Endogenous theta stimulation during meditation predicts reduced opioid dosing following treatment with Mindfulness-Oriented Recovery Enhancement

Veterans experience chronic pain at greater rates than the rest of society and are more likely to receive long-term opioid therapy (LTOT), which, at high doses, is theorized to induce maladaptive neuroplastic changes that attenuate self-regulatory capacity and exacerbate opioid dose escalation. Mindfulness meditation has been shown to modulate frontal midline theta (FMT) and alpha oscillations that are linked with marked alterations in self-referential processing. These adaptive neural oscillatory changes may promote reduced opioid use and remediate the neural dysfunction occasioned by LTOT. In this study, we used electroencephalography (EEG) to assess the effects of a mindfulness-based, cognitive training intervention for opioid misuse, Mindfulness-Oriented Recovery Enhancement (MORE), on alpha and theta power and FMT coherence during meditation. We then examined whether these neural effects were associated with reduced opioid dosing and changes in self-referential processing. Before and after 8 weeks of MORE or a supportive psychotherapy control, veterans receiving LTOT (N = 62) practiced mindfulness meditation while EEG was recorded. Participants treated with MORE demonstrated significantly increased alpha and theta power (with larger theta power effect sizes) as well as increased FMT coherence relative to those in the control condition—neural changes that were associated with altered self-referential processing. Crucially, MORE significantly reduced opioid dose over time, and this dose reduction was partially statistically mediated by changes in frontal theta power. Study results suggest that mindfulness meditation practice may produce endogenous theta stimulation in the prefrontal cortex, thereby enhancing inhibitory control over opioid dose escalation behaviors.Subject terms: Human behaviour, Addiction     

Increased Firearm Injury During the COVID-19 Pandemic: A Hidden Urban Burden

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Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network.     

The Evolution of Transcranial Laser Therapy for Acute Ischemic Stroke, Including a Pooled Analysis of NEST-1 and NEST-2

Intravenous tissue plasminogen activator is the only proven therapy for acute ischemic stroke. Not enough patients are eligible for treatment and additional new therapies are needed. Recently, laser technology has been applied to acute ischemic stroke. This noninvasive technique uses near-infrared wavelengths applied to the scalp within 24 h of symptom onset. The mechanism is incompletely understood but may involve increased mitochondrial adenosine triphosphate production. Animal models demonstrated safety and efficacy warranting randomized controlled trials in humans. NEST-1 (phase 2) and NEST-2 (phase 3) confirmed the safety of transcranial laser therapy, although efficacy was not found in NEST-2. Pooled analysis of NEST-1 and NEST-2 revealed a significantly improved success rate in patients treated with laser therapy. Further phase 3 testing is planned and may create a new paradigm for the treatment of acute ischemic stroke.     

From the Cover: Loss of phosphatidylinositol 4-kinase 2α activity causes late onset degeneration of spinal cord axons

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2α isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2α kinase activity initially appear normal. However, adult Pi4k2a^GT/GT animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a^GT/GT animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.     

Silent somatotroph pituitary adenomas: an update

Silent growth hormone adenomas (SGHA) are a rare entity of non-functioning pituitary neuroendocrine tumors. Diagnosis is invariably made post-operatively of a tumor immunopositive for GH (and Pit-1 in selected cases) but without clinical acromegaly. Mainly young females are affected, and tumors are often uncovered by investigation for headaches or oligoamenorrhea. Integration of clinical, pathological and biochemical data is required for proper diagnosis. Beside normal IGF-1 levels, a third of SGHAs displays elevated GH levels and some will eventually progress to acromegaly. Almost two-thirds will be mixed GH-prolactin tumors and sparsely-granulated monohormonal GH tumors seems the more aggressive subtype. Recurrence and need for radiation is higher than other non-functioning tumors so close follow-up is warranted.