Increased posterior cingulate cortex blood flow in cancer-related fatigue.

Fatigue is a common symptom associated with cancer treatments. Brain mechanisms underlying cancer-related fatigue (CRF) and its progression following therapy are poorly understood. Previous studies have suggested a role of the default mode network (DMN) in fatigue. In this study we used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) and compared resting cerebral blood flow (CBF) differences in the posterior cingulate cortex (PCC), a core hub of the DMN, between 16 patients treated with radiation therapy (RAT) for prostate (9 males) or breast (7 females) cancer and 18 healthy controls (HC). Resting CBF in patients was also measured immediately after the performance of a fatiguing 20-min psychomotor vigilance task (PVT). Twelve of 16 cancer patients were further followed between 3 and 7 months after completion of the RAT (post-RAT). Patients reported elevated fatigue on RAT in comparison to post-RAT, but no change in sleepiness, suggesting that the underlying neural mechanisms of CRF progression are distinct from those regulating sleep drive progression. Compared to HC, patients showed significantly increased resting CBF in the PCC and the elevated PCC CBF persisted during the follow up visit. Post-PVT, but not pre-PVT, resting CBF changes in the PCC correlated with fatigue changes after therapy in patients with CRF, suggesting that PCC CBF following a fatiguing cognitive task may be a biomarker for CRF recovery.

Perfusion Imaging of Fatigue and Time-on-Task Effects in Patients With Parkinson's Disease.

Fatigue is a highly prevalent and debilitating non-motor symptom in Parkinson's disease (PD), yet its' neural mechanisms remain poorly understood. Here we combined arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) with a sustained mental workload paradigm to examine the neural correlates of fatigue and time-on-task effects in PD patients. Twenty-one PD patients were scanned at rest and during continuous performance of a 20-min psychomotor vigilance test (PVT). Time-on-task effects were measured by the reaction time changes during the PVT and by self-reported fatigue ratings before and after the PVT. PD subjects demonstrated significant time-on-task effects, including progressively slower reaction time on the PVT and increased post-PVT fatigue ratings compared to pre-PVT. Higher levels of general fatigue were associated with larger increases in mental fatigue ratings after the PVT. ASL imaging data showed increased CBF in the right middle frontal gyrus (MFG), bilateral occipital cortex, and right cerebellum during the PVT compared to rest, and decreased CBF in the right MFG at post-task rest compared to pre-task rest. The magnitude of regional CBF changes in the right MFG and right inferior parietal lobe correlated with subjective fatigue rating increases after the PVT task. These results demonstrate the utility of continuous PVT paradigm for future studies of fatigue and cognitive fatigability in patients, and support the key role of the fronto-parietal attention network in mediating fatigue in PD.

Specific Changes in Brain Activity during Urgency in Women with Overactive Bladder after Successful Sacral Neuromodulation: A Functional Magnetic Resonance Imaging Study.

PURPOSE: The mechanism of sacral neuromodulation is poorly understood. We compared brain activity during urgency before and after sacral neuromodulation in women with overactive bladder and according to the response to treatment. MATERIALS AND METHODS: Women with refractory overactive bladder who elected sacral neuromodulation were invited to undergo functional magnetic resonance imaging before and after treatment. During imaging the bladder was filled until urgency was experienced. Regions of interest were identified a priori and brain activity in these regions of interest was compared before and after treatment as well as according to the treatment response. Whole brain exploratory analysis with an uncorrected voxel level threshold of p <0.001 was also performed to identify additional brain regions which changed after sacral neuromodulation. RESULTS: Of the 12 women who underwent a pretreatment functional magnetic resonance imaging examination 7 were successfully treated with sacral neuromodulation and underwent a posttreatment examination. After sacral neuromodulation brain activity decreased in the left anterior cingulate cortex, the bilateral insula, the left dorsolateral prefrontal cortex and the bilateral orbitofrontal cortex (each p <0.05). No new brain regions showed increased activity after sacral neuromodulation. Pretreatment brain activity levels in the bilateral anterior cingulate cortex, the right insula, the bilateral dorsolateral prefrontal cortex, the right orbitofrontal cortex, the right supplementary motor area and the right sensorimotor cortex were higher in women who underwent successful treatment (each p <0.05). CONCLUSIONS: Brain activity during urgency changes after successful sacral neuromodulation. Sacral neuromodulation may be more effective in women with higher levels of pretreatment brain activity during urgency.

Quantitative Changes in Cerebral Perfusion during Urinary Urgency in Women with Overactive Bladder.

PURPOSE: To quantitatively measure changes in cerebral perfusion in select regions of interest in the brain during urinary urgency in women with overactive bladder (OAB) using arterial spin labeling (ASL). METHODS: Twelve women with OAB and 10 controls underwent bladder filling and rated urinary urgency (scale 0-10). ASL fMRI scans were performed (1) in the low urgency state after voiding and (2) high urgency state after drinking oral fluids. Absolute regional cerebral blood flow (rCBF) in select regions of interest was compared between the low and high urgency states. RESULTS: There were no significant differences in rCBF between the low and high urgency states in the control group. In the OAB group, rCBF (mean ± SE, ml/100 g/min) increased by 10-14% from the low to the high urgency state in the right anterior cingulate cortex (ACC) (44.56 ± 0.59 versus 49.52 ± 1.49, p < 0.05), left ACC (49.29 ± 0.85 versus 54.02 ± 1.46, p < 0.05), and left insula (50.46 ± 1.72 versus 54.99 ± 1.09, p < 0.05). Whole-brain analysis identified additional areas of activation in the right insula, right dorsolateral prefrontal cortex, and pons/midbrain area. CONCLUSIONS: Urinary urgency is associated with quantitative increase in cerebral perfusion in regions of the brain associated with processing emotional response to discomfort.

A novel paradigm to evaluate conditioned pain modulation in fibromyalgia.

INTRODUCTION: Application of noxious stimulation to one body area reduces pain sensitivity in a remote body area through activation of an endogenous pain-inhibitory network, a behavioral phenomenon referred to as conditioned pain modulation (CPM). The efficiency of CPM is predictive of a variety of health outcomes, while impaired CPM has been associated with various chronic pain conditions. Current methods used to assess CPM vary widely, and interest in CPM method development remains strong. Here, we evaluated a novel method for assessing CPM in healthy controls and fibromyalgia (FM) patients using thumb pressure as both a test and conditioning stimulus. METHODS: Sixteen female FM patients and 14 matched healthy controls underwent CPM testing with thumbnail pressure as the test stimulus, and either cold water or noxious pressure as the conditioning stimulus. CPM magnitude was evaluated as the difference in pain rating of the test stimulus applied before and during the conditioning stimulus. RESULTS: In healthy controls, application of either pressure or cold water conditioning stimulation induced CPM as evidenced by a significant reduction in test stimulus pain rating during conditioning (P=0.007 and P=0.021, respectively). In contrast, in FM patients, neither conditioning stimulus induced a significant CPM effect (P>0.274). There was a significant difference in CPM magnitude for FM patients compared to healthy controls with noxious pressure conditioning stimulation (P=0.023); however, no significant difference in CPM was found between groups using cold water as a conditioning stimulus (P=0.269). CONCLUSION: The current study demonstrates that thumbnail pressure can be used as both a test and conditioning stimulus in the assessment of CPM. This study further confirms previous findings of attenuated CPM in FM patients compared with healthy controls.

Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.

UNLABELLED: The insular cortex (IC) and cingulate cortex (CC) are critically involved in pain perception. Previously we demonstrated that fibromyalgia (FM) patients have greater connectivity between the insula and default mode network at rest, and that changes in the degree of this connectivity were associated with changes in the intensity of ongoing clinical pain. In this study we more thoroughly evaluated the degree of resting-state connectivity to multiple regions of the IC in individuals with FM and healthy controls. We also investigated the relationship between connectivity, experimental pain, and current clinical chronic pain. Functional connectivity was assessed using resting-state functional magnetic resonance imaging in 18 FM patients and 18 age- and sex-matched healthy controls using predefined seed regions in the anterior, middle, and posterior IC. FM patients exhibited greater connectivity between 1) right mid IC and right mid/posterior CC and right mid IC, 2) right posterior IC and left CC, and 3) right anterior IC and left superior temporal gyrus. Healthy controls displayed greater connectivity between left anterior IC and bilateral medial frontal gyrus/anterior cingulate cortex; and left posterior IC and right superior frontal gyrus. Within the FM group, greater connectivity between the IC and CC was associated with decreased pressure-pain thresholds. PERSPECTIVE: These data provide further support for altered resting-state connectivity between the IC and other brain regions known to participate in pain perception/modulation, which may play a pathogenic role in conditions such as FM. We speculate that altered IC connectivity is associated with the experience of chronic pain in individuals with FM.

Lifestyle Modification in Blood Pressure Study II (LIMBS): study protocol of a randomized controlled trial assessing the efficacy of a 24 week structured yoga program versus lifestyle modification on blood pressure reduction.

Hypertension is a major public health issue affecting 68 million adults in the United States. Lifestyle modifications including complementary therapies such as the movement based mind body practice of yoga have become increasingly popular in the United States and have been considered as a potential alternative to medication in blood pressure reduction. We completed a pilot study in 2009 which showed meaningful decreases in 24-hour ambulatory blood pressure readings after a 12 week period of yoga participation. Based on data from our pilot study we are now completing The Lifestyle Modification and Blood Pressure Study (LIMBS II) which is a phase 2 randomized controlled trial designed to determine the effects of yoga therapy and enhanced lifestyle modification on lowering blood pressure in pre-hypertensive and stage 1 hypertensive subjects. Using 24-hour ambulatory blood pressure monitoring, LIMBS II aims to compare the effects on blood pressure reduction in subjects randomized for 24 weeks to one of the three following groups: yoga therapy versus blood pressure education program (sodium restriction and walking program) versus a combination program that involves components of both groups. LIMBS II will also examine the impact that changes in blood pressure have on cerebral blood flow. If successful, the LIMBS study will determine if yoga therapy combined with enhanced lifestyle modification will result in clinically meaningful decreases in blood pressure and thus can be implemented as an alternative to drug therapy for patients with prehypertension and stage 1 hypertension.

Augmented central pain processing in vulvodynia.

UNLABELLED: Vulvodynia (VVD) is a chronic pain disorder wherein women display sensitivity to evoked stimuli at the vulva and/or spontaneous vulvar pain. Our previous work suggests generalized hyperalgesia in this population; however, little is known about central neurobiological factors that may influence pain in VVD. Here we investigated local (vulvar) and remote (thumb) pressure-evoked pain processing in 24 VVD patients compared to 13 age-matched, pain-free healthy controls (HCs). As a positive control we also examined thumb pressure pain in 24 fibromyalgia patients. The VVD and fibromyalgia patients displayed overlapping insular brain activations that were greater than HCs in response to thumb stimulation (P < .005 corrected). Compared to HCs, VVD participants displayed greater levels of activation during thumb stimulation within the insula, dorsal midcingulate, posterior cingulate, and thalamus (P < .005 corrected). Significant differences between VVD subgroups (primary versus secondary and provoked versus unprovoked) were seen within the posterior cingulate with thumb stimulation and within the precuneus region with vulvar stimulation (provoked versus unprovoked only). The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder. Moreover, differing central activity between VVD subgroups suggests heterogeneous pathologies within this diagnosis. PERSPECTIVE: The presence of augmented brain responses to pressure stimuli remote from the vulva was observed in vulvodynia patients. These findings may guide treatment decisions for better response, as brain mechanisms may be a factor in some VVD patients.