Cognitive and neuroscientific perspectives of healthy ageing.

With dementia incidence projected to escalate significantly within the next 25 years, the United Nations declared 2021-2030 the Decade of Healthy Ageing, emphasising cognition as a crucial element. As a leading discipline in cognition and ageing research, psychology is well-equipped to offer insights for translational research, clinical practice, and policy-making. In this comprehensive review, we discuss the current state of knowledge on age-related changes in cognition and psychological health. We discuss cognitive changes during ageing, including (a) heterogeneity in the rate, trajectory, and characteristics of decline experienced by older adults, (b) the role of cognitive reserve in age-related cognitive decline, and (c) the potential for cognitive training to slow this decline. We also examine ageing and cognition through multiple theoretical perspectives. We highlight critical unresolved issues, such as the disparate implications of subjective versus objective measures of cognitive decline and the insufficient evaluation of cognitive training programs. We suggest future research directions, and emphasise interdisciplinary collaboration to create a more comprehensive understanding of the factors that modulate cognitive ageing.

Inflammation induces α1-adrenoceptor expression in peripheral blood mononuclear cells of patients with complex regional pain syndrome.

Persistent regional and systemic inflammation may promote pain and hyperalgesia in complex regional pain syndrome (CRPS). In this study, we investigated whether stimulation of α1-adrenoceptors (α1-AR) on peripheral blood mononuclear cells (PBMC) might contribute to this inflammatory state. PBMC were isolated from venous blood collected from 21 CRPS patients and 21 sex and age-matched controls. Lipopolysaccharide (LPS), a bacterial toxin, was administered to cultured PBMC for 24 h to trigger inflammation. Exposure to LPS resulted in heightened gene expression of α1-AR subtype B (α1B-AR) in PBMC of CRPS patients relative to controls. Interleukin (IL)-1ß and IL-6 levels did not change when the α1-AR agonist phenylephrine was administered to naïve PBMC. However, α1-AR stimulation following LPS treatment increased IL-6 mRNA and protein levels in PBMC of patients and controls. To investigate the possible consequence of heightened IL-6 levels on immunoglobulin G antibody production, PBMC were stimulated with CD40 ligand and IL-21 to generate plasmablasts (B cells that secrete antibodies). This response was similar in patients and controls. Adding IL-6 to the cell culture medium increased plasmablast differentiation in controls and antibody production both in patients and controls. These findings suggest that the inflammatory cascade associated with elevated levels of IL-6 may generate α1B-AR expression in CRPS PBMC. A reciprocal interaction between heightened α1-AR expression in PBMC and IL-6 secretion may contribute to systemic inflammation and antibody production in CRPS.

A Macroscopic Quantum Three-Box Paradox: Finding Consistency with Weak Macroscopic Realism.

The quantum three-box paradox considers a ball prepared in a superposition of being in any one of three boxes. Bob makes measurements by opening either box 1 or box 2. After performing some unitary operations (shuffling), Alice can infer with certainty that the ball was detected by Bob, regardless of which box he opened, if she detects the ball after opening box 3. The paradox is that the ball would have been found with certainty by Bob in either box if that box had been opened. Resolutions of the paradox include that Bob's measurement cannot be made non-invasively or else that realism cannot be assumed at the quantum level. Here, we strengthen the case for the former argument by constructing macroscopic versions of the paradox. Macroscopic realism implies that the ball is in one of the boxes prior to Bob or Alice opening any boxes. We demonstrate the consistency of the paradox with macroscopic realism, if carefully defined (as weak macroscopic realism, wMR) to apply to the system at the times prior to Alice or Bob opening any boxes but after the unitary operations associated with preparation or shuffling. By solving for the dynamics of the unitary operations and comparing with mixed states, we demonstrate agreement between the predictions of wMR and quantum mechanics: the paradox only manifests if Alice's shuffling combines both local operations (on box 3) and nonlocal operations, on the other boxes. Following previous work, the macroscopic paradox is shown to correspond to a violation of a Leggett-Garg inequality, which implies failure of non-invasive measurability if wMR holds.

Midpoint projection algorithm for stochastic differential equations on manifolds.

Stochastic differential equations projected onto manifolds occur in physics, chemistry, biology, engineering, nanotechnology, and optimization, with interdisciplinary applications. Intrinsic coordinate stochastic equations on the manifold are sometimes computationally impractical, and numerical projections are therefore useful in many cases. In this paper a combined midpoint projection algorithm is proposed that uses a midpoint projection onto a tangent space, combined with a subsequent normal projection to satisfy the constraints. We also show that the Stratonovich form of stochastic calculus is generally obtained with finite bandwidth noise in the presence of a strong enough external potential that constrains the resulting physical motion to a manifold. Numerical examples are given for a wide range of manifolds, including circular, spheroidal, hyperboloidal, and catenoidal cases, higher-order polynomial constraints that give a quasicubical surface, and a ten-dimensional hypersphere. In all cases the combined midpoint method has greatly reduced errors compared to other methods used for comparison, namely, a combined Euler projection approach and a tangential projection algorithm. We derive intrinsic stochastic equations for spheroidal and hyperboloidal surfaces for comparison purposes to verify the results. Our technique can handle multiple constraints, which allows manifolds that embody several conserved quantities. The algorithm is accurate, simple, and efficient. A reduction of an order of magnitude in the diffusion distance error is found compared to the other methods and an up to several orders of magnitude reduction in constraint function errors.

Effects of a polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment: A randomized, double-blind, placebo-controlled study.

Background: Polyphenols are naturally occurring organic compounds found in plants. Research suggests that their intake reduces the risk of cognitive decline and related dementias. Grapes and blueberries are polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Purpose: Examine the effects of supplementation with a standardized and patented polyphenol-rich grape and blueberry extract (Memophenol™) on cognitive function in older adults with mild cognitive impairment. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Methods: One hundred and forty-three volunteers aged 60 to 80 years with mild cognitive impairment were supplemented with either 150 mg of Memophenol™, twice daily or a placebo. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function (BRIEF-A), the Cognitive Failures Questionnaire, and the CASP-19. Results: Compared to the placebo, Memophenol™ supplementation was associated with greater improvements in the speed of information processing (p = 0.020), visuospatial learning (p = 0.012), and the BRIEF-A global score (p = 0.046). However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires. Memophenol™ supplementation was well-tolerated with no reports of significant adverse reactions. Conclusion: The promising results from this trial suggest that 6-months of supplementation with Memophenol™ may improve aspects of cognitive function in adults with mild cognitive impairment. Further research will be important to expand on the current findings and identify the potential mechanisms of action associated with the intake of this polyphenol-rich extract.

The sensory and affective components of pain differentially shape pupillary dilatation during cold pressor tests.

Nociceptive and affective stimuli increase reflex sympathetic outflow to the pupils. To investigate effects of stimulus intensity, unpleasantness and distress on these pupillary reflexes, and to assess their stability, healthy participants immersed their hand in ice-water three times (for 20, 40 and 60 s; or 60, 40 and 20 s; or three times for 60 s) (N = 21 in each condition). Each ice-water immersion was preceded by a 90 s warm water immersion. To evaluate phasic sympathetic influences on pupil diameter, pupillary re-dilatation after 1 s of bright light was assessed during the last 10 s of each immersion. By-and-large, pain ratings and pupil diameter were greater during longer than shorter ice-water immersions, and ice-water immersions facilitated pupillary re-dilatation after the flash stimulus. However, mean pupil diameter during ice- and warm water immersions, minor ipsilateral amplification of the pupillary response, and ratings of pain unpleasantness and distress decreased across the experiment. Together, these findings suggest that nociceptive input increased sympathetic pupillary tone and amplified phasic increases in sympathetic activity after exposure to light. However, tonic sympathetic influences on pupil diameter and lateralization decreased across repeated immersions, possibly as novel or threatening aspects of the experience declined. Pupillary nociceptive and affective reflexes involve the locus coeruleus, an integral component of neural circuits that heighten cortical arousal and regulate pain. As these reflexes appear to reflect different aspects of sensory and affective processing, their combined assessment might increase the sensitivity and specificity of tests of locus coeruleus function in patients with suspected deficits.

High Blood Glucose and Excess Body fat Enhance Pain Sensitivity and Weaken Pain Inhibition in Healthy Adults: A Single-blind Cross-over Randomized Controlled Trial.

To investigate links between blood glucose, body fat mass and pain, the effects of acute hyperglycaemia on pain sensitivity and pain inhibition were examined in healthy adults with normal (n = 24) or excess body fat (n = 20) determined by dual-energy X-ray absorptiometry. Effects of hyperglycaemia on heart rate variability and reactive hyperaemia were also explored. For the overall sample, ingesting 75-g glucose enhanced pain sensitivity during 1-minute cold-water immersion of both feet (conditioning stimulus) and weakened the pain inhibitory effect of cold water on pressure pain thresholds (test stimulus). Exploratory subgroup analyses not adjusted for multiple comparisons suggested that this effect was limited to people with excess fat mass. In addition, acute hyperglycaemia suppressed resting heart rate variability only in people with excess fat mass. Furthermore, regardless of blood glucose levels, people with excess fat mass had weaker pain inhibition for pinprick after cold water and reported more pain during 5-minutes of static blood flow occlusion. Neither high blood glucose nor excess body fat affected pinprick-temporal summation of pain or reactive hyperaemia. Together, these findings suggest that hyperglycaemia and excess fat mass interfere with pain processing and autonomic function. PERSPECTIVE: Ingesting 75-g glucose (equivalent to approximately 2 standard cans of soft drink) interfered with pain-processing and autonomic function, particularly in people with excess body fat mass. As both hyperglycaemia and overweight are risk factors for diabetes, whether these are sources of pain in people with diabetes should be further explored.

Stimulation of alpha-1 adrenoceptors may intensify cutaneous inflammation in complex regional pain syndrome.

ABSTRACT: Alpha-1 adrenoceptors are overexpressed in the epidermis of a subgroup of patients with complex regional pain syndrome (CRPS). Activating α 1 -adrenoceptors in epidermal cells increases production of the proinflammatory cytokine interleukin-6 (IL-6), a mediator of inflammation. To investigate whether this might exacerbate inflammation in CRPS, primary keratinocytes or dermal fibroblasts were cultured from skin biopsies obtained from the affected limb of 25 patients and a similar site in 28 controls. The fundamental proinflammatory cytokine, tumor necrosis factor alpha, was administered for 24 hours to initiate inflammation. After this, cells were incubated for 6 hours with the α 1 -adrenoceptor agonist phenylephrine. Exposure to tumor necrosis factor alpha induced proinflammatory cytokine mRNA production and protein secretion in keratinocytes and fibroblasts and enhanced α 1B -adrenoceptor mRNA expression in keratinocytes. Additional stimulation of α 1 adrenoceptors with phenylephrine increased the production of IL-6 mRNA and protein secretion in both cell types. Under all conditions, gene and protein α 1 -adrenoceptor levels and cytokine gene expression and protein secretion were similar, overall, in patients and controls, except for abnormally high α 1 -adrenoceptor protein levels in the keratinocytes of 3 of 17 patients. These findings suggest that persistent inflammation in CRPS is not due to dysfunction of skin cells but is a normal response to extrinsic signals. After α 1 -adrenoceptor stimulation of keratinocytes, increases in IL-6 mRNA but not protein were proportional to basal α 1 -adrenoceptor protein levels. Skin cells play an important role in persistent inflammation in CRPS. Potentially, a positive feedback loop between α 1 -adrenoceptors and IL-6 production in skin cells contributes to this inflammatory state.

Olfaction in Complex Regional Pain Syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is associated with a range of sensory disturbances on the symptomatic side of the body but whether this includes olfaction is uncertain. To clarify this, the aims of this study were to compare ratings of intensity and hedonic appeal of household odorants in CRPS patients and controls, and to determine whether ratings differed between the symptomatic and contralateral sides within the sample of patients. METHODS: Six odorants (vanilla, fish sauce, vinegar, eucalyptus, almond essence and acetone) were presented sequentially in random order on cottonwool buds held in the midline approximately 1 cm from both nostrils in 37 CRPS patients and 21 pain-free controls. Each odor was rated for intensity and hedonic appeal, and participants reported whether the odor was stronger and/or smelt different on one side than the other. RESULTS: The odorants smelt worse for patients than controls (P < .05 for the symptomatic and contralateral sides) but neither the intensity nor the unpleasantness of the odorants was greater on the symptomatic than contralateral side in the group as-a-whole. CONCLUSIONS: These findings suggest that the trigeminal component of olfaction interacts bilaterally with pain-sensitized circuits in the thalamus or higher cortical centers to distort odor perception in patients with CRPS. This aberrant process appears to differ from the mechanism that underlies hemilateral hyperalgesia in other sensory modalities.

Temple cooling increases parasympathetic activity and decreases pressure pain on the hand.

BACKGROUND: Applying an ice cube to the temple (the conditioning stimulus) inhibits electrically evoked pain in the forearm. The present study aimed to determine whether temple cooling also inhibits pressure- and heat-pain test stimuli in the upper limb and, if so, to investigate the intra-session test-retest reliability of this response. Additional aims were to establish whether pain inhibition evoked by temple cooling was associated with parasympathetic activity; and to explore sex differences in response. METHODS: The sample consisted of 40 healthy adults (24 females). Heart rate was recorded continuously throughout the session. An ice cube (3 × 4 cm contact area) was applied for 1 min to the temple on the dominant side. Before and immediately afterwards, the pressure pain threshold was measured from the dorsal hand and sensitivity to heat (individually adjusted at baseline to elicit moderate pain) was measured from the ventral forearm. The procedures were repeated 15 min later. RESULTS: Temple cooling inhibited pressure pain on the hand but not heat pain on the forearm. However, test-retest reliability of pressure pain inhibition was poor. Heart rate decreased during temple cooling, consistent with a "diving" reflex. Males had stronger pressure pain inhibition, lower heart rate and higher overall autonomic activity than females. However, cardiac parasympathetic activation during temple cooling was comparable in both sexes and was unrelated to pain inhibition. CONCLUSIONS: These findings indicate that temple cooling evokes pain inhibition that is stronger in males than in females. Cardiac parasympathetic activity does not appear to mediate this response. SIGNIFICANCE: The conditioning stimulus in the conditioned pain modulation paradigm is often applied to the upper or lower limbs. This may confound pain-inhibitory effects in people with peripheral neuropathy who typically have enhanced or diminished sensation in the extremities. Applying an ice cube at the temple area induces pain-inhibitory effects on the upper limb after the ice is removed. Future research examining pain modulation in people with peripheral neuropathy may consider adopting temple cooling as the conditioning stimulus.

Auditory disturbances in patients with complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) is often associated with reduced sound tolerance (hyperacusis) on the affected side, but the mechanism of this symptom is unclear. As compensatory increases in central auditory activity after cochlear injury may trigger hyperacusis, hearing and discomfort thresholds to pure tones (250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz) were assessed in 34 patients with CRPS and 26 pain-free controls. In addition, in 31 patients and 17 controls, auditory-evoked potentials to click stimuli (0.08 ms duration, 6 Hz, 60 dB above the hearing threshold) were averaged across 2000 trials for each ear. Auditory discomfort thresholds were lower at several pitches on the CRPS-affected than contralateral side and lower at all pitches on the affected side than in controls. However, ipsilateral hyperacusis was not associated with psychophysical or physiological signs of cochlear damage. Instead, neural activity in the ipsilateral brainstem and midbrain was greater when repetitive click stimuli were presented on the affected than contralateral side and greater bilaterally than in controls. In addition, click-evoked potentials, reflecting thalamo-cortical signal transfer and early cortical processing, were greater contralaterally in patients than controls. Together, these findings suggest that hyperacusis originates in the ipsilateral brainstem and midbrain rather than the peripheral auditory apparatus of patients with CRPS. Failure of processes that jointly modulate afferent auditory signalling and pain (eg, inhibitory influences stemming from the locus coeruleus) could contribute to ipsilateral hyperacusis in CRPS.

Defining pain-validation: The importance of validation in reducing the stresses of chronic pain.

Purpose: To validate an individual's feelings or behaviour is to sanction their thoughts or actions as worthy of social acceptance and support. In contrast, rejection of the individual's communicated experience indicates a denial of social acceptance, representing a potential survival threat. Pain-invalidation, though ill-defined, appears to be a fundamental component of psychosocial stress for people with chronic pain. As such, the aim of this paper was to define pain-validation and outline its importance for those with chronic pain. Methods: The pain-validation construct was defined using themes inherent in the narratives of those with chronic pain, as identified in a previously published systematic search and thematic analysis, together with examination of additional literature on pain-validation in the clinical context. Results: We present a construct definition, proposing that pain-validation must necessarily include: (i) belief that the pain experience is true for the individual, (ii) acceptability of the individual's expressions of pain, and (iii) communication of belief and acceptability to the individual experiencing pain. Further, we outline the importance of pain-validation as a protective factor and means of reducing many of the psychosocial stresses of chronic pain; for example, by indicating social support for pain-coping, buffering negative emotions, and re-enforcing unity and shared identity. Implications: The role of pain-validation in the current era of pain management intervention is discussed. Adhering to interventions that involve cognitive and behavioural change is often difficult. Acknowledging and validating the acceptability of the patient's pain experience in the early stages of pain management may, therefore, be a key component of intervention that encourages compliance to the treatment plan and achieving therapeutic goals.

A randomized, double-blind, placebo-controlled trial investigating the effects of an Ocimum tenuiflorum (Holy Basil) extract (HolixerTM) on stress, mood, and sleep in adults experiencing stress.

Background: In Ayurveda, Ocimum tenuiflorum (Holy Basil) is referred to as "the elixir of life" and is believed to promote longevity and general wellbeing. Although limited, there are clinical trials to suggest Ocimum tenuiflorum has anti-stress effects. Purpose: Examine the effects of a standardized Ocimum tenuiflorum extract (HolixerTM) on subjective and objective measures of stress and sleep quality in adults experiencing stress. Study design: Two-arm, parallel-group, 8-week, randomized, double-blind, placebo-controlled trial. Australian and New Zealand Clinical Trials Registry trial registration number ACTRN12621000609853. Methods: One hundred volunteers aged 18-65 years received either 125 mg of Ocimum tenuiflorum twice daily or a placebo. Outcome measures included the Perceived Stress Scale (PSS) (primary outcome measure), Profile of Mood States, Athens Insomnia Scale (AIS), Restorative Sleep Questionnaire, and the Patient-Reported Outcomes Measurement Information System-29. Sleep quality was also assessed using a wrist-worn sleep tracker (Fitbit), and stress changes were examined by measuring between-group differences in hair cortisol and stress responses after exposure to an experiment stress procedure known as the Maastricht Acute Stress Test (MAST). Results: Compared to the placebo, Ocimum tenuiflorum supplementation was associated with greater improvements in PSS (p = 0.003) and AIS (p = 0.025) scores; and at week 8, concentrations in hair cortisol were also lower (p = 0.025). Moreover, Ocimum tenuiflorum supplementation was associated with a buffered stress responses after exposure to the MAST as demonstrated by significantly lower concentrations in salivary cortisol (p = 0.001), salivary amylase (p = 0.001), systolic (p = 0.010) and diastolic (p = 0.025) blood pressure, and subjective stress ratings (p < 0.001). Ocimum tenuiflorum supplementation was well-tolerated with no reports of major adverse effects. Conclusion: The results from this trial suggest that 8 weeks of supplementation with an Ocimum tenuiflorum extract (HolixerTM) may reduce objective and subjective measures of stress, and improve subjective measures of sleep quality. However, further research using gold-standard objective sleep measures will be required to substantiate the sleep-related findings. Clinical trial registration: https://www.anzctr.org.au/ACTRN12621000609853p.aspx, identifier: ACTRN12621000609853p.

The Pain-Invalidation Scale: Measuring Patient Perceptions of Invalidation Toward Chronic Pain.

Increasing evidence reveals the damaging impact of having one's chronic pain symptoms invalidated through disbelief, discrediting, and critical judgement. In other instances, a caregiver's over-attentiveness to the daily tasks of individuals with pain can be problematic, potentially undermining rehabilitation. The aim of this study was to develop an instrument to measure different aspects of invalidation perceived by people with chronic pain. Item generation was informed through literature review and a thematic analysis of narratives from 431 peer-reviewed articles. The crowdsourcing platform Prolific was used to distribute survey items to participants. In Study 1A, Principal Component Analysis was performed on data from 302 respondents, giving rise to 4 subscales, including: Invalidation by the Self, Invalidation by Immediate Others, Invalidation by Healthcare Professionals, and Invalidation by Over-attentive Others. Confirmatory Factor Analysis of data collected from another 308 individuals in Study 1B supported the 4-factor model of the Pain-Invalidation Scale (Pain-IS) and identified a best-fit model with 24 items. The Pain-IS was further validated in another 300 individuals in Study 2. The Pain-IS demonstrates sound psychometric properties and may serve as a valuable tool for use by clinicians in the detection of pain-invalidation issues, as a first step in patient pain management. PERSPECTIVE: Links between pain-invalidation and pain levels, as well as functional detriment, highlight the importance of having one's chronic pain experience heard, believed, and accepted. The Pain-Invalidation Scale is designed to identify domains where invalidation of the patient's pain should be addressed to promote emotional processing, treatment adherence, and improved outcomes.

Asymmetry of the pupillary light reflex during a cold pressor test.

Pupillary light reflexes were monitored in 20 healthy participants while they immersed one foot in painfully cold water (the cold pressor test) or in warm water for 1 min. Pupillary dilatation was greater during the cold pressor test than during the warm-water immersion. In addition, during the cold pressor test, re-dilation after exposure to bright light proceeded more rapidly for the ipsilateral than contralateral pupil. These findings suggest that sympathetic pupillary drive is greater ipsilateral than contralateral to pain.

The Effects of Lutein and Zeaxanthin Supplementation on Cognitive Function in Adults With Self-Reported Mild Cognitive Complaints: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lutein and zeaxanthin are fat-soluble, dietary carotenoids with high concentrations in human brain tissue. There have been a number studies confirming an association between lutein and zeaxanthin and cognitive function. PURPOSE: Examine the effects of lutein and zeaxanthin supplementation on cognitive function in adults with self-reported cognitive complaints. STUDY DESIGN: Two-arm, parallel-group, 6-month, randomized, double-blind, placebo-controlled trial. METHODS: Ninety volunteers aged 40-75 years received either 10 mg of lutein and 2 mg of zeaxanthin, once daily or a placebo. Outcome measures included computer-based cognitive tasks, the Cognitive Failures Questionnaire, Behavior Rating Inventory of Executive Function, Profile of Mood States, and the Patient-Reported Outcomes Measurement Information System-29. RESULTS: Compared to the placebo, lutein and zeaxanthin supplementation was associated with greater improvements in visual episodic memory (p = 0.005) and visual learning (p = 0.001). However, there were no other statistically-significant differences in performance on the other assessed cognitive tests or self-report questionnaires. Lutein and zeaxanthin supplementation was well-tolerated with no reports of significant adverse effects. CONCLUSION: The results from this trial suggest that 6-months of supplementation with lutein and zeaxanthin may improve visual memory and learning in community-dwelling adults with self-reported cognitive complaints. However, it had no other effect on other computer-based measures of cognitive performance or self-report measures of cognition, memory, mood, or physical function.

Phase-space simulations of feedback coherent Ising machines.

A new, to the best of our knowledge, technique is demonstrated for carrying out exact positive-P phase-space simulations of the coherent Ising machine quantum computer. By suitable design of the coupling matrix, general hard optimization problems can be solved. Here, computational quantum simulations of a feedback type of photonic parametric network are carried out, which is the implementation of the coherent Ising machine. Results for success rates are obtained using this scalable phase-space algorithm for quantum simulations of quantum feedback devices.

Co-morbidity between trigeminal autonomic cephalalgias and complex regional pain syndrome: Two case reports.

BACKGROUND: Trigeminal autonomic cephalalgias and complex regional pain syndrome are rare conditions, and their co-occurrence has not been reported previously.Clinical findings: In two patients, ipsilateral trigeminal autonomic cephalalgias developed after the onset of upper limb complex regional pain syndrome. Hyperalgesia to thermal and mechanical stimuli extended beyond the affected limb to encompass the ipsilateral forehead, and was accompanied by ipsilateral hyperacusis and photophobia. In addition, examination of the painful limb and bright light appeared to aggravate symptoms of trigeminal autonomic cephalalgias. Detailed examination of the association between facial and upper limb pain indicated that both sources of pain cycled together. Furthermore, in one case, stellate ganglion blockade inhibited pain for an extended period not only in the affected limb but also the face. CONCLUSIONS: These findings suggest some overlap in the pathophysiology of complex regional pain syndrome and trigeminal autonomic cephalalgias. Specifically, central sensitization and/or disruption of inhibitory pain modulation on the affected side of the body in complex regional pain syndrome might trigger ipsilateral cranial symptoms and increase vulnerability to trigeminal autonomic cephalalgias.

Painful diabetic peripheral neuropathy: Role of oxidative stress and central sensitisation.

AIMS: Diabetic peripheral neuropathy (DPN) occurs in about half of people with diabetes, of whom a quarter may develop chronic pain. Pain may remain for years yet be difficult to treat because the underlying mechanisms remain unclear. There is consensus that processing excessive glucose leads to oxidative stress, interfering with normal metabolism. In this narrative review, we argue that oxidative stress may also contribute to pain. METHODS: We reviewed literature in PubMed published between January 2005 and August 2021. RESULTS AND CONCLUSIONS: In diabetes, hyperglycaemia and associated production of reactive species can directly increase pain signalling and activate sensory neurons; or the effects can be indirect, mediated by mitochondrial damage and enhanced inflammation. Furthermore, pain processing in the central nervous system is compromised in painful DPN. This is implicated in central sensitisation and dysfunctional pain modulation. However, central pain modulatory function is understudied in diabetes. Future research is required to clarify whether central sensitisation and/or disturbances in central pain modulation contribute to painful DPN. Positive results would facilitate early detection and future treatment.