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Painful and Painless Diabetic Neuropathies: What Is the Difference?
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Purpose of Review
The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.
Recent Findings
Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN.
Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.
KeywordsDiabetes Peripheral neuropathy Neuropathic pain Small fiber neuropathy Painful diabetic neuropathy Diabetic neuropathy
The worldwide prevalence of diabetes mellitus (DM) has reached epidemic proportions, and is set to increase to 629 million by 2045 [1]. Rising population growth, aging, urbanization, and an increased prevalence of obesity and physical inactivity are amongst the major contributing factors. Diabetic neuropathies are one of the most common chronic complications of DM [2], and distal symmetrical polyneuropathy (DPN) is the most prevalent form of diabetic neuropathy, which may affect up to 50% of patients [2, 3•, 4•]. The Toronto Expert Group has defined DPN as "a symmetrical, length dependent sensorimotor polyneuropathy attributable to metabolic and micro-vessel alterations as a result of chronic hyperglycaemia exposure and cardiovascular risk covariates" [5•]. A more recent definition of DPN in the American Diabetes Association Position Statement is "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes" [3•]. The rising numbers of patients diagnosed with neuropathic disorders related to DM will have an immense impact on health and social care provision [6].
DPN is a major risk factor for diabetic foot ulceration, which remains a major cause of morbidity and is the leading cause of non-traumatic amputations [7]. Although a large number of patients with DPN may be entirely asymptomatic, approximately 15–25% of people with DM present with neuropathic pain (painful-DPN) [8, 9, 10, 11, 12•, 13]. The neuropathic pain is of varying degree of intensity [14] DPN and painful-DPN has different clinical syndromes with the most common of which is a mixed large and small fiber neuropathy. Small nerve-fibers (SF) are small-caliber sensory fibers, which are primarily responsible for peripheral nociception [15]. Pure SF neuropathy may occur in DM and the clinical features include symptoms of painful peripheral neuropathy with signs of SF impairment (e.g., pinprick or thermal hypoalgesia or allodynia) in a peripheral neuropathy distribution in the absence of large fiber impairment (e.g., impaired light touch, vibration, proprioception or motor signs).
Risk Factors
Several risk factors for DPN in general have been described and confirmed in cohorts of type 1 and type 2 diabetes. The EURODIAB Prospective Complications Study screened 3250 type 1 DM patients at baseline and followed 1172 patients without DPN looking for risk factors that predicted the development of DPN [4•]. The study found that in addition to glycemic control, traditional vascular risk factors such as hypertension, raised triglycerides, obesity, and cigarette smoking were independent risk factors for the development of new onset DPN. Similar vascular risk factors were also found in T2DM [18•, 19, 20]. However, the risk factors for neuropathic pain in DM are less well known. This is partly because of the wide variation in the diagnostic and population selection methods employed by the epidemiological studies for painful-DPN [21••, 22]. The reported risk factors include increasing age [9, 10], elevated HbA1c [23••, 24], duration of DM [9], and obesity [10, 25]. A high alcohol intake, type of diabetes, macro and microvascular disease, and ethnicity have also been implicated [21••]. Recent large studies have also suggested nephropathy and female gender as risk factors for painful-DPN [26, 27••, 28••]. Indeed, female gender was the only risk factor identified in a large cross-sectional study (n = 816) performed by Truini et al. which diagnosed painful-DPN using widely agreed criteria [28••]. Thirteen percent were diagnosed with painful-DPN and the only distinguishing risk factor from painless-DPN was female gender. Gender differences are well recognized in chronic pain conditions and neuropathic pain intensity has previously been reported to be more severe in females [29, 30].
Recent advances in gene sequencing technology have led to several studies examining genetic variants associated with DPN and painful-DPN [31, 32, 33, 34, 35•, 36]. Two recent studies by Meng et al. conducted genome-wide association studies in Tayside, Scotland [32, 33]. Chr8p21.3, Chr1p35.1, and Chr8p21.3 polymorphisms were associated with neuropathic pain. However, the study did not use validated diagnostic criteria for painful-DPN. Recently also, there has been great interest in the role of voltage-gated sodium channels and their role in neuropathic pain. The Nav 1.7 sodium channel is well recognized to be involved in pain signaling and "gain of function" mutations of its encoding gene, SCN9A, cause rare pain disorders. Additionally, studies have identified Nav 1.7 mutations in idiopathic small fiber neuropathy [36] and painful-DPN [34]. Blesneac et al. looked at the relationship between Nav 1.7 variants and painful-DPN and found that none of the participants with painless-DPN (n = 78) were found to have a genetic variant [35•]. However, a total of 12 rare Nav 1.7 variants were identified in 10 out of 111 patients with painful-DPN. The subjects with these variants were found to have a shorter duration of diabetes yet more severe burning pain. Painful-DPN is a heterogeneous condition and subjects with rare sodium channel gene variants may represent a subgroup that may respond to a particular treatment.
In summary, while the risk factors for DPN are well recognized, those for painful-DPN are less certain. This might indicate the complexity of painful-DPN as many factors including genetics, cultural, psycho-social, and gender may be involved.
Clinical Features
Neuropathic pain in diabetes has distinct presentations as burning, sharp, aching, electric, and evoked pains [37]. However, patients may also describe symptoms of numbness, tingling, and pins and needles, irrespective of the presence of pain. Neuropathic pain may also induce various degrees of physical disability, depression, anxiety, insomnia, and a poorer quality of life than patients with painless-DPN, particularly with moderate to severe neuropathic pain [23••, 27••, 38]. Despite these profound differences in a patient's clinical presentation, there are few distinct differences in the neurological examination between painless- and painful-DPN. The majority of patients with painful-DPN demonstrate sensory loss on clinical examination but a small proportion of patients with painful-DPN have evidence of "gain of function" signs such as allodynia and hyperalgesia [23••]. There is controversy regarding whether the severity of neuropathic impairment is greater in painful-DPN. Several studies have reported a correlation between neuropathy severity and the presence and/or severity of neuropathic pain in DPN [8, 11, 15, 23••, 39, 40, 41] whereas other studies have not [18•, 28••]. Although the weight of evidence seems to suggest that an increasing severity of DPN may increase the risk of developing painful neuropathic symptoms, severe DPN and pain are not mutually exclusive, and there may have been a selection bias in recruiting painful-DPN patients from tertiary referral centers.
Cardiovascular Autonomic Neuropathy
Both autonomic neuropathy and painful-DPN involve small fibers, and a potential relationship was therefore investigated. In a small study, we demonstrated greater changes in heart rate variability studies, as measures of cardiovascular autonomic neuropathy (CAN) in subjects with painful- compared with painless-DPN [42], while other small studies reported that painful DPN was more likely to be associated with the absence of a nocturnal fall in blood pressure ("non-dipping") [43], or with reduced Valsalva ratio [40]. However, these are in contrast with other studies that have not found any differences in measures of CAN between painful and painless-DPN [39, 44, 45].
Diagnostic Methods of Painful-DPN
Conventional neurophysiological testing methods, which measure large fiber function, such as nerve conduction studies (NCS), cannot detect pure small fiber neuropathy (SFN) [46]. However, QST and more recent advances in diagnostic techniques, e.g., skin biopsy with intraepidermal nerve fiber density (IENFD) quantitation, corneal confocal microscopy (CCM), and laser Doppler imaging flare (LDI Flare) have allowed the reliable diagnosis of SFN [5•, 46]. Because of their role in physiological nociception, studies have explored whether damage or alterations in SF may relate to neuropathic pain in DPN.
Skin Biopsy
Immunostaining of skin biopsy samples with protein gene product 9.5 and quantitation of IENFD is a reliable means of diagnosing SFN [46]. However, IENFD is unable to distinguish between individuals with or without neuropathic pain [23••, 27••, 28••, 47••, 48, 49]. Other studies have been performed to determine whether morphological and functional markers of the epidermal innervation revealed differentiating features. Intraepidermal nerve fiber (IENF) regeneration, by measuring the ratio of growth associated protein-43 (GAP-43) to nerve fibers, has been shown to be enhanced in painful-compared with painless-DPN [49, 50•, 51]. However, Scheytt et al. found no relationship between pain and GAP-43 reactivity in subjects with peripheral neuropathies of varying etiologies [52]. There are contradictory findings in studies investigating other IENF markers to differentiate painful- from painless-DPN including IENF length [50•, 53] and axonal swellings, which are measures of axonal degeneration [49, 54]. Levels within the skin of the neurotrophin nerve growth factor (NGF) were increased in patients with DPN and sensory symptoms, including pain, compared to painless-DPN [55]. NGF has recently been shown to sensitize nociceptors in human skin and it has been hypothesized that the remaining IENF in painful-DPN may be exposed to excessive levels of NGF ("over-trophing") resulting in hypersensitivity and neuropathic pain [19, 55, 56, 57, 58].
Corneal Confocal Microscopy
Confocal corneal microscopy (CCM) can rapidly, non-invasively, and accurately image corneal nerves and is a recently developed diagnostic test for DPN [59, 60, 61]. Studies of CCM have explored the role of corneal innervation and neuropathic pain in DM [53, 62•, 63]. Quattrini et al. reported reduced corneal nerve fiber length with unaltered other CCM measures [53], whereas Marshall et al. found unaltered corneal nerve fiber length but reduced corneal nerve fiber density [62•]. Recently, Kalteniece et al. [63] described significantly lower corneal inferior whorl length, and average and total nerve length in painful- compared to painless-DPN. Changes within this region have been suggested to be indicative of early neuropathic damage. However, there were confounding factors, which could account for these group differences. Therefore, the association of CCM abnormalities to neuropathic pain in DPN is thus far inconclusive.
Evoked Responses
Non-invasive tests have been developed to investigate the peripheral function of SF to diagnose SFN. Such tests can measure evoked potentials in response to stimuli that activate the nociceptive pathway, for example contact heat-evoked potentials (CHEPS) [64]. CHEPs correlates with other measures of SFN including IENFD and leg skin flare responses [65, 66]. One small study found a relationship between enhanced brain CHEP amplitudes in subjects with painful-DPN; this result was most marked in those with thermal hyperalgesia and mechanical allodynia [67].
Quantitative Sensory Testing
QST is a psychophysical measure of the perception of different external stimuli of controlled intensity to assess a range of sensory modalities [68, 69]. Some studies with a relatively small sample size suggested that conventional QST measures of SF function may be statistically different between painful- and painless-DPN [41, 44, 70, 71]. More recent studies have employed the German Research Network on Neuropathic Pain (DFNS) QST protocol to quantify sensory loss, for small and large fiber function, and sensory gain abnormalities [72, 73••]. Three recent large cross-sectional cohort studies have applied this protocol to patients with painful- and painless-polyneuropathies with different etiologies [48] and painful- and painless-DPN [23••, 27••]. In two studies of painful-DPN, DFNS QST revealed more severe loss of function in those with neuropathic pain, particularly patients with moderate/severe pain [23••, 27••]. Thermal hyposensitivity was more severe in painful-DPN whereas mechanical stimuli showed fewer differences compared with painless-DPN. Gain of function abnormalities and preserved SF function with hyperalgesia were both rare. However, Üçeyler et al. studied patients with painful- and painless-polyneuropathies of different etiologies and found that patients with neuropathic pain demonstrated elevated mechanical pain and detection threshold, and lower mechanical pain sensitivity with no difference in SF deficits [48]. This perhaps indicates there may be a unique somatosensory phenotype associated with painful-DPN characterized by more severe SF dysfunction with thermal hyposensitivity [23••, 27••]. However, SF changes are common and can occur in early DPN without pain [74, 75, 76]; therefore, these findings alone are unable to completely explain why some patients develop neuropathic pain and others do not. Perhaps, other investigations into small fiber function and structure, such as skin biopsy studies, may shed further light onto this paradox.
Pathogenesis of Painful-DPN
Microvascular Blood Flow
Consistent with vascular risk factors increasing the risk of DPN [4•], both structural and functional microvascular abnormalities of the vasa-nervorum have been shown to be involved in the pathogenesis of DPN [77, 78, 79]. Patients with treatment induced neuropathy of diabetes who had extremely severe neuropathic pain have proliferating blood vessels on the epineurial surface bearing striking similarities to those found in proliferative diabetic retinopathy [80]. It is well recognized that very rapid improvement in glucose control can cause proliferative retinopathy mediated by retinal ischemia and a similar process appears to take place in the peripheral nerve. Furthermore, several studies have shown that regulation of peripheral blood flow is altered in patients with painful- compared with painless-DPN [81, 82, 83, 84]. Our group demonstrated elevated sural nerve epineurial oxygen saturation and faster blood flow in patients with painful- compared to painless-DPN, perhaps secondary to arteriovenous shunting [82]. Other studies have examined the role of skin microvascular vasodilator and vasoconstrictor responses in subjects with DPN, with contradictory findings [71, 85, 86, 87].
Studies measuring serum markers of angiogenesis (vascular endothelial growth factor, VEGF) and endothelial dysfunction (soluble intercellular adhesion molecule – 1, sICAM-1) have found them to be elevated in painful-DPN [86, 88•] and symptomatic DPN respectively [89]. Furthermore, punch skin biopsy studies have also indicated that skin microcirculation may be involved in the pathogenesis of painful-DPN. One study demonstrated evidence of hypoxia, by immunostaining with hypoxia inducible factor 1α (HIF-1 α), to be related to pain intensity in subjects with DPN [90]. Recently, our group has also found dermal von Willebrand factor (vWF) immunoreactivity, as a blood vessel marker, to be significantly elevated in subjects with painful-DPN, in comparison to subjects with painless-DPN, patients with DM without DPN and healthy volunteers [56]. Moreover, small studies have demonstrated that pain improves with topical application of vasodilator treatments [91, 92], perhaps indicating that local blood flow dysregulation could be a viable target for the management of pain in DPN.
Hyperglycemia and Downstream Effects
Hyperglycemia mediated metabolic pathways have long been associated in the pathogenesis of DPN, but their role in those with neuropathic pain is less clearly defined. Studies using DM rodent models have found neuropathic pain behaviors to be related to numerous metabolic pathways including the polyol pathway, protein kinase C activity, and increased advanced glycation end-products (AGEs) [93]. However, there is limited evidence to support glycemic control or lifestyle modifications in improving painful neuropathic symptoms [3•]. Moreover, the evidence to support pathogenic treatments for neuropathic pain in DPN has generally been disappointing and only a few pharmacotherapeutic agents are available in select countries [50•].
Methylglyoxal is a highly reactive dicarbonyl compound and is a precursor to the formation of (AGEs). The formation of AGEs has downstream deleterious effects on peripheral nerves and Schwann cells including inflammation and oxidative stress [94]. Methylglyoxal has been suggested to be an important factor in the development of DM and incident DPN [20•, 95]. In rodent models of painful-DPN, methylglyoxal has been shown to induce hyperalgesia via activation of the voltage-gated sodium channel Nav 1.8 and transient receptor potential channel ankyrin-1 [96, 97]. Similarly, in a small number of patients with DM (n = 30), serum methylglyoxal levels were found to be elevated in painful-DPN [96]. In contrast to these findings, a larger study (n = 882) reported methylglyoxal levels to be unrelated to painful-DPN [98]. Although the role of hyperglycemia mediated pathways in generating neuropathic pain is uncertain, pathogenically oriented treatments, particularly anti-oxidants, have been demonstrated to improve pain in some pre-clinical and clinical trials [99, 100].
Vitamin D
Although vitamin D is most commonly recognized for its role in calcium metabolism and bone health, vitamin D is involved in many disparate physiological processes [101]. Deficiency of vitamin D has been shown to be predictive of numerous chronic diseases including DM, DPN, and chronic pain [101, 102, 103, 104]. Pre-clinical studies indicate that vitamin D appears to play a critical role in nerve function in health and may play a role in neuropathic pain syndromes [105, 106, 107, 108, 109]. Our group recently found vitamin D levels to be significantly lower in patients with painful- compared to painless-DPN, with a significant correlation between serum 25-hydroxyvitamin D level and pain scores on the Doleur Neuropathique 4 neuropathic pain screening tool [110•]. The study was cross-sectional, and therefore cannot establish a causal relationship, but it does suggest a possible mechanistic link between vitamin D and painful-DPN. Indeed, three non-randomized clinical trials have demonstrated an improvement in painful neuropathic symptoms with vitamin D therapy but, further, larger, adequately powered RCTs are necessary to investigate this further [111, 112, 113].
Inflammation has been postulated to play a major part in DM and DPN [114]. Low grade inflammation has been suggested as a link between obesity and T2DM, via inflammation induced insulin resistance [114]. Inflammatory chemokine and cytokine production has been reported to be induced by several metabolic pathways implicated in the pathogenesis of DPN [115, 116•]. Multiple studies have demonstrated higher systemic acute-phase proteins, cytokines, and chemokines in DPN [88•, 117•], recently reviewed by Bönhof et al. [118•]. Furthermore, rodent models of neuropathic pain associated with the metabolic syndrome and T2DM demonstrate elevated pro-inflammatory mediator expression in the serum [119] and the dorsal root ganglia [119, 120]. The outcomes of studies examining the association of inflammatory biomarkers and painful-DPN have been variable. Numerous inflammatory markers have been associated with painful-DPN: C-reactive protein (CRP) [86], tumor necrosis factor-α (TNF-α) [121], inducible nitric oxide synthase [121], and interleukin 6 [117•]. Additionally, inflammatory mediators have been shown to differentiate between painful- from painless-neuropathies of various etiologies, including elevated serum IL-2, TNF-α, and reduced anti-inflammatory IL-10 [122]; IL-6 and IL-10 sural nerve biopsy expression [123]; and TNF-α in human Schwann cells [124].
The Central Nervous System
Technological advances in imaging modalities have enabled detailed in vivo investigation of the nervous system in DM. Key differences have been identified within the CNS in painful-DPN, using a variety of different techniques, especially advanced MR imaging modalities.
Spinal Cord Changes in Painful-DPN
We have identified a reduction in the cross-sectional area of the spinal cord in subjects with DPN in comparison to patient with DM without DPN, healthy controls, and disease control subjects with hereditary sensory motor neuropathy type 1A [125]. However, structural differences in the spinal cord area have not been found between subjects with painless- and painful-DPN [125]. Recent studies have indicated that spinal disinhibition, measured using the rate dependent depression (RDD) of the Hoffman reflex (H-reflex), may be a potential biomarker of spinally mediated pain to differentiate painful- from painless-DPN [126]. The RDD has been demonstrated to assess γ-aminobutyric acid (GABA) type A receptor-mediated spinal inhibitory function in neuropathic pain models of DM rats [127]. Impaired RDD was found in DM rat models of T1DM and T2DM with neuropathic pain phenotypes [62•]. Also, the RDD in groups of healthy controls and T1DM subjects with painful- and painless-DPN was evaluated and it was significantly impaired in those with painful-DPN. Patients with greater RDD attenuation had higher pain scores but no difference in measures of large or small fiber dysfunction, perhaps suggesting spinal inhibitory dysfunction may occur independent of PNS alterations in painful-DPN.
Advanced MRI Studies of the Brain
Functional MRI (fMRI) measures the activity of brain regions by detecting changes in the oxygenation of hemoglobin, the blood oxygen level dependent signal (BOLD). The neurological signature of physical pain has been identified by fMRI and includes activation of the venterolateral thalamus, dorsal posterior insula, and somatosensory cortex, as well as brain regions related to emotional pain processing, including the anterior insula and anterior cingulate cortex (ACC) [128, 129, 130].
The Thalamus
The thalamus receives somatosensory signals from the spinal cord where they are processed, modulated, and transmitted to higher brain centers. A variety of brain alterations have been demonstrated in DPN and painful-DPN using advanced imaging techniques that examine brain neurochemistry, microvascular blood flow, and functional changes. MR spectroscopy (MRS) enables the measurement of selected metabolites within the brain [131]. Our group has used MRS to show neuronal dysfunction within the thalamus, by reduced N-acetyl aspartate (NAA) to choline ratio as a neuronal marker, in subjects with painless-DPN [132]. Furthermore, DM animal models of painful-DPN have shown that the thalamus may be responsible for central amplification of somatosensory signals [133, 134]. Similarly, thalamic dysfunction appears to play a key role in human painful-DPN. We have recently shown preserved thalamic NAA and the GABA levels within the thalamus in patients with painful-DPN, whereas these levels were reduced in patients with painless-DPN [135, 136]. These findings suggest that neurochemical measures of the thalamic neuronal function and neurotransmitters may be essential for pain signal transmission and/or amplification in painful-DPN.
Recently, we performed a study administering exogenous perfusion contrast to subjects with painful- and painless-DSPN to compare the thalamic microvascular perfusion at rest [137•]. Subjects with DPN both demonstrated delayed bolus arrival time to the thalamus, but subjects with neuropathic pain had a significantly taller peak concentration, a higher mean cerebral blood volume, and the longest blood transit time compared to painless-DPN. Therefore, microvascular vasodilation within the thalamus may induce hyperperfusion which could be related to elevated thalamic neuronal activity. Finally, fMRI study of the brain has indicated there may be disruption in thalamocortical connectivity in painful-DPN. Cauda et al. measured resting state fMRI to determine temporal correlations of brain activity in a small number of subjects with painful-DPN and healthy control patients [138]. Compared with the control group, there was reduced synchrony between the somatosensory cortex and thalamic nuclei in painful-DPN patients.
Descending Inhibition
It is well recognized that the midbrain and medullary brain regions can exert bidirectional control over nociception [139]. The periaqueductal gray (PAG) and rostroventromedial medulla (RVM) are key sites for the control of descending pain modulation, disruption of which in rodent models of painful-DPN has been shown to lead to enhancement of descending pain facilitation [140, 141]. In human studies, our group performed MR-dynamic susceptibility contrast imaging at rest and under experimental pain, by applying heat pain to the lateral thigh where participants did not experience neuropathy [142]. During experimental pain, the time to peak concentration of contrast reduced in healthy volunteers but significantly increased in subjects with painful-DPN in the bilateral sensory cortices and thalami, perhaps indicating an underlying impairment in descending inhibition. Segerdahl et al. interrogated the ventrolateral PAG (vlPAG) using resting state fMRI and arterial spin labelling to determine cerebral blood flow at rest and during heat stimulation to the foot [143•]. The painful-DPN group demonstrated altered vlPAG functional connectivity, which correlated to their pain intensity and the cerebral blood flow changes induced by experimental thermal stimulation. These studies indicate that abnormalities within the descending pain modulatory system may result not only in reduced inhibition of pain but increased amplification of pain signals in painful-DPN.
Higher Brain Centers
The higher brain centers are involved in the localization of pain (e.g., somatosensory cortex) as well as the behavioral, cognitive, and emotional response to painful stimuli (e.g., ACC, amygdala, insular cortex). Using a technique known as voxel-based morphometry, we calculated the brain volumes in subjects with DPN and identified total brain volume reduction which was localized to the somatosensory regions [144, 145]. Furthermore, our group has performed the largest cohort study of brain volume changes in DPN and painful-DPN to date [146]. In painful-DPN, cortical atrophy is localized within the somatomotor cortex and insula. We have also demonstrated abnormal cortical interactions within the somatomotor network at rest which correlated with measures of pain and behavior in subjects with painful-DPN [147]. A recent study performed single-photon emission computed tomography to assess cerebral blood flow (CBF) in 24 subjects with painful- and 20 painless-DPN [148]. The painful-DPN group demonstrated increased CBF within the right ACC and left nucleus accuumbens. However, the painless-DPN group demonstrated more severe neurophysiological neuropathic impairment which may be a potential confounding factor. Furthermore, application of thermal heat stimuli resulted in altered BOLD fMRI responses in painful- compared with painless-DPN, seen in two studies [149, 150]. A pilot study within our group found greater BOLD response within the primary somatosensory cortex, lateral frontal, and cerebellar regions [149]. Whereas Tseng et al. demonstrated augmented responses in multiple limbic and striatal structures (i.e., ACC, superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus, and premotor area) with the BOLD signal in the ACC and lentiform nucleus correlating with pain rating to thermal stimulation [150]. It is currently unknown whether the CNS changes described in these studies are a response to peripheral nervous system afferent inputs or a primary mechanism responsible for the maintenance of neuropathic pain.
Recently reported differences between painful- and painless-diabetic peripheral neuropathy
Contributing factor
Difference associated with painful-DPN
Risk factors
Female gender
Nav 1.7 mutations
Small nerve fiber alterations
Hyposensitivity phenotype
Epidermal nerve fiber regeneration
Microvascular alterations
Elevated immunostaining for blood vessels
Vitamin D
Reduced 25-hydroxyvitamin D levels
Inflammatory biomarkers
C-reactive protein, tumor necrosis factor-α, inducible nitric oxide synthase and interleukin 6.
Central nervous system
Spinal cord
Impaired spinal inhibitory function
Preserved thalamic NAA and GABA neurochemistry
Thalamic hyperperfusion
Altered somatosensory cortex and thalamic functional connectivity
Descending modulatory pain centers
Descending pain facilitation
Higher brain centers
Somatomotor cortex and insula cortical atrophy
Abnormal cerebral blood flow at rest and in response to heat pain
Altered functional connectivity in higher brain centers at rest and experimental pain conditions
Compliance with Ethical Standards
Conflict of Interest
Pallai Shillo, Gordon Sloan, Marni Greig, Leanne Hunt, Dinesh Selvarajah, Jackie Elliott, Rajiv Gandhi, and Iain D. Wilkinson declare that they have no conflict of interest.
Solomon Tesfaye reports grants from Impeto Medical; personal fees from Neurometrix, Pfizer, Miro, Worwag Pharma, Mundipharma, Merck, and Mitsubishi Pharma; and personal fees and other from Novo Nordisk.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


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Ready to bring you right into the action, the Pioneer Andrew Jones center-channel speaker will help you elevate your home audio setup. Thanks to the two 4-inch woofers and one dome tweeter, the speaker can deliver up to 90 watts of room-shaking realism, crisp vocals, and robust explosions. A full-size curved cabinet design reduces standing sound waves for a more striking sound. Finally, for more accurate highs, mids, and lows, the speaker takes advantage of a sophisticated six-element high-quality capacitor/inductor crossover.
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Remember when you found out that fast food companies would artistically render their food for commercials to look more appealing? Well, kitchen trends can be the same. You see pictures or videos of a remodeled kitchen, and you think, "I want that for my kitchen." However, some of them don't work out as well as they looked. Here are some trends that might seem like a good idea, but you may regret it later.
Open Shelving
This is a trend that looks great in staged photos and videos, but in real life, it can be infuriating. In pictures, you'll see cups and dishes stacked up, and it looks nice and open. We found that in real life, that leads to broken dishes and a lot of messes to clean up.
Subway Tile Backsplash
Not only can the subway tile be visually confusing, but it can be a pain to clean. Not only do you have to clean the surface, but the grout lines too. Got a toothbrush ready? Instead of this, you can go with a large one-piece granite or marble piece. Easy to clean and, in our opinion, more aesthetically pleasing
Desk in Kitchen
Putting a desk in the kitchen was all the rage for a while because after all, a lot of family life does revolve around the kitchen. However, the problem is that a kitchen desk just ends up stacked with papers and clutter that you don't want to see. Pass on the desk and relegate household business to the home office.
Tiled Countertops
Like the subway tile backsplash, this has the same issues, but worse. Because you'll be preparing food and working on the counter, you can double up on the grime, crumbs, and gunk in the grout. While you're at it, better double up on toothbrushes too. Luckily, the same solution for the tile backsplash can be applied to countertops also.
Stainless Steel Appliances
Do you want fingerprints? Because you'll get a ton of them. Not to mention, it's more costly than the same appliances made of other materials. Cleaning stainless steel kitchen appliances isn't always an easy task. While they are strong and resistant to corrosion, they tend to show even minor amounts of dirt and dust.
Whatever your design needs are, even if you decide you like one of these, Riverside Kitchen & Bath can meet them. You can call us at 570-296-4458 or visit our website. If you're in the area, check out our showroom located at 129 Route 6 Milford, PA 18337.


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Five ways to turn Tories' hi-tech dreams into reality
'For the sake of our economy and our society, we need to harness the power of fast-changing technology." So reads the Tory manifesto. But whichever political party finds itself pulling the strings next week, they will need to turn that from a soundbite into serious change.
So, dear Prime Minister, whoever you might be, here are five ideas.
Build a hyper loop
Heathrow has two fabulous new terminals. But let's be honest, even if the third runway is finally built, it will soon be full up and Londoners simply won't tolerate more din at 5am.
So, what if we could link our London airports, turning them into separate terminals of one super-sized airport? "Hyperloop", already being tested in the Nevada...
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Publisher: Sunsout (US), published date 2018 Title: "Summertime Memories" by Sam Timm, 550 pieces Finished size: 15″ x 24″ OUR RATING: 8.75/10 I was in need of a bit of sunshine this week, so I worked this brand new Sam Timm puzzle. Sam Timm is known for his lovely bird paintings, and I have enjoyed quite a few of his puzzles. See the end of this review for some more of my Sam Timm favorites. Box Quality: (7/10) The Sunsout boxes are very largeRead more
Posts tagged: #500 pieces
Review: "Waterfall Valley" by Charles Wysocki, Buffalo Games – 9/10
Publisher: Buffalo Games (US), published 2016 Size: 500 pieces Title: "Waterfall Valley" by Charles Wysocki Finished size: 21.25″ x 15″ OUR RATING: 9/10 Check out the end of this review for more of my favorite Charlies Wysocki puzzles on Puzzle Warehouse right now! Box Quality: (9/10) The Buffalo Games boxes are very sturdy and have nice packaging design. The box is small at 8″ x 8″, but it comes with a poster inside so you don't need to depend on the image on theRead more
Review: "Whistle Stop Christmas" by Charles Wysocki — Buffalo Games 9.25/10
"Whistle Stop Christmas" is a sweet holiday puzzle from artist Charles Wysocki and Buffalo Games. It's an easy puzzle to assemble with 500 pieces and strong color and detail that makes it clear where each piece goes. I love the theme of people arriving home for Christmas. As you assemble the puzzle, you'll smile at the happiness on all the individual faces. The unique costumes and expressions are delightful. I partricularly liked the orange sky on the horizon, the red train station with all the windows, bows, and detailing, and the wintery "white Christmas" snow. The Buffalo Games quality is very good with grid cut pieces and a nice box that comes with a poster. Recommended to all fans of Christmas puzzles.Read more
Review: "Trick or Treat Hotel" by Charles Wysocki, Buffalo Games – 9.25/10
I love this 500 piece Halloween puzzle from Charles Wysocki and Buffalo Games. The artwork has a wry, adult tone reminiscent of Edward Gorey. The scene is populated by strange creatures, pumpkins, cobwebs, and tongue-in-cheek signs like "Rooms to Ferment" and the "Pithias Bloodlust Wrinkledeath" motto on the hearse. The puzzle is mostly easy but the forest behind the mansion has a random pattern which offers a little more challenge and makes the puzzle overall more satisfying to complete. The Buffalo Games quality is quite good. The pieces feel thick and are pleasant to work with. It comes with a poster in the box so you have a larger image to work with. There is some glare off the glossy surface under strong overhead lights. This puzzle is a real treat. Highly recommended!Read more
"Ring-Necked Pheasants" by Linda Picken, Cobble Hill – 8.5/10
"Ring-Necked Pheasants" is a pretty wildlife puzzle with terrific fall colors. This Cobble Hill puzzle features large pieces that are sturdy, have a snug fit, and a glare-free linen finish. I really enjoyed working with the bigger pieces and they have a nice feeling in your hand. The image by Linda Picken is very peaceful and serene. The gold tones are bright and cheerful to work with. The puzzle is fairly easy due to its 500 piece size, but all the gold adds a touch of challenge. Recommended.Read more
Review: "Winter" — Trefl, 7.8/10
This beautiful winter collage puzzle is a super easy and relaxing puzzle to assemble. The distinctive colors, and the three separate photo scenes, make the puzzle go together quickly. The Trefl brand from Poland is a grid-cut puzzle with standard piece shapes and sizes. The pieces are not as thick as some Euro brands like Ravensburger or Jumbo, but thick enough to resist bending and damage. Recommended for children, seniors, and anyone who enjoys 500 piece puzzles. 7.8/10Read more
Review: "4th of July Parade" by Bob Pettes, Sunsout — 8.25/10
This 4th of July themed puzzle is an easy family project for those warm summer evenings. The round shape makes for an unusual and fun puzzle assembly. There are plenty of small figures throughout to discover as you put the puzzle together. Like most Sunsout puzzles, the pieces feel thick & sturdy. However, the cut is close to a grid cut with standard piece shapes even though corners don't quite meet up. There's a lot of green grass in the image, but objects and people break it up in most areas of the puzzle. The brown path with its marching figures is particularly fun to assemble. Recommended for anyone who likes Americana or holiday-themed puzzles.Read more
Review: "A Trip to the Shops" by Trevor Mitchell, Gibsons — 9.5/10
Gibsons puzzles are a high-quality puzzle from the UK with beautiful blue boxes, very thick pieces, and a waxy matte finish. This set contains four separate 500-piece puzzles. The four puzzles together show a family spending the day in a market town and visiting various vintage shops and vendors. This is a lovely British nostalgia collection by artist Trevor Mitchell and was specifically commissioned by Gibsons. There's so much color and detail in these images that assemble is very quick and easy. You can do each 500 piece puzzle separately or mix them together into a 2000 piece puzzle for more of a challenge. The 4×500 format is unique to Gibsons and offers something for all levels of puzzlers. Highly recommended.Read more
Review: "Garden Birds" by Greg and Company, Cobble Hill — 8.25/10
Publisher: Cobble Hill (Canada), 2016 Title: "Garden Birds" by Greg & Company 500 pieces, 18″ x 24″ Review by Jane OUR RATING: 8.25/10 Box Quality: (8/10) The box is shown above and below. It's an attractive rectangular box similar in size to Ravensburger and Jumbo, but it has a nice linen finish. The front does not show the artist or image name. Back: The back is a generic Cobble Hill back. There's nothing specific about the artist or puzzle image here. The sides: The sides have a nice close-up detail fromRead more


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How would auto technology impact evolution? 'Graham' shows us
Karen Graham
Jul 23, 2016 in
- From the first steam-powered automobile capable of human transportation built in 1768, to the Google self-driving car of today, automotive technology has evolved in leaps and bounds, leaving us humans in the dust, evolution-wise.
Melbourne, Australia's Transport Accident Commission is well-known for its perchance for ads that have a certain amount of shock value, so when they came up with their
Toward Zero road-safety campaign
, it turned out to be a bit different.
Enter Graham, a redesigned human sculpture of "the only person designed to survive on our roads," according to his creators at Clemenger BBDO in Melbourne, Australia. Instead of using shock-value to get safe driving messages across to the public, they decided to "fix" the human body.
Graham has a number of evolutionary improvements, designed to protect the body from injury in a car crash.
Australia's Transport Accident Commission
The Clemenger team collaborated with crash investigator David Logan, trauma surgeon Christian Kenfield, and sculptor Patricia Piccinini to come up with "Graham," a life-sized mock-up of an
evolutionarily advanced human
capable of surviving a low-speed car crash.
Graham is not someone a woman might want to pick on a dating website, and he has a torso that looks like he's a stand-in for the Hulk. And his face? Well, it looks like he was hit upside the head with a two-by-four. As for his neck, it just isn't there, and all those air sacs lining his rib cage make him rather unattractive, if not down-right ugly.
But as Clemerger explains it, every modification given to Graham is based on the concept of evolution if it were speeded up to go hand-in-hand with automotive technology, with apologies to Charles Darwin, of course.
Graham doesn't need his neck anymore. His ribcage has become elongated and is designed to protect his spinal cord.
Australia's Transport Accident Commission
Starting at the top of Graham, the oversize head comes with "crumple-zones," and extra padding around the skull, meant to protect the brain. Graham doesn't have a neck. Instead, he has an elongated rib cage that protects his spinal cord, preventing a whiplash in a collision, according to
CTV News Canada
Graham's nose is missing, too, so there is no way he could break it if his head slams into the steering wheel. "Head mobility is greatly reduced and his knees also move laterally, which may mean he's a little wobbly," said Stephen de Wolf, creative director at Clemenger BBDO
Graham's large chest with the added fatty looking air-sacs between his ribs are for the protection of his rib cage and internal organs against any crushing injuries. And if Graham happens to be on the street instead of inside his car, his legs are constructed with pedestrian collisions in mind, also.
His lower ankle area has an extra joint to give him increased mobility, in case he has to jump out of the way of a speeding car. This makes his feet look more like hooves, though. And Graham's knees have been made more flexible to withstand an impact injury.
With an extra joint in the ankle, Graham has greater versatility, making it easier to get out of the way of oncoming cars if he is on the street.
Australia's Transport Accident Commission
While Graham may not be pretty to look at, it was important to his creators that "people could connect with him, that he needed humanity," de Wolf said. "He had to be as real as possible, and while he looks great in print and online, seeing him in the flesh, so to speak, is something else entirely."
Curious Melburnians can see Graham in person at the State Library of Victoria, but everyone else can view his biological adaptations online. The
"Meet Graham" site
is the first in Australia to use the augmented reality capabilities of
Google Tango
, which allows users to peer beneath Graham's skin and view his enhancements from the inside.
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A classic midi-length dolman sleeve dress. This modern design is constructed with two pieces of fabric coming together to create a natural drape with an open back. Hand-braided button loop. Relaxed fit, intended for the style to drape loosely along the body.
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