Richard Kwiatek

Regional cerebral blood flow in fibromyalgia: Single-photon–emission computed tomography evidence of reduction in the pontine tegmentum and thalami

OBJECTIVE To determine whether regional cerebral blood flow (rCBF) is abnormal in any cerebral structure of women with fibromyalgia (FM), following a report that rCBF is reduced in the thalami and heads of caudate nuclei in FM. METHODS Seventeen women with FM and 22 healthy women had a resting single-photon-emission computed tomography (SPECT) brain scan to assess rCBF and a T1-weighted magnetic resonance imaging (MRI) scan to enable precise anatomic localization. Additionally, all participants underwent 2 manual tender point examinations and completed a set of questionnaires evaluating clinical features. SPECT scans were analyzed for differences in rCBF between groups using statistical parametric mapping (SPM) and regions of interest (ROIs) manually drawn on coregistered MRI. RESULTS Compared with control subjects, the rCBF in FM patients was significantly reduced in the right thalamus (P = 0.006), but not in the left thalamus or head of either caudate nucleus. SPM analysis indicated a statistically significant reduction in rCBF in the inferior pontine tegmentum (corrected P = 0.006 at the cluster level and corrected P = 0.023 for voxel of maximal significance), with consistent findings from ROI analysis (P = 0.003). SPM also detected a reduction in rCBF on the perimeter of the right lentiform nucleus. No correlations were found with clinical features or indices of pain threshold. CONCLUSION Our finding of a reduction in thalamic rCBF is consistent with findings of functional brain imaging studies of other chronic clinical pain syndromes, while our finding of reduced pontine tegmental rCBF is new. The pathophysiologic significance of these changes in FM remains to be elucidated.

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis

To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel‐based regressions against clinical scores. Using SPM5 we performed voxel‐based morphometry (VBM) and analysed T1‐ and T2‐weighted spin‐echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24‐h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1‐weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).

Validation of fully automatic brain SPET to MR co-registration

Abstract.Fully automatic co-registration of functional to anatomical brain images using information intrinsic to the scans has been validated in a clinical setting for positron emission tomography (PET), but not for single-photon emission tomography (SPET). In this paper we evaluate technetium-99m hexamethylpropylene amine oxime to magnetic resonance (MR) co-registration for five fully automatic methods. We attached six small fiducial markers, visible in both SPET and MR, to the skin of 13 subjects. No increase in the radius of SPET acquisition was necessary. Distortion of the fiducial marker distribution observed in the SPET and MR studies was characterised by a measure independent of registration and three subjects were excluded on the basis of excessive distortion. The location of each fiducial marker was determined in each modality to sub-pixel precision and the inter-modality distance was averaged over all markers to give a fiducial registration error (FRE). The component of FRE excluding the variability inherent in the validation method was estimated by computing the error transformation between the arrays of MR marker locations and registered SPET marker locations. When applied to the fiducial marker locations this yielded the surface registration error (SRE), and when applied to a representative set of locations within the brain it yielded the intrinsic registration error (IRE). For the best method, mean IRE was 1.2 mm, SRE 1.5 mm and FRE 2.4 mm (with corresponding maxima of 3.3, 4.3 and 5.0 mm). All methods yielded a mean IRE <3 mm. The accuracy of the most accurate fully automatic SPET to MR co-registration was comparable with that published for PET to MR. With high standards of calibration and instrumentation, intra-subject cerebral SPET to MR registration accuracy of <2 mm is attainable.

Evidence in chronic fatigue syndrome for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression

White matter (WM) involvement in chronic fatigue syndrome (CFS) was assessed using voxel‐based regressions of brain MRI against CFS severity scores and CFS duration in 25 subjects with CFS and 25 normal controls (NCs). As well as voxel‐based morphometry, a novel voxel‐based quantitative analysis of T1‐ and T2‐weighted spin‐echo (T1w and T2w) MRI signal level was performed. Severity scores included the Bell CFS disability scale and scores based on the 10 most common CFS symptoms. Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores were included as nuisance covariates. By relaxing the threshold for cluster formation, we showed that the T1w signal is elevated with increasing CFS severity in the ventrolateral thalamus, internal capsule and prefrontal WM. Earlier reports of WM volume losses and neuroinflammation in the midbrain, together with the upregulated prefrontal myelination suggested here, are consistent with the midbrain changes being associated with impaired nerve conduction which stimulates a plastic response on the cortical side of the thalamic relay in the same circuits. The T2w signal versus CFS duration and comparison of T2w signal in the CFS group with the NC group revealed changes in the right middle temporal lobe WM, where impaired communication can affect cognitive function. Adjustment for depression markedly strengthened cluster statistics and increased cluster size in both T1w severity regressions, but adjustment for anxiety less so. Thus, depression and anxiety are statistical confounders here, meaning that they contribute variance to the T1w signal in prefrontal WM but this does not correlate with the co‐located variance from CFS severity. MRI regressions with depression itself only detected associations with WM volume, also located in prefrontal WM. We propose that impaired reciprocal brain–body and brain–brain communication through the midbrain provokes peripheral and central responses which contribute to CFS symptoms. Although anxiety, depression and CFS may share biological features, the present evidence indicates that CFS is a distinct disorder.

Age related preservation and loss in optimized brain Spect

BackgroundRecent single photon emission computed tomography (SPECT) studies have reported age related increases in regional brain perfusion (called preservation here) as well as losses. AimTo apply optimized SPECT processing to better define and understand both age related preservation and loss in brain SPECT. MethodsBrain SPECT was performed on 85 healthy subjects using 99mTc hexamethylpropylene amine oxime (HMPAO), processed using findings from recent optimization work, and subjected to voxel based statistical analysis. ResultsSPECT preservation was seen in white matter. This distribution differs from other SPECT reports, but is similar to that for preservation observed with structural magnetic resonance imaging (MRI). This suggests that SPECT preservation may arise from age related changes in brain anatomy, not regional cerebral blood flow (rCBF), and we demonstrate that it can arise from the partial-volume effect in areas where white matter contracts with age. Age related losses extended over the whole pre-frontal midline area and an extended pattern of focal losses was seen in the peripheral cortex that was consistent with major sulci. There were also focal losses in the cerebellum. The most significant SPECT loss was in the anterior cingulate, although no structural changes were observed there in the MRI study. A model of sulcal widening at the junction of the inter-hemispheric fissure and cingulate sulcus, when degraded by the partial-volume effect, could explain this anterior cingulate loss. ConclusionOptimized processing has revealed spatial patterns for age related preservation and losses in brain SPECT that indicate their origin is primarily structural. Correction for structural effects in optimized SPECT is needed to confirm whether any regional ageing effects derive from changes in rCBF.

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study

To examine progressive brain changes associated with chronic fatigue syndrome (CFS).

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT‐T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT‐T1w intensities (family‐wise error corrected cluster, PFWE < 0.05) and between PSQI and T1w intensities (PFWE < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison

BACKGROUND Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), and Multiple Sclerosis (MS) may share some similarities in relation to reduced NK cell activity. It is likely that other cells such as regulatory T (Tregs), invariant Natural Killer T (iNKT) and gamma delta T (γδ T) cells may also be dysregulated in CFS/ME and MS. OBJECTIVE To evaluate and compare specific immune regulatory cells of patients with CFS/ME, patients with MS and healthy controls. METHOD Sixty three volunteers were included in this study: 24 were CFS/ME patients, 11 were MS patients and 27 were healthy controls. Blood samples were obtained from all participants for flow cytometry analysis of iNKT cells, Tregs and γδ T cell phenotypes. RESULTS We observed a significant increase in Tregs in the CFS/ME group (p≤0.05) compared to the healthy control group. Total γδ and γδ2 T cells were significantly reduced in MS patients in comparison with the healthy control group. Conversely, CD4+iNKT percentage of iNKT, was significantly increased in the CFS/ME group compared with healthy controls and the double-negative iNKT percentage of iNKT significantly decreased compared with the healthy control group. CONCLUSIONS This study has not identified any immunological disturbances that are common in both MS and CFS/ME patients. However, the differential expression of cell types between the conditions investigated suggests different pathways of disease. These differences need to be explored in further studies.