Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug.

Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences and for which there are currently no FDA-approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in dorsal striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes associated with protein folding, mRNA processing, immune signaling, and neurotransmission in dorsal striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analyses. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion during abstinence does not alter methamphetamine-seeking. Taken together, these results suggest that methamphetamine induces both short and long-term changes in dorsal striatal microglia that contribute to altered drug-taking behavior and may provide valuable insights into the pathophysiology of MUD.

Responsive neurostimulation for treatment of pediatric refractory epilepsy: A pooled analysis of the literature.

BACKGROUND: Drug-resistant epilepsy (DRE) is a complex medical condition often requiring resective surgery and/or some form of neurostimulation. In recent years responsive neurostimulation (RNS) has shown promising results in adult DRE, however there is a paucity of information regarding outcomes of RNS among pediatric patients treated with DRE. In this individual patient data meta-analysis (IPDMA) we seek to elucidate the effects RNS has on the pediatric population. METHODS: Literature regarding management of pediatric DRE via RNS was reviewed in accordance with individual patient data meta-analysis guidelines. Four databases were searched with keywords ((Responsive neurostimulation) AND (epilepsy)) through December of 2022. From 1624 retrieved full text studies, 15 were ultimately included affording a pool of 98 individual participants. RESULTS: The median age at implantation was 14 years (n = 95) with 42% of patients having undergone prior resective epilepsy surgery, 18% with prior vagus nerve stimulation (VNS), and 1% with prior RNS. At a median follow up time 12 months, median percent seizure reduction was 75% with 57% of patients achieving Engel Class < 2 outcome, 9.7% of which achieved seizure freedom. We report a postoperative complication rate of 8.4%, half of which were device-related infections. Magnetic resonance imaging (MRI)-negative cases were negatively associated with magnitude of seizure reduction, and direct targeting techniques were associated with stronger treatment response when compared to other methods. CONCLUSIONS: This review suggests RNS to be an effective treatment modality for pediatric patients with a postoperative complication rate comparable to that of RNS in adults. Investigation of prognostic clinical variables should be undertaken to augment patient selection. Last, multi-institutional prospective study of long-term effects of RNS on pediatric patients would stand to benefit clinicians in the management of pediatric DRE.

Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis.

Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, has been approved for the treatment of mild to moderate atopic dermatitis. Atopic dermatitis is often associated with increased pain. Using a mouse model, this study investigated whether crisaborole suppresses pain associated with atopic dermatitis and the potential mechanisms underlying it. The mouse model for atopic dermatitis was developed by repeatedly applying MC903. MC903-treated mice had increased spontaneous scratching (itch-related behaviour) and wiping behaviour (pain-related behaviour). Crisaborole was topically applied to the cheek skin of MC903-treated mice, and it reduced both itch- and pain-related behaviours in these mice. Immunofluorescence staining revealed that crisaborole reduced neutrophil infiltration and interaction of neutrophils with sensory neurones. Intradermal injection of S100A8/A9, proinflammatory neutrophil mediator, enhanced not only itch-related behaviours evoked by histamine or chloroquine, but also pain-related behaviours evoked by capsaicin. Calcium imaging of mouse dorsal root ganglion neurones revealed that pretreatment with S100A8/A9 significantly increased calcium responses to histamine and capsaicin, and the proportion of chloroquine-sensitive neurones. These findings suggest that the PDE4 inhibitor reduces itch and pain, in part by inhibiting infiltration of S100A8/A9-containing neutrophils in a mouse model of MC903-induced atopic dermatitis.

Thalamic responsive neurostimulation for the treatment of refractory epilepsy: an individual patient data meta-analysis.

OBJECTIVE: In recent years, the treatment of drug-resistant epilepsy (DRE) has made greater use of surgery and expanded options for neurostimulation or neuromodulation. Up to this point, responsive neurostimulation (RNS) has been very promising but has mainly used only the cortex as a target. In this individual patient data meta-analysis (IPDMA), the authors sought to establish if a novel RNS target, the thalamus, can be used to treat DRE. METHODS: The literature regarding the management of DRE by targeting the thalamus with RNS was reviewed per IPDMA guidelines. Five databases were searched with keywords [((Responsive neurostimulation) OR (RNS)) AND ((thalamus) OR (thalamic) OR (Deep-seated) OR (Diencephalon) OR (limbic))] in March 2022. RESULTS: The median (interquartile range) age at implantation was 17 (13.5-27.5) years (n = 42) with an epilepsy duration of 12.1 (5.8-15.3) years. In total, 52.4% of patients had previously undergone epilepsy surgery, 28.6% had prior vagus nerve stimulation, and 2.4% had prior RNS. The median preimplant seizure frequency was 12 per week. The median seizure reduction at last follow-up was 73%. No study in this IPDMA reported complications, although 7 cases (16.3%) did require reoperation. Behavioral improvements and reduced antiepileptic drug dose or quantity were reported for 80% and 28.6% of patients, respectively. CONCLUSIONS: This review indicates that thalamic RNS may be safe and effective for treating DRE. Long-term and controlled studies on thalamic RNS for DRE would further elucidate this technique's potential benefits and complications and help guide clinical judgment in the management of DRE.

Surgically Treated Brain Metastases from Uterine Origin: A Case Series and Systematic Review.

OBJECTIVE: We aimed to describe our institutional case series of 9 surgically treated uterine brain metastases and perform a survival analysis through a systematic review and a pooled individual patient data study. METHODS: This study was divided into 2 sections: 1) a retrospective, single center patient series assessing outcomes of neurosurgical treatment modalities in patients with malignancy arising in the uterus with brain metastases and 2) a systematic review of the literature between 1980 and 2021 regarding treatment outcomes of individual patients with intracranial metastasis of uterine origin. Pooled cohort survival analysis was done via univariate and Cox regression multivariable analysis and Kaplan-Meier curves. RESULTS: Final statistical analysis included a total of 124 pooled cohort patients: one hundred fifteen patients from literature review studies plus 9 patients from our institution. Median age at the time of diagnosis was 54 years. Median time from diagnosis of the primary cancer to brain metastasis was 19 months (0-166 months). Surgery and radiotherapy resulted in the highest median OS of 11 months (P < 0.001). Multivariable analyses indicated that the presence of more than one central nervous systemlesion had an increased risk on OS (P = 0.003). Microsurgery, stereotactic radiosurgery, and whole brain radiotherapy remain the evidence-based mainstay applicable to the treatment of multiple brain metastases. CONCLUSIONS: Brain metastases of cancer arising in the uterus appear to result most often in multiple lesions with dismal prognosis. The seemingly most efficacious treatment modality is surgery and radiotherapy. However, this treatment is often not an option when more than 1 or 2 brain lesions are present.

Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure.

Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.SIGNIFICANCE STATEMENT Withdrawal plays a key role in the cycle of addiction to opioids like morphine. We studied how repeated cycles of naloxone-precipitated withdrawal from otherwise continuous opioid exposure can change brain function of the nucleus accumbens, which is an important brain region for reward and addiction. Different patterns of opioid exposure caused unique changes in communication between neurons in the nucleus accumbens, and the nature of these changes depended on the type of neuron being studied. The specific changes in communication between neurons caused by repeated cycles of withdrawal may increase vulnerability to opioid use disorders. This highlights the importance of reducing or preventing the experience of withdrawal during opioid treatment.

Microglial calcium signaling is attuned to neuronal activity in awake mice.

Microglial calcium signaling underlies a number of key physiological and pathological processes in situ, but has not been studied in vivo in awake mice. Using multiple GCaMP6 variants targeted to microglia, we assessed how microglial calcium signaling responds to alterations in neuronal activity across a wide range. We find that only a small subset of microglial somata and processes exhibited spontaneous calcium transients in a chronic window preparation. However, hyperactive shifts in neuronal activity (kainate status epilepticus and CaMKIIa Gq DREADD activation) triggered increased microglial process calcium signaling, often concomitant with process extension. Additionally, hypoactive shifts in neuronal activity (isoflurane anesthesia and CaMKIIa Gi DREADD activation) also increased microglial process calcium signaling. Under hypoactive neuronal conditions, microglia also exhibited process extension and outgrowth with greater calcium signaling. Our work reveals that microglia have highly distinct microdomain signaling, and that processes specifically respond to bi-directional shifts in neuronal activity through increased calcium signaling.