The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability.

BACKGROUND: Many pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and an inability to accurately classify at-risk individuals. Preliminary evidence has shown that high pain sensitivity is associated with slow peak alpha frequency (PAF), and depression of corticomotor excitability (CME), potentially due to impairments in ascending sensory and descending motor pathway signalling respectively NEW METHOD: The present study evaluated the reliability of PAF and CME responses during sustained pain. Specifically, we determined whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. RESULTS: Using a weighted peak estimate, PAF reliability (n = 75) was in the excellent range even without standard pre-processing and ∼2 min recording length. Using a single peak estimate, PAF reliability was in the moderate-good range. For CME (n = 74), 80% of participants showed facilitation or depression of CME beyond an optimal cut-off point, with the stability of these changes in the good range. COMPARISON WITH EXISTING METHODS: No study has assessed the reliability of PAF or feasibility of classifying individuals as facilitators/depressors, in response to sustained pain. PAF was reliable even in the presence of pain. The use of a weighted peak estimate for PAF is recommended, as excellent test-retest reliability can be obtained even when using minimal pre-processing and ∼2 min recording. We also showed that 80% of individuals exhibit either facilitation or depression of CME, with these changes being stable across sessions. CONCLUSIONS: Our study provides support for the reliability of PAF and CME as prospective cortical biomarkers. As such, our paper adds important methodological advances to the rapidly growing field of pain biomarkers.

The influence of sensory potentials on transcranial magnetic stimulation - Electroencephalography recordings.

OBJECTIVE: It remains unclear to what extent Transcranial Magnetic Stimulation-evoked potentials (TEPs) reflect sensory (auditory and somatosensory) potentials as opposed to cortical excitability. The present study aimed to determine; a) the extent to which sensory potentials contaminate TEPs using a spatially-matched sham condition, and b) whether sensory potentials reflect auditory or somatosensory potentials alone, or a combination of the two. METHODS: Twenty healthy participants received active or sham stimulation, with the latter consisting a sham coil click combined with scalp electrical stimulation. Two additional conditions i) electrical stimulation and ii) auditory stimulation alone, were included in a subset of 13 participants. RESULTS: Signals from active and sham stimulation were correlated in spatial and temporal domains > 55 ms post-stimulation. Relative to auditory or electrical stimulation alone, sham stimulation resulted in a) larger potentials, b) stronger correlations with active stimulation and c) a signal that was not a linear sum of electrical and auditory stimulation alone. CONCLUSIONS: Sensory potentials can confound interpretations of TEPs at timepoints > 55 ms post-stimulation. Furthermore, TEP contamination cannot be explained by auditory or somatosensory potentials alone, but instead reflects a non-linear interaction between both. SIGNIFICANCE: Future studies may benefit from controlling for sensory contamination using spatially-matched sham conditions, and which consist of combined auditory and somatosensory stimulation.

Selective, high-contrast detection of syngeneic glioblastoma in vivo.

Glioblastoma is a highly malignant, largely therapy-resistant brain tumour. Deep infiltration of brain tissue by neoplastic cells represents the key problem of diffuse glioma. Much current research focuses on the molecular makeup of the visible tumour mass rather than the cellular interactions in the surrounding brain tissue infiltrated by the invasive glioma cells that cause the tumour's ultimately lethal outcome. Diagnostic neuroimaging that enables the direct in vivo observation of the tumour infiltration zone and the local host tissue responses at a preclinical stage are important for the development of more effective glioma treatments. Here, we report an animal model that allows high-contrast imaging of wild-type glioma cells by positron emission tomography (PET) using [18 F]PBR111, a selective radioligand for the mitochondrial 18 kDa Translocator Protein (TSPO), in the Tspo-/- mouse strain (C57BL/6-Tspotm1GuMu(GuwiyangWurra)). The high selectivity of [18 F]PBR111 for the TSPO combined with the exclusive expression of TSPO in glioma cells infiltrating into null-background host tissue free of any TSPO expression, makes it possible, for the first time, to unequivocally and with uniquely high biological contrast identify peri-tumoral glioma cell invasion at preclinical stages in vivo. Comparison of the in vivo imaging signal from wild-type glioma cells in a null background with the signal in a wild-type host tissue, where the tumour induces the expected TSPO expression in the host's glial cells, illustrates the substantial extent of the peritumoral host response to the growing tumour. The syngeneic tumour (TSPO+/+) in null background (TSPO-/-) model is thus well suited to study the interaction of the tumour front with the peri-tumoral tissue, and the experimental evaluation of new therapeutic approaches targeting the invasive behaviour of glioblastoma.

Author Correction: Selective, high-contrast detection of syngeneic glioblastoma in vivo.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats.

Chemotherapy can cause serious neurotoxic side effects, such as painful peripheral neuropathies and disabling cognitive impairments. Four experiments examined whether Ibudilast, a clinically approved neuroimmune therapy, would reduce tactile allodynia and memory impairments caused by oxaliplatin in laboratory rats. Rats received an intraperitoneal injection of oxaliplatin (6mg/kg i.p.) or vehicle and were assessed for tactile allodynia 3 or 5days after injection, memory impairments in the novel object and novel location recognition tests 10-12days after injection, and fear conditioning 14days after injection. Ibudilast (7.5mg/kg) or vehicle was administered prior to oxaliplatin (Experiments 1 and 3) or prior to behavioural testing (Experiments 2 and 4). Ibudilast treatment prior to oxaliplatin prevented the development of tactile allodynia and memory impairments. Ibudilast treatment prior to behavioural testing reduced oxaliplatin-induced tactile allodynia, memory impairments, and impaired renewal of fear conditioning. These results suggest that Ibudilast could be an effective treatment against oxaliplatin-induced neuropathies and cognitive impairments.