However, as effects caused by alterations in cardiac output are likely to be systemic in nature and the group age difference in this study being comparatively small, it is assumed that potential effects between different intra-cranial functional areas are secondary to the proposed NAEPA neuropathic effects. The significant correlation found with increasing neuropathic severity supports this hypothesis. Additionally, in terms of group response to pain-provoking stimulation, there were no significant differences between median temperatures that were delivered and their resultant pain ratings to either of the groups. This was a cross-sectional screening study, with myeloma patients having already developed neuropathy in the context of receiving different anti-myeloma therapies. Some therapeutic regimens included more than one possible CIPN-inducing agent. Since no other known major risk factors for peripheral neuropathy were identified, such as diabetes, human immunodeficiency virus infection, chronic alcoholism, amyloidosis or renal failure, it would seem that a chemo-therapeutic response was the major overall causal factor linked to differences in both peripheral and central nervous systems. In addition, although peripheral neuropathy is seen at presentation in a small minority of patients with untreated MM, in our study, neuropathic pain started only after having received one of the anti-myeloma therapies described above. Most drugs used as an anti-myeloma treatment cannot permeate the blood�Cbrain barrier. The blood-nerve barrier protecting the peripheral system does however appear to be sensitive to the aforementioned agents. The PNS is thus more readily affected by circulating drug neurotoxicity than CNS structures. In the light of this, the Naltrindole isothiocyanate hydrochloride observed cerebral differences in BOLD response to heat stimulation may result from changes in sensory input to the brain or feedback circuitry via the spinal cord/brainstem. Longitudinal data from patients with myeloma embarking on chemotherapy would help to identify that CNS alterations do not occur prior to peripheral changes and thus the primary effect-site being the PNS. Such data would also help elucidate whether CNS and PNS changes occur concurrently or whether alterations in cerebral response follow a time lag suggestive of, for example, brain function accustomisation.