Striatal GABA-MRS predicts response inhibition performance and its cortical electrophysiological correlates

Response inhibition processes are important for performance monitoring and are mediated via a network constituted by different cortical areas and basal ganglia nuclei. At the basal ganglia level, striatal GABAergic medium spiny neurons are known to be important for response selection, but the importance of the striatal GABAergic system for response inhibition processes remains elusive. Using a novel combination of behavior al, EEG and magnetic resonance spectroscopy (MRS) data, we examine the relevance of the striatal GABAergic system for response inhibition processes. The study shows that striatal GABA levels modulate the efficacy of response inhibition processes. Higher striatal GABA levels were related to better response inhibition performance. We show that striatal GABA modulate specific subprocesses of response inhibition related to pre-motor inhibitory processes through the modulation of neuronal synchronization processes. To our knowledge, this is the first study providing direct evidence for the relevance of the striatal GABAergic system for response inhibition functions and their cortical electrophysiological correlates in humans

Brain morphology predicts individual sensitivity to pain: a multicenter machine learning approach

ABSTRACT: Sensitivity to pain shows a remarkable interindividual variance that has been reported to both forecast and accompany various clinical pain conditions. Although pain thresholds have been reported to be associated to brain morphology, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity (as measured with pain thresholds) using structural magnetic resonance imaging-based cortical thickness data from a multicentre data set (3 centres and 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson r = 0.36, P < 0.0002, R2 = 0.13). The predictions were found to be specific to physical pain thresholds and not biased towards potential confounding effects (eg, anxiety, stress, depression, centre effects, and pain self-evaluation). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus, and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain

GABA levels in left and right sensorimotor cortex correlate across individuals

Differences in -aminobutyric acid (GABA) levels measured with Magnetic Resonance Spectroscopy have been shown to correlate with behavioral performance over a number of tasks and cortical regions. These correlations appear to be regionally and functionally specific. In this study, we test the hypothesis that GABA levels will be correlated within individuals for functionally related regions—the left and right sensorimotor cortex. In addition, we investigate whether this is driven by bulk tissue composition. GABA measurements using edited MRS data were acquired from the left and right sensorimotor cortex in 24 participants. T1-weighted MR images were also acquired and segmented to determine the tissue composition of the voxel. GABA level is shown to correlate significantly between the left and right regions (r = 0.64, p < 0.03). Tissue composition is highly correlated between sides, but does not explain significant variance in the bilateral correlation. In conclusion, individual differences in GABA level, which have previously been described as functionally and regionally specific, are correlated between homologous sensorimotor regions. This correlation is not driven by bulk differences in voxel tissue composition

Changes in Clinical Pain in Fibromyalgia Patients Correlate with Changes in Brain Activation in the Cingulate Cortex in a Response Inhibition Task

Objective The primary symptom of fibromyalgia is chronic, widespread pain; however, patients report additional symptoms including decreased concentration and memory. Performance‐based deficits are seen mainly in tests of working memory and executive functioning. It has been hypothesized that pain interferes with cognitive performance; however, the neural correlates of this interference are still a matter of debate. In a previous, cross‐sectional study, we reported that fibromyalgia patients (as compared with healthy controls) showed a decreased blood oxygen level dependent (BOLD) response related to response inhibition (in a simple G o/ N o‐ G o task) in the anterior/mid cingulate cortex, supplementary motor area, and right premotor cortex. Methods Here in this longitudinal study, neural activation elicited by response inhibition was assessed again in the same cohort of fibromyalgia patients and healthy controls using the same G o/ N o‐ G o paradigm. Results A decrease in percentage of body pain distribution was associated with an increase in BOLD signal in the anterior/mid cingulate cortex and the supplementary motor area, regions that have previously been shown to be “hyporeactive” in this cohort. Conclusions Our results suggest that the clinical distribution of pain is associated with the BOLD response elicited by a cognitive task. The cingulate cortex and the supplementary motor area are critically involved in both the pain system as well as the response inhibition network. We hypothesize that increases in the spatial distribution of pain might engage greater neural resources, thereby reducing their availability for other networks. Our data also point to the potential for, at least partial, reversibility of these changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108346/1/pme12460.pd

Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study

Objective Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. Material and methods We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. Results MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn > 100 μg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. Conclusions MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB

Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study

OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23μg/m3 and 110μg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β)=0.87, p<0.01) and choline (exp(β)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations

Altered Resting State Connectivity of the Insular Cortex in Individuals With Fibromyalgia

The insular (IC) and cingulate cortices (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. Here we more thoroughly evaluate the degree of resting state connectivity to multiple regions of the IC in individuals with FM and healthy controls (HC). 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 HC using pre-defined 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 the left CC; and (3) right anterior IC and left superior temporal gyrus. HCs displayed greater connectivity between: left anterior IC and the bilateral medial frontal gyrus/ACC; and left posterior IC and the 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 playing 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 fibromyalgia