Protocol and methods for testing the efficacy of well-being therapy in chronic migraine patients: a randomized controlled trial.

BACKGROUND: Chronic migraine is a chronic medical condition associated with resistance to pharmacological treatment and poor benefits from the psychological interventions studied to date, including acceptance and commitment therapy or mindfulness. This manuscript describes the rationale and methods for a pilot feasibility study designed to (1) establish and (2) evaluate the feasibility and acceptability of research procedures and interventions to investigate whether well-being therapy improves outcomes relative to a control condition. METHODS: The current intervention will use a randomized controlled trial design, wherein 30 outpatients with chronic migraine will be randomized (1:1) to well-being therapy (n = 15) or to a control condition (n = 15). Primary outcomes include the level of disability caused by migraine and the frequency, duration, and intensity of migraine attacks; the secondary outcomes focus on anxiety, depression, psychological well-being, euthymia, and distress. Primary and secondary outcomes will be assessed at baseline, after sessions 4 and 8, and at 3-month follow-up. The Ethical Review Boards at the University-Hospital Careggi has approved the study (5th December 2017). DISCUSSION: Identifying medium-term interventions able to improve chronic migraine is relevant to manage this illness. The present randomized trial might represent a step forward for managing chronic migraine by means of psychological interventions. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT03404336 . Registered on 19 January 2018.

Post onset, oral rapamycin treatment delays development of mitochondrial encephalopathy only at supramaximal doses.

Mitochondrial encephalopathies are fatal, infantile neurodegenerative disorders caused by a deficit of mitochondrial functioning, for which there is urgent need to identify efficacious pharmacological treatments. Recent evidence shows that rapamycin administered both intraperitoneally or in the diet delays disease onset and enhances survival in the Ndufs4 null mouse model of mitochondrial encephalopathy. To delineate the clinical translatability of rapamycin in treatment of mitochondrial encephalopathy, we evaluated the drug's effects on disease evolution and mitochondrial parameters adopting treatment paradigms with fixed daily, oral doses starting at symptom onset in Ndufs4 knockout mice. Molecular mechanisms responsible for the pharmacodynamic effects of rapamycin were also evaluated. We found that rapamycin did not affect disease development at clinically-relevant doses (0.5 mg kg-1). Conversely, an oral dose previously adopted for intraperitoneal administration (8 mg kg-1) delayed development of neurological symptoms and increased median survival by 25%. Neurological improvement and lifespan were not further increased when the dose raised to 20 mg kg-1. Notably, rapamycin at 8 mg kg-1 did not affect the reduced expression of respiratory complex subunits, as well as mitochondrial number and mtDNA content. This treatment regimen however significantly ameliorated architecture of mitochondria cristae in motor cortex and cerebellum. However, reduction of mTOR activity by rapamycin was not consistently found within the brain of knockout mice. Overall, data show the ability of rapamycin to improve ultrastructure of dysfunctional mitochondria and corroborate its therapeutic potential in mitochondrial disorders. The non-clinical standard doses required, however, raise concerns about its rapid and safe clinical transferability.

Acute and chronic triptan exposure neither alters rodent cerebral blood flow nor worsens ischemic brain injury.

Although it is still debated whether vasoconstriction underlies migraine resolution by triptans, they are not recommended in patients at cardiovascular risk. However, relationship between stroke incidence and triptan use is unclear, and it is unknown whether acute or chronic use of these drugs worsens ischemic brain injury. To address this issue, we investigated the effect of clinically-relevant doses of the potent cerebral artery vasoconstrictor eletriptan on cerebral blood flow (CBF) and brain infarct volumes, as well as on expression of genes involved in cerebrovascular regulation. We report that acute treatment of rats or mice with eletriptan did not reduce basal CBF, which promptly dropped upon treatment with prazosin or dihydroergotamine. Acute of chronic (1month) eletriptan also did not affect CBF changes and infarct volumes in mice undergoing brain ischemia/reperfusion. Finally, chronic eletriptan reduced brain mRNAs for PACAP and VIP, leaving unaffected those for 5HT1B/DR and CGRP. No significant transcript changes were found in dura mater. Data suggest that the impact of triptans on cerebral hemodynamic should be re-evaluated, as well as their propensity to increase stroke risk in migraineurs.