Quantification of white matter hyperintensities in type 1 diabetes and its relation to neuropathy and clinical characteristics.

AIMS: The aims were to quantify periventricular and deep white matter hyperintensities (WMHs) in adults with type 1 diabetes with different neuropathic phenotypes and to correlate WMH measurements to explanatory factors in diabetes. METHODS: WMH measurements were obtained from brain magnetic resonance imaging of 56 adults with type 1 diabetes in subgroups including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN and 20 healthy controls using Fazekas scale and automatic segmentation analysis. RESULTS: No differences in Fazekas assessed WMHs were found (individuals with periventricular lesions: diabetes 66 % vs. controls 40 %, p = 0.063, deep lesions: diabetes 52 % vs. controls 50 %, p = 1.0). Using automatic detection, there were no significant differences in count of periventricular (p = 0.30) or deep (p = 0.31) WMHs. Higher periventricular lesion burden was present in diabetes compared with controls (0.21 % vs. 0.06 %, p = 0.048), which was associated with more severe DPN, increased age, decreased cognitive function, and reduced volumetric and metabolic brain measures (all p < 0.05). CONCLUSIONS: Our findings indicate increased burden of periventricular WMHs in diabetes which were associated to DPN severity and measurements reflecting neurodegeneration. Deep WMHs, often considered as chronic ischemic, were not significantly different. Mechanisms reflecting neurodegeneration and accelerated brain aging could be an overlooked aspect of peripheral and central neuropathy.

Neuropathic phenotypes of type 1 diabetes are related to different signatures of magnetic resonance spectroscopy-assessed brain metabolites.

OBJECTIVES: The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. METHODS: We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. RESULTS: The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A1c (HbA1c) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. CONCLUSIONS: Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. SIGNIFICANCE: Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes.

Cognitive function in individuals with and without painful and painless diabetic polyneuropathy-A cross-sectional study in type 1 diabetes.

INTRODUCTION: Previous studies suggest that cognitive impairment is more prevalent in individuals with painful and painless diabetic peripheral neuropathy (DPN). However, the current evidence is not well described. This study investigated cognitive function in adults with type 1 diabetes mellitus (T1DM) and the association to painful/painless DPN and clinical parameters. METHODS: This cross-sectional, observational, case-control study included 58 participants with T1DM, sub-grouped into 20 participants with T1DM and painful DPN, 19 participants with T1DM and painless DPN, 19 participants with T1DM without DPN, and 20 healthy controls were included. The groups were matched for sex and age. The participants performed Addenbrooke's examination III (ACE-III), which assesses attention, memory, verbal fluency, language and visuospatial skills. Working memory was evaluated using an N-back task. Cognitive scores were compared between the groups and correlated to age, diabetes duration, HbA1c and nerve conduction measurements. RESULTS: Compared to healthy controls, T1DM participants showed lower total ACE-III (p = .028), memory (p = .013) and language scores (p = .028), together with longer reaction times in the N-back task (p = .041). Subgroup analyses demonstrated lower memory scores in those with painless DPN compared with healthy controls (p = .013). No differences were observed between the three T1DM subgroups. Cognitive scores and clinical parameters were not associated. CONCLUSIONS: This study supports the notion of cognitive alterations in T1DM and indicates that cognitive function is altered in T1DM regardless of underlying neuropathic complications. The memory domain appears altered in T1DM, particularly in those with painless DPN. Further studies are needed to verify the findings.

Alterations in Functional Connectivity of Thalamus and Primary Somatosensory Cortex in Painful and Painless Diabetic Peripheral Neuropathy.

OBJECTIVE: In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity. RESEARCH DESIGN AND METHODS: In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores. RESULTS: Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071). CONCLUSIONS: Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.

Gray Matter Brain Alterations in Type 1 Diabetes - Findings Based on Detailed Phenotyping of Neuropathy Status.

AIMS: This study investigated brain structure in patients of type 1 diabetes with diabetic peripheral neuropathy (DPN) and type 1 diabetes with neuropathic pain and the associations to clinical, peripheral, and cognitive measurements. METHODS: Sixty individuals with type 1 diabetes and 20 healthy controls were included in the study. Nineteen individuals with type 1 diabetes and neuropathic pain, 19 with type 1 diabetes and DPN, 18 with type 1 diabetes without DPN, and 20 healthy controls were included in the brain analyses. We utilized structural brain magnetic resonance imaging to investigate total and regional gray matter volume. RESULTS: Significant lower gray matter volume was found in type 1 diabetes with neuropathic pain and in type 1 diabetes without DPN compared to healthy controls (p=0.024 and p=0.019, respectively). Lower insula volume was observed in all three diabetes groups (all p≤0.050). Thalamus and hippocampus volume was lower in type 1 diabetes with neuropathic pain, cerebellum volume was lower in type 1 diabetes with DPN, and somatosensory cortex volume was lower in type 1 diabetes without DPN (all p≤0.018). Attenuated memory was associated with lower gray matter volume in type 1 diabetes with DPN. No associations were found between gray matter volume and clinical/peripheral measurements. CONCLUSION: We demonstrated lower gray matter volume in individuals with type 1 diabetes regardless of the presence of DPN and neuropathic pain. Hence, central gray matter alteration was not associated with peripheral alterations.

Reduced Thalamic Volume and Metabolites in Type 1 Diabetes with Polyneuropathy.

OBJECTIVE: Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. METHODS: 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. RESULTS: In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. CONCLUSIONS: In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

Tapentadol and oxycodone affect resting-state functional brain connectivity: A randomized, placebo-controlled trial.

BACKGROUND AND PURPOSE: The changes in functional brain connectivity induced by treatment with analgesics are poorly investigated. Unfortunately, results from clinical studies investigating treatments in patients with pain are often confounded by co-medication and comorbidity. Thalamus is central in sensory processing, and we hypothesized that functional connectivity between thalamus and other brain areas in healthy volunteers was different in treatment with oxycodone, representing a pure opioid, compared to treatment with tapentadol, which has a dual effect on the opioidergic and adrenergic systems. METHODS: Twenty-one healthy male volunteers were included in a randomized, double-blind, three-armed, placebo-controlled, cross-over study. All received tapentadol (50 mg extended release), oxycodone (10 mg extended release), or placebo twice daily for 14 days. Resting-state functional magnetic resonance imaging data were obtained before and after treatment. Seed-based functional connectivity analyses were performed between thalamus and other brain regions. RESULTS: Compared to placebo, tapentadol increased functional connectivity between left thalamus and precentral cortex (P = .048), whereas oxycodone decreased functional connectivity between bilateral thalamus and the anterior cingulate cortex (P ≤ .005). CONCLUSIONS: This study has shown that the functional connectivity between thalamus and other brain areas central in pain processing was different for the tapentadol and oxycodone treatments compared to placebo. This supports that the two treatments exert different mechanism of action. Further studies with larger sample sizes need to be carried out in order to validate this.

Altered brain morphology in chronic pancreatitis patients and its association with pain and other disease characteristics.

OBJECTIVE: Abnormal pain processing in the central nervous system is a hallmark of chronic pancreatitis (CP). We characterized brain structure in CP patients and identified disease characteristics that impact the brain structure in CP patients. PATIENTS AND METHODS: Thirty-three CP patients and 23 matched healthy controls underwent brain MRI. Total and regional gray matter volume (GMV) and cortical thickness analyses were carried out. Multivariate linear regression models were used to determine the independent predictors of total GMV. RESULTS: CP patients had 31.9 ± 9.3 ml (mean ± SE) (5.1%) reduced total GMV compared with the healthy controls (587.1 ± 5.8 vs. 619.0 ± 7.0 cm, P < 0.001). Alcoholic etiology was associated independently with a decreased total GMV (P < 0.001), whereas no association was observed for pain or other disease characteristics (all P > 0.05). Similarly, regional GMV loss and cortical thinning were observed for several cortical areas in patients with alcoholic etiology compared with their nonalcoholic counterparts (P < 0.05). These regional differences were particularly evident for pain-related cortical areas; however, no significant differences in regional GMV or cortical thickness were observed between patients with and without pain (all P > 0.05). CONCLUSION: Patients with CP have GMV loss that is associated with alcoholic disease etiology. No associations were detected between pain and GMV loss, likely because the potential effect of long-lasting pain on brain structure is masked by the effects of previous alcohol use. The findings imply that alcoholic etiology is the most prominent contributing factor for structural brain alterations in CP patients.

Differential effects of oxycodone and venlafaxine on resting state functional connectivity-A randomized placebo-controlled magnetic resonance imaging study.

AIM: Different mechanisms may be involved in the antinociceptive effects of oxycodone (opioid) and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and the aim of this study was to investigate the effect of these drugs on brain functional connectivity. METHODS: Resting state functional magnetic resonance imaging was acquired in 20 healthy volunteers before and after a 5-day treatment with oxycodone, venlafaxine, or placebo in a randomized, double-blind, crossover study. Functional connectivity analyses were performed between four predefined seeds (dorsal anterior cingulate cortex, rostral anterior cingulate cortex, posterior insula, and prefrontal cortex), and the whole brain. RESULTS: The overall interpretation was that there were differences between the effects of oxycodone and venlafaxine on functional connectivity. Oxycodone mainly showed decreased functional connectivity between limbic structures and to supralimbic areas (all P < 0.05). Venlafaxine also showed decreased functional connectivity between limbic structures and to supralimbic areas, but increased functional connectivity to structures in the midbrain and brain stem was also found (all P < 0.05). CONCLUSIONS: Oxycodone and venlafaxine showed differential effects on resting-state functional connectivity as compared to placebo. This supports that the two drugs exert different mechanisms, and that the drugs in combination may exert additive effects and could potentially improve pain therapy.

Objective methods for the assessment of the spinal and supraspinal effects of opioids.

BACKGROUND AND PURPOSE: Opioids are potent analgesics. Opioids exert effects after interaction with opioid receptors. Opioid receptors are present in the peripheral- and central nervous system (CNS), but the analgesic effects are primarily mediated via receptors in the CNS. Objective methods for assessment of opioid effects may increase knowledge on the CNS processes responsible for analgesia. The aim of this review was to provide an overview of the most common objective methods for assessment of the spinal and supraspinal effects of opioids and discuss their advantages and limitations. METHOD: The literature search was conducted in Pub Med (http://www.ncbi.nlm.nih.gov/pubmed) from November 2014 to June 2016, using free-text terms: "opioid", "morphine" and "oxycodone" combined with the terms "pupillometry," "magnetic resonance spectroscopy," "fMRI," "BOLD," "PET," "pharmaco-EEG", "electroencephalogram", "EEG," "evoked potentials," and "nociceptive reflex". Only original articles published in English were included. RESULTS: For assessment of opioid effects at the supraspinal level, the following methods are evaluated: pupillometry, proton magnetic resonance spectroscopy, functional resonance magnetic imaging (fMRI), positron emission tomography (PET), spontaneous electroencephalogram (EEG) and evoked potentials (EPs). Pupillometry is a non-invasive tool used in research as well as in the clinical setting. Proton magnetic resonance spectroscopy has been used for the last decades and it is a non-invasive technique for measurement of in vivo brain metabolite concentrations. fMRI has been a widely used non-invasive method to estimate brain activity, where typically from the blood oxygen level-dependent (BOLD) signal. PET is a nuclear imaging technique based on tracing radio labeled molecules injected into the blood, where receptor distribution, density and activity in the brain can be visualized. Spontaneous EEG is typically quantified in frequency bands, power spectrum and spectral edge frequency. EPs are brain responses (assessed by EEG) to a predefined number of short phasic stimuli. EPs are quantified by their peak latencies and amplitudes, power spectrum, scalp topographies and brain source localization. For assessment of opioid effects at the spinal level, the following methods are evaluated: the nociceptive withdrawal reflex (NWR) and spinal EPs. The nociceptive withdrawal reflex can be recorded from all limbs, but it is standard to record the electromyography signal at the biceps femoris muscle after stimulation of the ipsilateral sural nerve; EPs can be recorded from the spinal cord and are typically recorded after stimulation of the median nerve at the wrist. CONCLUSION AND IMPLICATIONS: The presented methods can all be used as objective methods for assessing the centrally mediated effects of opioids. Advantages and limitations should be considered before implementation in drug development, future experimental studies as well as in clinical settings. In conclusion, pupillometry is a sensitive measurement of opioid receptor activation in the CNS and from a practical and economical perspective it may be used as a biomarker for opioid effects in the CNS. However, if more detailed information is needed on opioid effects at different levels of the CNS, then EEG, fMRI, PET and NWR have the potential to be used. Finally, it is conceivable that information from different methods should be considered together for complementary information.

The effects of analgesics on central processing of tonic pain: A cross-over placebo controlled study.

INTRODUCTION: Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat moderate to severe pain, but the central mechanisms underlying their analgesia remain unclear. This study investigated how brain activity at rest and exposed to tonic pain is modified by oxycodone (opioid) and venlafaxine (SNRI). METHODS: Twenty healthy males were included in this randomized, cross-over, double-blinded study. 61-channel electroencephalogram (EEG) was recorded before and after five days of treatment with placebo, oxycodone (10 mg extended release b.i.d) or venlafaxine (37.5 mg extended release b.i.d) at rest and during tonic pain (hand immersed in 2 °C water for 80 s). Subjective pain and unpleasantness scores of tonic pain were recorded. Spectral analysis and sLORETA source localization were done in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz) frequency bands. RESULTS: Oxycodone decreased pain and unpleasantness scores (P < 0.05), whereas venlafaxine decreased the pain scores (P < 0.05). None of the treatments changed the spectral indices or brain sources underlying resting EEG. Venlafaxine decreased spectral indices in alpha band of the EEG to tonic pain, whereas oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands (all P < 0.05). The brain source activity predominantly decreased in the insula and inferior frontal gyrus. CONCLUSION: The decrease of activity within insula and inferior frontal gyrus is likely involved in pain inhibition due to oxycodone treatment, whereas the decrease in alpha activity is likely involved in pain inhibition due to venlafaxine treatment.

Integrity of central nervous function in diabetes mellitus assessed by resting state EEG frequency analysis and source localization.

Diabetes mellitus (DM) is associated with structural and functional changes of the central nervous system. We used electroencephalography (EEG) to assess resting state cortical activity and explored associations to relevant clinical features. Multichannel resting state EEG was recorded in 27 healthy controls and 24 patients with longstanding DM and signs of autonomic dysfunction. The power distribution based on wavelet analysis was summarized into frequency bands with corresponding topographic mapping. Source localization analysis was applied to explore the electrical cortical sources underlying the EEG. Compared to controls, DM patients had an overall decreased EEG power in the delta (1-4Hz) and gamma (30-45Hz) bands. Topographic analysis revealed that these changes were confined to the frontal region for the delta band and to central cortical areas for the gamma band. Source localization analysis identified sources with reduced activity in the left postcentral gyrus for the gamma band and in right superior parietal lobule for the alpha1 (8-10Hz) band. DM patients with clinical signs of autonomic dysfunction and gastrointestinal symptoms had evidence of altered resting state cortical processing. This may reflect metabolic, vascular or neuronal changes associated with diabetes.

Single-sweep spectral analysis of contact heat evoked potentials: a novel approach to identify altered cortical processing after morphine treatment.

AIMS: The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which are confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. METHODS: In a crossover study 15 single-sweep CHEPs were analyzed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalized spectral indices in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were compared to identify alterations induced by morphine. RESULTS: Reproducibility between baseline CHEPs was demonstrated. As compared with placebo, morphine decreased the spectral indices in the delta and theta bands by 13% (P = 0.04) and 9% (P = 0.007), while the beta and gamma bands were increased by 10% (P = 0.006) and 24% (P = 0.04). CONCLUSION: The decreases in the delta and theta band are suggested to represent a decrease in the pain specific morphology of the CHEPs, which indicates a diminished pain response after morphine administration. Hence, assessment of spectral indices in single-sweep CHEPs can be used to study cortical mechanisms induced by morphine treatment.

Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain processing?

BACKGROUND AND AIM: Intractable pain usually dominates the clinical presentation of chronic pancreatitis (CP). Slowing of electroencephalogram (EEG) rhythmicity has been associated with abnormal cortical pain processing in other chronic pain disorders. The aim of this study was to investigate the spectral distribution of EEG rhythmicity in patients with CP. PATIENTS AND METHODS: Thirty-one patients with painful CP (mean age 52 years, 19 male) and 15 healthy volunteers (mean age 49, nine male) were included. A multichannel EEG was recorded from 62 surface electrodes. Amplitude strengths of the resting EEG were retrieved based on wavelet frequency analysis and summarized in frequency bands with corresponding topographic mapping. RESULTS: Patients with CP had slowed EEG rhythmicity compared with healthy volunteers. This was evident as increased activity in the lower frequency bands δ (1-3.5 Hz) (P=0.05), θ (3.5-7.5 Hz) (P<0.001) and α (7.5-13.5 Hz) (P<0.001). Due to normalization a reciprocal relationship was observed for the high frequency band ß (13.5-32 Hz). In a sub-analysis, δ band activity was modified by diabetes, opioid treatment and alcohol aetiology of CP. However, no effect modification was seen for the θ or α bands. Differences in θ activity were located over centro-frontal brain regions, whereas differences in δ, α and ß band activity were located in frontal regions. CONCLUSION: Slowed EEG rhythmicity was evident in patients with CP. This possibly mirrors abnormal central pain processing and may serve as a clinically useful biomarker of abnormal central pain processing.