Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations-a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.     

Plasma Cytokine Analysis in Patients with Advanced Extremity Melanoma Undergoing Isolated Limb Infusion

Background

Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma.

Methods

Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated.

Results

Of 180 ILIs performed, 28 % (95 % confidence interval 22–35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients.

Conclusions

Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.     

Effect of Intrathecal Baclofen Concentration on Spasticity Control: Case Series

Background/Objective: Intrathecal baclofen (ITB) has been shown to be an effective treatment for severe spasticity of spinal or cerebral origin. Although most patients respond well to an ITB trial, there are often difficulties in achieving and/or maintaining such effectiveness with ITB pump treatment. There are few published guidelines for dosing efficacy and no studies looking at the effect of concentration of ITB on spasticity management.

Methods: Case series of 3 adults with severe spasticity treated with ITB pump: a 44-year-old man with C7 tetraplegia using a 40-mL Medtronic SynchroMed II pump with 500-μg/mL concentration; a 35-year-old woman with traumatic brain injury with right spastic hemiplegia using a 18-mL Medtronic SynchroMed EL pump with 2,000-μg/mL concentration; and a 43-year-old woman with spastic diplegic cerebral palsy using a 40-mL Medtronic SynchroMed II pump with 2,000-μg/mL concentration.

Results: After reducing ITB concentrations in the pump, either as part of a standard protocol for dye study to assess the integrity of pump and catheter system or secondary to plateau in therapeutic efficacy, patients experienced temporary, significant reduction in spasticity based on range of motion, Modified Ashworth scores, and verbal feedback.

Conclusions: Decreasing the concentration of ITB seems to affect spasticity control. Further research in this area is needed for those patients with refractory spasticity to optimize efficacy of ITB therapy.     

Sexual Dysfunction Associated With Intrathecal Baclofen Use: A Report of Two Cases

Abstract

Background/Objective: Intrathecal baclofen is considered standard treatment for severe spasticity of spinal cord and cerebral origin. Recognized side effects include fatigue and constipation. There are few reported findings of sexual dysfunction in men and none in women.

Methods: Two case reports.

Results: A male and a female patient with spasticity treated with intrathecal baclofen were recognized to have sexual dysfunction side effects from treatment. On reduction of the intrathecal baclofen dose, complete return to baseline sexual function was achieved for both subjects.

Conclusions: Intrathecal baclofen can impair sexual function and ejaculation in some patients. Clinicians should be aware of this risk and ask about it during routine clinic follow-up for spasticity. Dosing adjustments need to be considered in these patients.     

Oscillatory support for rapid frequency change processing in infants

Rapid auditory processing and auditory change detection abilities are crucial aspects of speech and language development, particularly in the first year of life. Animal models and adult studies suggest that oscillatory synchrony, and in particular low-frequency oscillations play key roles in this process. We hypothesize that infant perception of rapid pitch and timing changes is mediated, at least in part, by oscillatory mechanisms. Using event-related potentials (ERPs), source localization and time-frequency analysis of event-related oscillations (EROs), we examined the neural substrates of rapid auditory processing in 4-month-olds. During a standard oddball paradigm, infants listened to tone pairs with invariant standard (STD, 800–800 Hz) and variant deviant (DEV, 800–1200 Hz) pitch. STD and DEV tone pairs were first presented in a block with a short inter-stimulus interval (ISI) (Rapid Rate: 70 ms ISI), followed by a block of stimuli with a longer ISI (Control Rate: 300 ms ISI). Results showed greater ERP peak amplitude in response to the DEV tone in both conditions and later and larger peaks during Rapid Rate presentation, compared to the Control condition. Sources of neural activity, localized to right and left auditory regions, showed larger and faster activation in the right hemisphere for both rate conditions. Time-frequency analysis of the source activity revealed clusters of theta band enhancement to the DEV tone in right auditory cortex for both conditions. Left auditory activity was enhanced only during Rapid Rate presentation. These data suggest that local low-frequency oscillatory synchrony underlies rapid processing and can robustly index auditory perception in young infants. Furthermore, left hemisphere recruitment during rapid frequency change discrimination suggests a difference in the spectral and temporal resolution of right and left hemispheres at a very young age.     

Construct damage and loosening around glenoid implants: A longitudinal micro‐CT study of five cadaver specimens

The evolution of failure of bone and cement leading to loosening of glenoid components following shoulder arthroplasty is not well understood. The purpose of this study was to identify and visualize potential mechanisms of mechanical failure within cadavers, cemented with two types of components, and subject to cyclic loading. Five glenoid cadaver bones were implanted with either a three‐pegged polyethylene component, or prototype posteriorly augmented component which addresses posterior bone loss. Specimens were loaded by constant glenohumeral compression combined with cyclic anterior–posterior displacement of the humeral head relative to the glenoid. At six time points across 100,000 cycles, implant loosening micromotions were optically measured, and specimens were imaged by micro‐computed tomography. Scans were 3D registered and inspected for crack initiation and progression, and micro‐CT based time‐lapse movies were created. Cement cracking initiated at stress concentrations and progressed with additional cyclic loading. Failure planes within trabecular bone and the bone–cement interface were identified in four of the five specimens. Implant subsidence increased to greater than 1.0 mm in two specimens. Cemented glenoid structural failure can occur within the cement, along planes of trabecular bone, or at the bone cement interface. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1053–1060, 2016.