Bradley R. Foerster

Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.

Background:Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment. Methods:To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia. Results:The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = −0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo. Conclusions: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.

Reduced insular γ-aminobutyric acid in fibromyalgia

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 (Spearmans 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.

Amyloid deposition in Parkinson's disease and cognitive impairment: A systematic review

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 among patients with Parkinsons disease with dementia (PDD), Parkinsons disease with mild cognitive impairment (PD‐MCI) and dementia with Lewy bodies (DLB). We included amyloid positron emission tomography (PET) imaging studies using Pittsburgh Compound B (PiB).

Decreased motor cortex γ-aminobutyric acid in amyotrophic lateral sclerosis

Objectives: To determine if there are in vivo differences in γ-aminobutyric acid (GABA) in the motor cortex and subcortical white matter of patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls using proton magnetic resonance spectroscopy (1H-MRS). Methods: In this cross-sectional study, 10 patients with ALS and 9 age- and sex-matched healthy controls (HCs) underwent 3T edited 1H-MRS to quantify GABA centered on the motor cortex and the subcortical white matter. Results: Compared with healthy controls, patients with ALS had significantly lower levels of GABA in the left motor cortex (1.42 ± 0.27 arbitrary institutional units vs 1.70 ± 0.24 arbitrary institutional units, p = 0.038). There was no significant difference in GABA levels between groups in the subcortical white matter (p > 0.05). Conclusion: Decreased levels of GABA are present in the motor cortex of patients with ALS compared to HCs. Findings are consistent with prior reports of alterations in GABA receptors in the motor cortex as well as increased cortical excitability in the context of ALS. Larger, longitudinal studies are needed to confirm these findings and to further our understanding of the role of GABA in the pathogenesis of ALS.

Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: A prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain

Purpose: To investigate whether apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues in neuropsychiatric systemic lupus erythematosus (NPSLE) patients differ from those of healthy controls. Material and Methods: Eight NPSLE patients (aged 23–55 years, mean 42.9 years) and 20 healthy age-matched controls (aged 22–59 years, mean 44.4 years) underwent conventional brain magnetic resonance (MR) and diffusion tensor imaging (DTI). The ADC, FA, principal eigenvalue (λ∥), and the corresponding average perpendicular eigenvalue (λ⊥) ( = (λ2+λ3)/2) were measured in selected regions of normal appearing gray and white matter brain parenchyma. For statistical evaluation of differences between the two groups, a Students t-test was used. The P value for statistical significance was set to P = 0.0025 after Bonferroni correction for multiple measurements. Results: Significantly increased ADC values were demonstrated in normal-appearing areas in the insular cortex (P<0.001), thalamus (P<0.001), and the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients. Significantly decreased FA values were demonstrated in normal-appearing thalamus (P<0.001), corpus callosum (P = 0.002), and in the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients compared to healthy controls. The λ⊥ was significantly higher in several of these regions in NPSLE patients compared to healthy controls. Conclusion: Our study demonstrates alterations in normal-appearing gray and white matter brain parenchyma of patients with NPSLE by means of abnormal ADC, FA, and eigenvalues. These alterations may be based on loss of tissue integrity in part due to demyelination. It is possible that DTI in the future could assist in the diagnosis of NPSLE and possibly help to further elucidate the pathogenesis of NPSLE.

25 years of neuroimaging in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which a precise cause has not yet been identified. Standard CT or MRI evaluation does not demonstrate gross structural nervous system changes in ALS, so conventional neuroimaging techniques have provided little insight into the pathophysiology of this disease. Advanced neuroimaging techniques—such as structural MRI, diffusion tensor imaging and proton magnetic resonance spectroscopy—allow evaluation of alterations of the nervous system in ALS. These alterations include focal loss of grey and white matter and reductions in white matter tract integrity, as well as changes in neural networks and in the chemistry, metabolism and receptor distribution in the brain. Given their potential for investigation of both brain structure and function, advanced neuroimaging methods offer important opportunities to improve diagnosis, guide prognosis, and direct future treatment strategies in ALS. In this article, we review the contributions made by various advanced neuroimaging techniques to our understanding of the impact of ALS on different brain regions, and the potential role of such measures in biomarker development.

An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-t proton magnetic resonance spectroscopy

IMPORTANCE A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS). OBJECTIVE To determine whether there are reductions in γ-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy. DESIGN Case-control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS. SETTING Tertiary referral center. PARTICIPANTS Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls. EXPOSURE Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS. MAIN OUTCOMES AND MEASURES Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N-acetylaspartate (a marker of neuronal integrity). RESULTS Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls (P < .01). Patients with ALS also had significantly lower levels of N-acetylaspartate in the motor cortex (P < .01), subcortical white matter (P < .05), and pons (P < .01) and higher levels of myo-inositol in the motor cortex (P < .001) and subcortical white matter (P < .01) than did healthy controls. Riluzole-naive patients with ALS had higher levels of Glx than did riluzole-treated patients with ALS (P < .05 for pons and motor cortex) and healthy controls (P < .05 for pons and motor cortex). Riluzole-naive patients with ALS had higher levels of creatine in the motor cortex (P < .001 for both comparisons) and subcortical white matter (P ≤ .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N-acetylaspartate in the motor cortex than did riluzole-treated patients with ALS (P < .01). CONCLUSIONS AND RELEVANCE There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed.

Intracranial infections : Clinical and imaging characteristics

The radiologist plays a crucial role in identifying and narrowing the differential diagnosis of intracranial infections. A thorough understanding of the intracranial compartment anatomy and characteristic imaging findings of specific pathogens, as well incorporation of the clinical information, is essential to establish correct diagnosis. Specific types of infections have certain propensities for different anatomical regions within the brain. In addition, the imaging findings must be placed in the context of the clinical setting, particularly in immunocompromised and human immunodeficiency virus (HIV)-positive patients. This paper describes and depicts infections within the different compartments of the brain. Pathology-proven infectious cases are presented in both immunocompetent and immunocompromised patients, with a discussion of the characteristic findings of each pathogen. Magnetic resonance spectroscopy (MRS) characteristics for several infections are also discussed.

Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: A systematic review and individual patient data meta-analysis

RATIONALE AND OBJECTIVES There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MATERIALS AND METHODS MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. RESULTS Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. CONCLUSION Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.

Proton MR Spectroscopy in the Evaluation of Cerebral Metabolism in Patients with Fibromyalgia : Comparison with Healthy Controls and Correlation with Symptom Severity

BACKGROUND AND PURPOSE: Widespread pain sensitivity in patients with fibromyalgia (FM) suggests a central nervous system (CNS)-processing problem. Therefore, it is conceivable that metabolic alterations exist in pain-processing brain regions of people with FM compared with healthy controls (HC) and that such metabolic data could correlate with clinical symptoms. The purpose of this study was to test these hypotheses using proton MR spectroscopy (1H-MR spectroscopy). Materials and METHODS: There were 21 patients with FM and 27 HC who underwent conventional structural MR imaging and additional 2D-chemical shift imaging (CSI) MR-spectroscopy sequences. For the 2D-CSI spectroscopy, larger volumes of interest (VOIs) were centered at the level of the basal ganglia and the supraventricular white matter. Within these larger areas, 16 smaller voxels were placed in a number of regions previously implicated in pain processing. N-acetylaspartate (NAA)/creatine(Cr), choline (Cho)/Cr and NAA/Cho ratios were calculated for each voxel. Subjects underwent clinical and experimental pain assessment. RESULTS: Mean metabolite ratios and ratio variability for each region were analyzed by using repeated-measures analysis of variance (ANOVA). Correlations between clinical symptoms and metabolite ratios were assessed. Cho/Cr variability in the right dorsolateral prefrontal cortex (DLPFC) was significantly different in the 2 groups; a significant correlation between Cho/Cr in this location and clinical pain was present in the FM group. Evoked pain threshold correlated significantly with NAA/Cho ratios in the left insula and left basal ganglia. CONCLUSION: Our data suggest that there are baseline differences in the variability of brain metabolite relative concentrations between patients with FM and HC, especially in the right DLPFC. Furthermore, there are significant correlations between metabolite ratios and clinical and experimental pain parameters in patients with FM.