The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics.

Objective. Fibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain-processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM.Methods. Ten patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H-MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H-MRS, the anterior and posterior insular regions were examined separately using single-voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Fibromyalgia (FM) is a chronic widespread pain disorder that affects ϳ2-4% of individuals in industrialized countries (1). Although the underlying etiology of this condition is unknown, dysfunction within the central nervous system has been implicated. Results from functional magnetic resonance imaging (FMRI) (2,3), singlephoton emission tomography (4), and positron emission tomography (5) support this hypothesis.One structure that is consistently found to be associated with augmented evoked pain activity in FM is the insula (2,3). In addition to its function in speech, taste, and auditory systems, the insula is also intimately involved in somatosensory and visceral pain processing (6). It is strategically located in a bidirectional pathway between the secondary somatosensory cortex and the amygdala (6). This anatomic position may give the insula ClinicalTrials.gov identifier: NCT00142597.

Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.

Objective Recent scientific findings have reinvigorated interest in examining the role of γ-aminobutyric acid (GABA), the major inhibitory central nervous system neurotransmitter, in chronic pain conditions. Decreased inhibitory neurotransmission is a proposed mechanism in the pathophysiology of chronic pain syndromes such as fibromyalgia (FM). The purpose of this study was to test the hypothesis that decreased levels of insular and anterior cingulate GABA would be present in FM patients, and that the concentration of this neurotransmitter would be correlated with pressure–pain thresholds. Methods Sixteen FM patients and 17 age- and sex-matched healthy controls underwent pressure–pain testing and a 3T proton magnetic resonance spectroscopy session in which the right anterior insula, right posterior insula, anterior cingulate, and occipital cortex were examined in subjects at rest. Results GABA levels in the right anterior insula were significantly lower in FM patients compared with healthy controls (mean ± SD 1.17 ± 0.24 arbitrary institutional units versus 1.42 ± 0.32 arbitrary institutional units; P = 0.016). There was a trend toward increased GABA levels in the anterior cingulate of FM patients compared with healthy controls (P = 0.06). No significant differences between groups were detected in the posterior insula or occipital cortex (P > 0.05 for all comparisons). Within the right posterior insula, higher levels of GABA were positively correlated with pressure–pain thresholds in the FM patients (Spearman's rho = 0.63; P = 0.02). Conclusion Diminished inhibitory neurotransmission resulting from lower concentrations of GABA within the right anterior insula may play a role in the pathophysiology of FM and other central pain syndromes.

Background Varying degrees of cortical amyloid deposition are reported in the setting of Parkinsonism with cognitive impairment. We performed a systematic review to estimate the prevalence of Alzheimer disease (AD) range cortical amyloid deposition amongst patients with Parkinson disease with dementia (PDD), Parkinson disease with mild cognitive impairment (PD-MCI) and dementia with Lewy bodies (DLB). We included amyloid PET imaging studies using Pittsburgh Compound B (PiB). Methods We searched the databases Ovid MEDLINE, PubMed, Embase, Scopus, and Web of Science for articles pertaining to amyloid imaging in Parkinsonism and impaired cognition. We identified 11 articles using PiB imaging to quantify cortical amyloid. We used the metan module in Stata, version 11.0, to calculate point prevalence estimates of patients with “PiB-positive” studies, ie patients showing AD range cortical Aβ-amyloid deposition. Heterogeneity was assessed. A scatterplot was used to assess publication bias. Results Overall pooled prevalence of “PiB-positive” studies across all three entities along the spectrum of Parkinson disease and impaired cognition (specifically PDD, PD-MCI and DLB) was 0.41 (95% CI 0.24-0.57). Prevalence of “PiB-positive” studies was 0.68 (95% CI 0.55-0.82) in the DLB group, 0.34 (95% CI 0.13-0.56) in the PDD group and 0.05 (95% CI -0.07-0.17) in the PD-MCI group. Conclusion There is substantial variability in the prevalence of “PiB-positive” studies in subjects with Parkinsonism and cognitive impairment. Higher prevalence of PiB positive studies was encountered among subjects with DLB as opposed to subjects with PDD. PD-MCI subjects showed overall lower prevalence of PiB positive studies than reported findings in non-PD related MCI.

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IMPORTANCELittle is known about the relative contributions of multisystem degenerative processes across the spectrum of predemented cognitive decline in Parkinson disease (PD).OBJECTIVE To investigate the relative frequency of caudate nucleus dopaminergic and forebrain cholinergic deficits across a spectrum of cognitively impaired patients with PD to explore their relative, individual, and combined contributions to cognitive impairment in PD. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional study at an academic movement disorders clinic that included a predominantly nondemented cohort of 143 patients with PD. The mean (SD) age of patients was 65.5 (7.4) years and the mean (SD) Hoehn and Yahr stage was 2.4 (0.6). MAIN OUTCOMES AND MEASURESBinary classification of carbon 11-labeled [ 11 C]PMP acetylcholinesterase and caudate nucleus [ 11 C]DTBZ monoaminergic positron-emission tomography imaging based on normative data. The frequency of significant degenerative processes based on normative values was determined for consecutive intervals of cognitive impairment, ranging from no or minimal (z > −0.5) to more severe (z Յ −2) cognitive impairment.RESULTS Across the spectrum from minimal (z > −0.5) to more severe (z Յ −2) global cognitive impairment scores, caudate nucleus dopaminergic denervation was relatively frequent in individuals with minimal or no cognitive changes (51.1%) and increased in patients with more severe cognitive impairments (χ 2 = 12.8; P = .01). Cortical cholinergic denervation frequency increased monotonically with increasing cognitive impairment from 24.7% (z > −0.5) to 85.7% (z Յ −2); χ 2 = 23.2; P = .001). Eighty-seven percent of patients with neocortical cholinergic deficits had caudate nucleus dopaminergic deficits. Multiple regression analysis (F = 7.51; P < .001) showed both independent cognitive predictions for caudate nucleus dopaminergic (F = 7.25; P = .008) and cortical cholinergic (F = 7.50; P = .007) degenerations as well as interaction effects (F = 5.40; P = .02). CONCLUSIONS AND RELEVANCECortical cholinergic denervation is a major neurodegeneration associated with progressive declines across the spectrum of cognitive impairment in PD and typically occurs in the context of significant caudate nucleus dopaminergic denervation. Our findings imply that dopaminergic and cholinergic degenerations exhibit both independent and interactive contributions to cognitive impairment in PD.