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PART FIVE  METHODS FOR SYMPTOMATIC CONTROL

such as the pregenual anterior cingulate cortex, whereas only burst SCS reduced the connectivity between the dorsal anterior cingulate and the parahippocampal cortices. The originators of the burst paradigm 72 claim that the burst type of SCS preferentially modulates the medial spinothalamic pathway leading to activity changes in subcortical centers involved in emotions, whereas conventional SCS acts more on the lateral tract leading to the lateral thalamic nuclei and eventually to the sensory cortex. They hypothesize that burst stimulation modulates the medial pain pathway by actions of C fibers synapsing onto lamina I neurons with projections to the dorsomedial nucleus of the thalamus and from there to the dorsal anterior cingulum. An earlier functional magnetic reso­ nance imaging (fMRI) study 73 demonstrated that conventional SCS predominantly modulated the lateral pain pathways as judged by changes in blood oxygen levels in the somatosensory cortices. Burst SCS, at least in rat models, does not seem to involve the DC system 74 —another difference to conventional pares­ thetic SCS. More recent data indicate that the effects of burst SCS do not rely on activation of GABA-B receptors 75 as has been claimed for conventional SCS (e.g., Cui et al., 39 Cui et al., 40 Meyerson et al., 44 Cui et al., 76 Ultenius et al. 77 ). Burst SCS is commonly administered at amplitudes that do not produce paresthesia. In spite of this, as the average fre­ quency is higher, the energy consumption is larger than that of conventional SCS. A recent finding is that the efficacy of burst SCS seems to relate to the electric charge per burst, at least as found in a rat model of neuropathic pain. 78 In conclusion, burst SCS as now most often used clinically (5 pulses at 500 Hz repeated with 40-Hz rate at subparesthetic amplitude) cannot be completely explained on the basis of physiologic mechanisms activated or inhibited by stimulation of the dorsal aspect of the spinal cord. Preclinical and clini­ cal studies are underway to shed more light on mechanisms of these novel algorithms. At present, almost all manufacturers produce stimulators that can generate stimulation frequencies up to and above 1 kHz and PWs up to 1 m sec. Higher frequencies than those typically used for SCS have been available for many years 79 but have been used and reported for pain only anecdotally. A few centers during the 80s applied high cervical SCS (around 1,000 Hz) for torticollis. 80 Because the higher frequencies and longer PWs were avail­ able already in the existing stimulators, many centers tried to adapt the stimulation parameters especially in cases with ther­ apy failure after some time with conventional SCS but eventu­ ally also in new cases during trials. It must be kept in mind that frequencies above 800 Hz with stimulation-induced paresthesias can be perceived as very unpleasant, 13 and so these parameters usually were used at subparesthetic amplitude. In this way, higher amounts of electric charge could be transmitted from the electrode poles to the neural tissue without discomfort or damage to the ner­ vous system. 81 Recent experiments in the rat have demonstrated that sub­ sensory SCS can exert clear effects on symptoms of neuropathic pain. 60,64,67 These studies also show that moderately increased frequencies of 1,000 Hz can be as effective at the subsensory level as 10-kHz SCS. Such changes in SCS parameters to in­ crease transfer of electric charge have been tried clinically in recent years referring to the fact that pulse density (i.e., the percentage active stimulation during a pulse cycle) can be in­ creased from just 1% to 2% up to 20% to 25% for the maxi­ mal available settings at a subsensory mode. MODERATE CHANGES OF CONVENTIONAL SPINAL CORD STIMULATION PARAMETERS

The few clinical reports on this type of stimulation now available 14,82–84 will be discussed below. Furthermore, some re­ cent studies also illustrate that for each patient, the SCS ther­ apy could be optimized by the use of “individualized” settings and that some patients actually like to keep their paresthetic SCS as part of their stimulation program. 14,84 In conclusion to this section, it must be admitted that we are just at the begin­ ning of exploration of the efficacy of slightly changed SCS pa­ rameters, and only short-term results are available so far. The mechanisms behind an increased effect has not been studied (besides using higher frequencies; e.g., 500 and 1,000 Hz), and the neurophysiologic/neurochemical correlates are not known. COMPUTER MODELING STUDIES Finite element computer models of SCS electrical fields in the spinal cord 85–87 have confirmed the current and voltage dis­ tribution measurements previously obtained in cadavers and primates. 88 Application of these models has also led to the pre­ diction that (1) an electrode’s longitudinal position governs its segmental effect; (2) bipolar stimulation with contacts sepa­ rated by 6 to 8 mm optimizes selection of midline, longitu­ dinally oriented fibers (a longer distance reduces therapeutic effect by favoring dorsal root stimulation); and (3) the elec­ trical field between two cathodes placed on either side of the physiologic midline does not sum constructively in the midline. Clinical experience confirms that the correct position and spac­ ing of SCS electrodes is essential for therapeutic success and that, instead of expanding the area of paresthesia, positioning electrodes cephalad to the involved spinal levels commonly elicits unwanted, excessive, local segmental effects. 10 The first computerized models developed to study the spi­ nal canal represented the meninges, cerebrospinal fluid, fiber tracts, and gray matter with geometric shapes. 89,90 The equally simplistic, two-dimensional initial computer models of dor­ sal epidural stimulation 91–93 were soon replaced by a three-dimensional model that took into account fiber tracts, their branch points, and dorsal roots. 85,94 In 1991, Holsheimer and Struijk 95 developed a new model that merged this three-dimensional construct with a McNeal-type 96 cable model of the electrical behavior of myelinated nerve fibers and data derived from mammalian myelinated fibers. 97 The resulting “University of Twente SCS Computer Model” allowed investigators to determine the impact of the location and configuration (anode/cathode, on/off) of SCS electrodes (e.g., to maximize recruitment of deep, midline, longitudinal axons rather than of the lateral, or dorsal root, fibers that can cause discomfort and motor responses) and to suggest ways to optimize SCS equipment design. The University of Twente model was further refined when the investigators were able to apply data from human sensory fibers. 98 This improved the accuracy of predictions about the impact of various SCS threshold voltages. 99 An additional improvement streamlined the mathematical techniques used to predict stimulation effects when computing the three-dimensional action potential field. 100 Model predictions for “transverse tripole” electrode performance have been validated in part by clinical studies. 101 Lempka et al. 61 recently applied a similar model to kilohertz frequency SCS and reported that at intensities used clinically, stimulation probably does not cause the direct activation or conduction block of dorsal column or dorsal root fibers. 61 Arle et al., 102 on the other hand, inferred from a similar model that because of an interaction between ion gate dynamics and the anodal current distribution over axons, larger fibers that cause paresthesia in low-frequency simulation are blocked at higher frequencies, whereas medium and smaller fibers are recruited, leading to pain relief by inhibiting centrally projecting WDR cells in the DH.