A Systematic Review and Meta-analysis of Non-pharmacological Methods to Manipulate Experimentally Induced Secondary Hypersensitivity.

This systematic review and meta-analysis investigated the effects of non-pharmacological manipulations on experimentally induced secondary hypersensitivity in pain-free humans. We investigated the magnitude (change/difference in follow-up ratings from pre-manipulation ratings) of secondary hypersensitivity (primary outcome), and surface area of secondary hypersensitivity (secondary outcome), in 27 studies representing 847 participants. Risk of bias assessment concluded most studies (23 of 27) had an unclear or high risk of performance and detection bias. Further, 2 (of 27) studies had a high risk of measurement bias. Datasets were pooled by the method of manipulation and outcome. The magnitude of secondary hypersensitivity was decreased by diverting attention, anodal transcranial direct current stimulation, or emotional disclosure; increased by directing attention toward the induction site, nicotine deprivation, or negative suggestion; and unaffected by cathodal transcranial direct current stimulation or thermal change. Area of secondary hypersensitivity was decreased by anodal transcranial direct current stimulation, emotional disclosure, cognitive behavioral therapy, hyperbaric oxygen therapy, placebo analgesia, or spinal manipulation; increased by directing attention to the induction site, nicotine deprivation, or sleep disruption (in males only); and unaffected by cathodal transcranial direct current stimulation, thermal change, acupuncture, or electroacupuncture. Meta-analytical pooling was only appropriate for studies that used transcranial direct current stimulation or hyperbaric oxygen therapy, given the high clinical heterogeneity among the studies and unavailability of data. The evidence base for this question remains small. We discuss opportunities to improve methodological rigor including manipulation checks, structured blinding strategies, control conditions or time points, and public sharing of raw data. PERSPECTIVE: We described the effects of several non-pharmacological manipulations on experimentally induced secondary hypersensitivity in humans. By shedding light on the potential for non-pharmacological therapies to influence secondary hypersensitivity, it provides a foundation for the development and testing of targeted therapies for secondary hypersensitivity.

Cerebral blood flow rates in recent great apes are greater than in Australopithecus species that had equal or larger brains.

Brain metabolic rate (MR) is linked mainly to the cost of synaptic activity, so may be a better correlate of cognitive ability than brain size alone. Among primates, the sizes of arterial foramina in recent and fossil skulls can be used to evaluate brain blood flow rate, which is proportional to brain MR. We use this approach to calculate flow rate in the internal carotid arteries (Q˙ICA), which supply most of the primate cerebrum. Q˙ICA is up to two times higher in recent gorillas, chimpanzees and orangutans compared with 3-million-year-old australopithecine human relatives, which had equal or larger brains. The scaling relationships between Q˙ICA and brain volume (Vbr) show exponents of 1.03 across 44 species of living haplorhine primates and 1.41 across 12 species of fossil hominins. Thus, the evolutionary trajectory for brain perfusion is much steeper among ancestral hominins than would be predicted from living primates. Between 4.4-million-year-old Ardipithecus and Homo sapiens, Vbr increased 4.7-fold, but Q˙ICA increased 9.3-fold, indicating an approximate doubling of metabolic intensity of brain tissue. By contrast, Q˙ICA is proportional to Vbr among haplorhine primates, suggesting a constant volume-specific brain MR.

A systematic review of experimental methods to manipulate secondary hyperalgesia in humans: protocol.

BACKGROUND: Neuropathic pain affects 7-10% of people, but responds poorly to pharmacotherapy, indicating a need for better treatments. Mechanistic research on neuropathic pain frequently uses human surrogate models of the secondary hyperalgesia that is a common feature of neuropathic pain. Experimentally induced secondary hyperalgesia has been manipulated with pharmacological and non-pharmacological methods to clarify the relative contributions of different mechanisms to secondary hyperalgesia. However, this literature has not been systematically synthesised. The aim of this systematic review is to identify, describe, and compare methods that have been used to manipulate experimentally induced secondary hyperalgesia in healthy humans. METHODS: A systematic search strategy will be supplemented by reference list checks and direct contact with identified laboratories to maximise the identification of data reporting the experimental manipulation of experimentally induced secondary hyperalgesia in healthy humans. Duplicated screening, risk of bias assessment, and data extraction procedures will be used. Authors will be asked to provide data as necessary. Data will be pooled and meta-analyses conducted where possible, with subgrouping according to manipulation method. Manipulation methods will be ranked for potency and risk. DISCUSSION: The results of this review will provide a useful reference for researchers interested in using experimental methods to manipulate secondary hyperalgesia in humans and will help to clarify the relative contributions of different mechanisms to secondary hyperalgesia. SYSTEMATIC REVIEW REGISTRATION: This protocol will be registered on PROSPERO before the review begins. Review records will be updated on PROSPERO once the review is complete. This review is intended for publication in a peer-reviewed journal. Analyses and scripts will be made publicly available.