Spinal Cord fMRI

4.1.1.2.1

Neurovascular Coupling in the Spinal Cord

As in the brain, spinal neurons require energy supplied by ATP and so are dependent on the delivery of oxygen via blood flow. To study this relationship, Marcus et al. induced a metabolic response in the lumbosacral spinal cord following stimulation of the femoral and sciatic nerves in dog, lamb, and sheep. They concurrently measured blood flow using microelectrodes, detecting a 50% local blood flow increase in the ipsilateral gray matter but no significant blood flow increases in the ipsilateral white matter nor in the whole contralateral region. The authors therefore concluded that the hemodynamic response following a metabolic stimulus is extremely localized in terms of vascular reaction close to the activated neurons. This observation has since been confirmed by intrinsic optical imaging studies in the cervical and lumbar spinal cord of rats.

Complementary insight into blood flow control comes from a study by Nix et al., who compared vascular reactivity between the spinal cord and the brain in the rat. They used microelectrodes to measure arterial partial pressure of O ₂ $\left(P_{O_2}\right)$ changes to a CO ₂ challenge (“hypercapnia”). A brisker vascular response was observed in the cord compared to the brain, leading the authors to conclude that “spinal cord blood flow regulation is somewhat more sensitive to CO ₂ than is that in the brain cortex”. We could hypothesize that vascular coupling is tighter in the spinal cord than that in the brain, yielding less washout of deoxyhemoglobin and therefore lower BOLD effect.

4.1.1.2.2

Hemodynamic Response Function

The timing of the BOLD response depends on the coupling between oxygen demand from neurons and the vascular response. The temporal profile of this response is characterized by a hemodynamic response function (HRF), whose height, shape, and phase (relative to the onset of oxygen demand) are a fundamental component in the modeling process commonly used in fMRI analysis. A canonical HRF, available in most fMRI processing packages (e.g., SPM, FSL, AFNI) is typically used for analyzing brain fMRI data. Despite this common usage, the HRF is known to vary across brain regions, and one human study has demonstrated a slower HRF in the spinal cord compared to the brain canonical HRF. Given the contradictory results from human in vivo studies using fMRI and more direct experimental animal studies using e.g., laser Doppler blood flow, characterizing the HRF in the spinal cord in response to various stimuli warrants further investigation.

4.1.1.3.1

Motor Tasks

The hand has been the preferred target for motor tasks as it can be used with relatively little co-motion of more proximal muscles that might result in bulk movement of the spinal cord. Fist clenching may be expected to yield a functional response over a large extent of the spinal cord due to its involvement of the muscles of the forearm and all the digits of the hand and their coordinated motion. Unsurprisingly, it was used in the first spinal fMRI study and has been the basis for characterizing the temporal features of the spinal BOLD response. It should be noted that motor tasks will inevitably involve both a motor and a proprioceptive/sensory component. Through finger tapping experiments, researchers have investigated spinal cord responses specific to the complexity and speed of performing finger movements. Both greater complexity and higher rate were associated with greater BOLD responses.

Leg movements are of particular interest for spinal cord injury studies and locomotor rehabilitation but are difficult to achieve without inducing task-related movement that may induce false positive results.

4.1.1.3.2

Sensory Stimulation

Different classes of afferent nerve fibers convey sensory information from the body surface, muscles, and viscera to the spinal cord. These fibers are specialized, in that some respond preferentially to light touch, vibration, stretch, moving stimuli, or temperature and others to potentially tissue-damaging stimuli (so called nociceptors).

The role of the spinal cord in the processing of painful stimuli has been an active area of investigation with electrical, laser, and thermal stimuli being applied in imaging experiments. Studies comparing noxious and non-noxious electrical stimuli in rats have shown notably higher reproducibility and sensitivity of BOLD responses to noxious stimuli. A similar distinction has been observed in humans between noxious laser heating and innocuous brush strokes to the dorsum of the hand. These findings correspond well with prior reports in animal models using autoradiography and invasive measurements. In agreement with known neuroanatomical pathways, increased BOLD signal has been observed primarily ipsilateral to the side of nociceptive stimulation. A first investigation of the influence of placebo modulation of spinal responses to painful sensory stimuli has been reported by Eippert et al. Rather limited effort has gone into BOLD studies of non-nociceptive stimuli in their own right. Tactile stimulation (vibration at the finger tips at 3 Hz) has been shown to produce activation of the cervical cord in humans.

4.1.2.1.1

Cross-Sectional Distribution of Gray Matter Specialization

The primary synaptic connections in the motor and sensory systems of the spinal cord are distributed as illustrated in the Annex (Figures 7–14). In general the cell bodies and synapses of motor neurons are located in the ventral horn. In contrast, sensory neurons have their cell bodies located in the dorsal root ganglion outside the spinal cord and rely on interneurons, with which they form synaptic connections in the dorsal horn, to relay sensory information to supraspinal regions. From the spinal cord, the motor system gives rise to the ventral nerve roots, while sensory information is carried via the dorsal nerve roots.

4.1.2.1.2

Vertebral/Spinal Nerve Equivalence

Motor stimulation paradigms involving a particular muscle or muscle group (collectively known as a myotome) or sensory stimulation of a particular region of the skin (served by a single spinal nerve, and referred to as a dermatome) will be associated with cord activity corresponding to the representative nerve root (ventral—motor, dorsal—sensory). It is thus established neurophysiological practice to describe the position of such spinal cord responses in terms of the corresponding spinal nerve root (“spinal” or “segmental” level). Unfortunately, an important discrepancy has emerged in that spinal cord fMRI results are typically analyzed and interpreted relative to the vertebral level. This can be problematic as the spinal and vertebral levels are not anatomically matched. Although there is a gross model for finding spinal nerve entries relative to vertebral levels (see Annex), this correspondence is not entirely accurate as there is intersubject variability. In short, the human spinal column (vertebral bones, ligaments, and intervertebral discs) grows at a more rapid pace and in response to different forces than the human spinal cord. As a result the spinal cord is considerably shorter than the spinal column in adults (less so in infants), and the nerve roots tend to exit the spinal canal considerably lower than the position of their entry/exit from the spinal cord. Concerning the cervical cord, it is worth noting that the nerve roots for the 2nd to 7th spinal nerves exit at or above the level of their corresponding vertebral bodies, but the 8th cervical nerve root is not associated with a vertebral body and exits immediately below the 7th cervical and above the 1st thoracic vertebral body. Thereafter the spinal nerves exit below, and sometimes some distance from, the level of their associated vertebral body.

Recent studies have investigated this issue by performing structural imaging of nerve rootlets and by finding the correspondence between spinal and vertebral levels. Moreover, the spinal nerves are not comprised of a single unit but rather as a series of rootlets fanning out over some rostral-caudal extent. A consequence of this structural formation is that a given nerve root can be expected to form synapses across a relatively extended segment of the spinal cord ( Figure 4.1.2 ). For any given subject, the exact distribution of spinal rootlets is rarely known and is likely to vary across subjects, leading to variability in response location along the spinal cord within the territory of a given nerve root.

4.1.2.1.3

Distribution of Neuronal Activity in Response to Sensory/Motor Stimulus

The spatial distribution of neuronal activity in the axial and rostro-caudal dimensions is likely to further vary across individuals as the location of dermatome boundaries and polysynaptic pathways differ slightly between individuals. The contribution from descending modulation was also shown to vary, hence motor tasks can elicit variable distribution of activity across subjects.

Moreover, most motor tasks are not “purely motor” as they also involves sensory inputs. For example, a ball-squeezing task also involves sensory inputs from the palm and fingers as well as proprioceptive inputs.

4.1.2.1.4

Ipsi/Contralaterality

Although consistent ipsilateral activation has been reported, its poor reproducibility has also been noted. Ipsilateral neurons of the spinal cord are expected to activate predominantly when performing motor or sensory tasks. However, contralateral motorneurons and interneurons are also involved through various crossed spinal pathways. Thus, lateralization of activity is not a clear-cut issue.

Further complicating the differentiation of ipsi- and contralateral activity are partial volume effects (voxels can include both right and left sides). To minimize the effect of partial volume effect, axial acquisition with high in-plane resolution is recommended.

Previous studies in the brain have also raised possibility of a “blood stealing” effect in which “negative BOLD” signal is recorded in an inactive area near the site of increased metabolic demand. This effect is caused by the reduction in blood supply (hence decrease of T ₂ ^∗ -weighted signal), due to an increase of blood flow in a neighboring vasculature area where neuronal activation occurs. As the anterior arterial supply to the spinal cord is carried by a midline vessel, the scope exists for steal even in the contralateral cord, as well as distal to the cord along the longitudinally running posterior arteries. However, intrinsic optical imaging techniques applied in the rat spinal cord, which directly measure the relative proportions of deoxygenated and oxygenated blood through light reflectance, revealed a predominantly ipsilateral response to right and left forepaw electrical nerve stimulation. Furthermore, Sasaki et al. did not find any evidence for vascular stealing, suggesting that in the anesthetized rat normal neurovascular coupling leads to ipsilateral increased blood flow following stimulation, without apparent compensatory changes in the contralateral cord.