Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.

The purpose of this study is to find the optimal stiffness and volume of bone cement and their biomechanical effects on the adjacent vertebrae to determine a better strategy for conducting vertebroplasty. A three-dimensional finite-element model of a functional spinal unit was developed using computed tomography scans of a normal motion segment, comprising the T11, T12 and L1 vertebrae. Volumes of bone cement, with appropriate mechanical properties, were inserted into the trabecular core of the T12 vertebra. Parametric studies were done by varying the volume and stiffness of the bone cement. When the bone cement filling volume reached 30% of the volume of a vertebral body, the level of stiffness was restored to that of normal bone, and when higher bone cement exceeded 30% of the volume, the result was stiffness in excess of that of normal bone. When the bone cement volume was varied, local stress in the bony structures (cortical shell, trabecular bone and endplate) of each vertebra monotonically increased. Low-modulus bone cement has the effect of reducing strain in the augmented body, but only in cases of relatively high volumes of bone cement (>50%). Furthermore, varying the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies. The volume of cement was considered to be the most important determinant in endplate fracture. Changing the stiffness of bone cement has a negligible effect on the stress distribution of vertebral bodies.

We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[¹⁸F]-fluoro-D-glucose ([¹⁸F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery.

Neuropathic pain is a debilitating condition caused by the hyperexcitability of spinal dorsal horn neurons and is often characterized by allodynia. Although neuron-independent mechanisms of hyperexcitability have been investigated, the contribution of astrocyte-neuron interactions remains unclear. Here, we show evidence of reactive astrocytes and their excessive GABA release in the spinal dorsal horn, which paradoxically leads to the tonic excitation of neighboring neurons in a neuropathic pain model. Using multiple electrophysiological methods, we demonstrated that neuronal hyperexcitability is attributed to both increased astrocytic GABA synthesis via monoamine oxidase B (MAOB) and the depolarized reversal potential of GABA-mediated currents (E_GABA) via the downregulation of the neuronal K⁺/Cl⁻ cotransporter KCC2. Furthermore, longitudinal 2-deoxy-2-[¹⁸F]-fluoro-D-glucose microPET imaging demonstrated increased regional glucose metabolism in the ipsilateral dorsal horn, reflecting neuronal hyperexcitability. Importantly, inhibiting MAOB restored the entire astrocytic GABA-mediated cascade and abrogated the increased glucose metabolism and mechanical allodynia. Overall, astrocytic GABA-mediated tonic excitation is critical for neuronal hyperexcitability, leading to mechanical allodynia and neuropathic pain.

Background and Objectives.. Ultrasound-guided cervical periradicular steroid injection (US-CPSI) is an attractive alternate to conventional C-arm guide

Clozapine (CLZ) has been proposed as an agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), to replace Clozapine-N-oxide (CNO); however, there are no reliable guidelines for the use of CLZ for chemogenetic neuromodulation. We titrated the optimal dose of CLZ required to evoke changes in neural activity whilst avoiding off-target effects. We also performed [¹⁸F]Fluoro-deoxy-glucose micro positron emission tomography (FDG-microPET) scans to determine the global effect of CLZ-induced hM3D(Gq) DREADD activation in the rat brain. Our results show that low doses of CLZ (0.1 and 0.01 mg/kg) successfully induced neural responses without off-target effects. CLZ at 1 mg/kg evoked a stronger and longer-lasting neural response but produced off-target effects, observed as changes in locomotor behavior and FDG-microPET imaging. Unexpectedly, FDG-microPET imaging failed to demonstrate an increase in regional glucose metabolism in the stimulated cortex during CLZ chemogenetic neuromodulation. Therefore, caution should be used when interpreting FDG-PET images in the context of cortical chemogenetic activation.