The investigation of ERD changes associated with brushing described in this thesis was the first study to publish electrophysiological data regarding abnormal cortical processes during innocuous somatosensory stimuli in FMS patients (Fallon et al., 2013). Recently, this finding was followed by a study utilising MEG and innocuous somatosensory stimulation, which demonstrated abnormal event-related field potentials overlying somatosensory processing regions of FMS patients (Maestu et al., 2013). These studies show that FMS patients demonstrate alterations to processing of innocuous somatosensory stimuli, which may provide further insight into central sensitisation in FMS. Investigations of somatosensory processing may
164 eventually help to elucidate the mechanisms of allodynia pain in FMS. Prior to this thesis, psychophysical studies have primarily focused on abnormal processing of painful stimuli in FMS (Gracely et al., 2002; Cook et al., 2004; Staud et al., 2008). However, the role of somatosensory processing should not be underestimated in the disorder. Allodynia pain is particularly problematic in FMS and relates to other symptoms such as sleep disturbance (Chiu et al., 2005). It was previously proposed that pain and abnormal processing of somatosensory stimuli may relate to the pathophysiological mechanisms underlying the development of the syndrome (Staud et al., 2009; Staud, 2010). The findings of this thesis suggest that, rather than merely considering FMS as a dysfunction of pain processing, it is also important to consider the dysfunctional processing of somatosensory afferents to fully understand the mechanisms involved in FMS pain. This notion is further supported by recent findings which suggest peripheral pathophysiological causes such as small fibre neuropathy may contribute to FMS pain (Serra, 2012).
Event-related potential analysis of EEG data recorded during viewing of pain photographs revealed augmented source activations in FMS patients which were localised to the left parahippocampal gyrus. The enhanced source activation also covaried with the amount of pain attributed to images and measures of clinical and psychological disturbance. Alternatively, the resting-state functional connectivity analysis revealed reduced functional connectivity between the PCC in the DMN and the right parahippocampal gyrus. The degree of this disruption may relate to ongoing symptoms of FMS, as indicated by a significant correlation with years of symptom duration. Taken together, these findings appear to indicate that functional alterations localised to the parahippocampal gyri may be important to various clinical and psychological aspects of FMS.
165 The parahippocampal gyrus makes up part of the hippocampal formation (Insausti and Amaral, 2004), and it is functionally important in episodic and semantic memory retrieval (Binder et al., 2009; Langston et al., 2010). Cognitive function is impaired in FMS, and patients exhibit deficits in attention and working memory (Park et al., 2001; Leavitt and Katz, 2006; Dick et al., 2008). Dysfunction of the parahippocampal gyri in FMS may relate to such cognitive deficits. Although it is not considered to be a region of the ‘pain matrix’ (Apkarian et al., 2005), parahippocampal activations are commonly seen during experimental pain (Bingel et al., 2002; Veldhuijzen et al., 2009; Villemure and Bushnell, 2009; Berna et al., 2010), and activations in this region may encode emotional context during experimental pain (Ploghaus et al., 2001; Stancak et al., 2012a). Therefore, the parahippocampal gyrus may be functionally relevant to both memory and the emotional aspects of pain processing in FMS. Abnormal functioning of the parahippocampal gyri could relate to psychological aspects of pain in FMS such as empathic processing during observation of pain. Alternatively, such dysfunction may relate to abnormal resting-state connectivity with the structure, which appears to deteriorate over time and could relate to cognitive disturbance in FMS.
This thesis identified morphological alterations in the grey matter and subcortical structures of FMS patients relative to a healthy control group, but no alterations in white matter microstructure. Previously, a wide-range of cortical grey matter changes in FMS were identified using VBM methods (Kuchinad et al., 2007; Schmidt-Wilcke et al., 2007; Luerding et al., 2008; Lutz et al., 2008; Burgmer et al., 2009; Valet et al., 2009; Robinson et al., 2011), with little consistency or replication of findings. Therefore, the subcortical shape and volume alterations seen in the brainstem, identified using a novel shape analysis technique, may prove to be a
166 particularly relevant finding in FMS. Brainstem morphological alterations were previously shown in chronic pain patients, including those with FMS (May, 2009). The brainstem contains nuclei which underlie a wide range of processes such as homeostatic regulation, postural maintenance, and sleep cycle control (Naidich and Duvernoy, 2009), as well as structures which are vital for endogenous pain modulation (Lovick, 2008; Naidich and Duvernoy, 2009). Brainstem malformations could therefore be related to the symptoms seen in FMS. Morphological alterations to the brainstem could also be a causal factor in the various cortical alterations seen in previous VBM studies. Underlying subcortical alterations could interact with comorbidities and environmental factors to bring about the variety of cortical grey matter alterations seen in previous studies. FMS symptoms also show similarities with those seen in Chiari I malformation (Holman, 2008), and the syndrome is more than 10 times more likely to occur following a neck injury than after trauma to lower extremities (Buskila et al., 1997). The current findings accord with a potential cervico-spinal aspect of FMS pathophysiology. Whilst it would be inaccurate to suggest that FMS patients simply suffer from Chiari I malformation, it is possible that brainstem malformation, or abnormal pressure on the brainstem, could affect at least a proportion of patients.
White matter findings from previous studies in FMS patients are sparse and the findings of the final study of the thesis revealed no white matter anatomical alterations in FMS patients. However, this negative finding is still important as it suggests that the pathogenesis of FMS is unlikely to relate to abnormal development of white matter pathways, which primarily occurs during infancy and childhood (Hermoye et al., 2006; Huang et al., 2006). Therefore, grey matter and subcortical
167 alterations are more likely to contribute to any morphological pathophysiology of FMS.