidity, requiring skilled researchers and dedicated subjects. For these reasons and others, most neuroimaging studies use von Frey hairs, brushes or other stimuli manually administered by the investigator or a confederate during the scanning procedure. The motivation behind these techniques is often that they are simply and easily applied. However, if one wishes to go beyond categorical tactile activation studies and deliver calibrated, reproducible stimuli, more sophisticated methods are required.

3.1.2 Interactions Between M RI Environm ent and Experim ental Equipm ent During MRI procedures, the subject is exposed to three different forms of electromagnetic radiation: the static field (Bo field), gradient magnetic fields (B% field), and radiofrequency fields (the r.f. pulses used in image formation; see Chapter two). It is generally believed that no significant health effects arise from patient exposure to the above sources of radiation during routine MR investigations. Studies have failed to find any effects o f static fields on skin temperature (Tenforde, 1986), EGG waveforms (Dimick et al., 1987), or the CNS itself (up to fields of 2T; Kanal et al., 1990). The effects of gradient fields are more obvious. Fast switching of magnetic fields will induce current in appropriately orientated conductors, including biological tissue. There are a great number of variables that influence the strength and direction of induced currents in the body: for example, the effects are likely to be strongest in distal tissue (i.e. towards the periphery). The bioeffects of the induced fields can be of two forms: thermal (unlikely to be of great consequence; Kanal et al., 1990), or caused by the direct effects of the current itself, such as direct nerve stimulation. The latter is

rarely seen, even when using rapid gradient switching techniques such as EPI. The final effect is from exposure to if fields, which are thought to be principally thermogenic, (Shellock et al., 1986).

It follows from the evidence above that a standard MR procedure should not pose a significant health risk to normal subjects. However, the minor effects produced by the combination of static, rapidly shifting and r.f. fields can seriously disrupt the functioning of pieces of electrical equipment. Moreover, the electromagnetic interference generated by the presence of electronic circuitry within the magnet itself can be problematic. Thus the MR environment presents its own unique challenge to the delivery of physiological stimulation to experimental subjects, and to the recording of electrophysiological data.