Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

Amplified pain syndromes in children: treatment and new insights into disease pathogenesis.

PURPOSE OF REVIEW: Although many diagnostic terms are used for pediatric chronic pain, evidence suggests a common thread of signal amplification, leading to the unifying term 'amplified pain syndromes'. Ongoing research provides new insights into biopsychosocial contributors and treatments for pediatric amplified pain syndromes. RECENT FINDINGS: Basic science indicates a complex interplay of genetic, epigenetic, neurochemical, endocrine, and inflammatory contributors, along with environmental and psychological factors. Although medications and interventions remain common approaches to children with chronic pain, their evidence is limited. Preliminary evidence exists for mindfulness-based therapies, yoga, and other complementary/alternative medicine approaches. The strongest evidence is for exercise-based and cognitive-behavioral treatments, in particular, when combined in a multidisciplinary format. Intensive approaches (pain rehabilitation) have the potential to effectively and efficiently treat those most disabled by amplified pain syndromes, and lead to sustained improvement in pain, functioning, and medical utilization. SUMMARY: Although understanding of the mechanisms underlying pediatric amplified pain syndromes evolves, standard of care is multidisciplinary emphasizing exercise therapy, cognitive-behavioral treatment, and self-regulation. Treatment should target full return to physical function, which leads to subsequent improvement or resolution of pain. Multidisciplinary care can be coordinated by a rheumatologist or other physician with appropriate referrals, or through a multidisciplinary team.

Evolving concepts in neurogenic osteoporosis.

Convincing evidence has accumulated of regulation of bone by the central nervous system. The neural connection between brain and bone is mediated centrally by classic neurotransmitters and several neuropeptides, and peripherally by many of the same neurotransmitters and neuropeptides, albeit with actions opposite to their central effects. Pharmacologic blockade of ß2-adrenergic receptors or disruption of the gene encoding them increases bone mass, whereas increased activity of the sympathetic nervous system (SNS) contributes to bone loss. Brainstem serotonergic neurons regulate SNS activity and its modulation by leptin. Physiologic stimulation of osteoblastic nicotinic receptors results in proliferation and deposition of bone, whereas higher levels inhibit osteoblast function. Activation of sensory nerves has a centrally mediated action on bone, albeit poorly understood. The relative importance of, and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are also not clear in healthy individuals, and less so in pathologic states.