Nonaneurysmal perimesencephalic subarachnoid hemorrhage on noncontrast head CT: An accuracy, inter-rater, and intra-rater reliability study.

BACKGROUND AND PURPOSE: To evaluate the reliability and accuracy of nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) on Noncontrast Head CT (NCCT) between numerous raters. MATERIALS AND METHODS: 45 NCCT of adult patients with SAH who also had a catheter angiography (CA) were independently evaluated by 48 diverse raters; 45 raters performed a second assessment one month later. For each case, raters were asked: 1) whether they judged the bleeding pattern to be perimesencephalic; 2) whether there was blood anterior to brainstem; 3) complete filling of the anterior interhemispheric fissure (AIF); 4) extension to the lateral part of the sylvian fissure (LSF); 5) frank intraventricular hemorrhage; 6) whether in the hypothetical presence of a negative CT angiogram they would still recommend CA. An automatic NAPSAH diagnosis was also generated by combining responses to questions 2-5. Reliability was estimated using Gwet's AC1 (κG), and the relationship between the NCCT diagnosis of NAPSAH and the recommendation to perform CA using Cramer's V test. Multi-rater accuracy of NCCT in predicting negative CA was explored. RESULTS: Inter-rater reliability for the presence of NAPSAH was moderate (κG = 0.58; 95%CI: 0.47, 0.69), but improved to substantial when automatically generated (κG = 0.70; 95%CI: 0.59, 0.81). The most reliable criteria were the absence of AIF filling (κG = 0.79) and extension to LSF (κG = 0.79). Mean intra-rater reliability was substantial (κG = 0.65). NAPSAH weakly correlated with CA decision (V = 0.50). Mean sensitivity and specificity were 58% (95%CI: 44%, 71%) and 83 % (95%CI: 72 %, 94%), respectively. CONCLUSION: NAPSAH remains a diagnosis of exclusion. The NCCT diagnosis was moderately reliable and its impact on clinical decisions modest.

Functional adaptation of glial cells at neuromuscular junctions in response to injury.

Synaptic elements from neuromuscular junctions (NMJs) undergo massive morphological and functional changes upon nerve injury. While morphological changes of NMJ-associated glia in response to injury has been investigated, their functional properties remain elusive. Perisynaptic Schwann cells (PSCs), glial cells at the NMJ, are essential for NMJ maintenance and repair, and are involved in synaptic efficacy and plasticity. Importantly, these functions are regulated by PSCs ability to detect synaptic transmission through, notably, muscarinic (mAChRs) and purinergic receptors' activation. Using Ca2+ imaging and electrophysiological recordings of synaptic transmission at the mouse NMJ, we investigated PSC receptors activation following denervation and during reinnervation in adults and at denervated NMJs in an ALS mouse model (SOD1G37R ). We observed reduced PSCs mAChR-mediated Ca2+ responses at denervated and reinnervating NMJs. Importantly, PSC phenotypes during denervation and reinnervation were distinct than the one observed during NMJ maturation. At denervated NMJs, exogenous activation of mAChRs greatly diminished galectin-3 expression, a glial marker of phagocytosis. PSCs Ca2+ responses at reinnervating NMJs did not correlate with the number of innervating axons or process extensions. Interestingly, we observed an extended period of reduced PSC mAChRs activation after the injury (up to 60 days), suggesting a glial memory of injury. PSCs associated with denervated NMJs in an ALS model (SOD1G37R mice) did not show any muscarinic adaptation, a phenotype incompatible with NMJ repair. Understanding functional mechanisms that underlie this glial response to injury may contribute to favor complete NMJ and motor recovery.

Purinergic-Dependent Glial Regulation of Synaptic Plasticity of Competing Terminals and Synapse Elimination at the Neuromuscular Junction.

The precise wiring of synaptic connections requires the elimination of supernumerary inputs competing for innervation of the same target cell. This competition is activity-dependent, strengthening some inputs whereas others are eliminated. Although glial cells are required for the elimination and clearance of terminals, their involvement in activity-dependent synaptic competition remains ill-defined. Here, we used the developing neuromuscular junctions of mice to show that perisynaptic glial cells, through 2Y1 purinergic receptors (P2Y1Rs), decode synaptic efficacy of competing terminals in a Ca2+-dependent manner. This glial activity induces long-lasting synaptic potentiation of strong but not weak terminals via presynaptic adenosine 2A receptors. Blockade of glial activity by intracellular Ca2+ chelation or blockade of P2Y1Rs prevents this plasticity. In addition, blockade of P2Y1Rs delays synapse elimination in vivo. Hence, P2Y1Rs drive glial cell regulation of strong synaptic inputs and influence synapse competition and elimination.

Neuromuscular synaptogenesis: coordinating partners with multiple functions.

The formation of highly efficient and reliable synapses at the neuromuscular junction (NMJ) relies on dynamic molecular interactions. Studies of the development and maturation of the NMJ have focused on events that are dependent on synaptic activity and that require the coordinated actions of nerve- and muscle-derived molecules with different targets and effects. More recently, perisynaptic Schwann cells--the glial cells at NMJs--have become an important focus of research. These glia concomitantly contribute to pre- and postsynaptic maturation while undergoing maturation themselves. Thus, an intricate 'danse à trois''regulates the maturation of the NMJ to form a highly efficient communication unit, in which fine glial processes lie in close proximity to a highly concentrated population of postsynaptic receptors and perfectly aligned presynaptic release sites.

Glial cells decipher synaptic competition at the mammalian neuromuscular junction.

It is now accepted that glial cells actively interact with neurons and modulate their activity in many regions of the nervous system. Importantly, modulation of synaptic activity by glial cells depends on the proper detection and decoding of synaptic activity. However, it remains unknown whether glial cells are capable of decoding synaptic activity and properties during early postdevelopmental stages, in particular when different presynaptic nerve terminals compete for the control of the same synaptic site. This may be particularly relevant because a major determinant of the outcome of synaptic competition process is the relative synaptic strength of competing terminals whereby stronger terminals are more likely to occupy postsynaptic territory and become stabilized while weaker terminals are often eliminated. Hence, because of their ability to decode synaptic activity, glial cells should be able to integrate neuronal information of competing terminals. Using simultaneous glial Ca(2+) imaging and synaptic recordings of dually innervated mouse neuromuscular junctions, we report that single glial cells decipher the strength of competing nerve terminals. Activity of single glial cells, revealed by Ca(2+) responses, reflects the synaptic strength of each competing nerve terminal and the state of synaptic competition. This deciphering is mediated by functionally segregated purinergic receptors and intrinsic properties of glial cells. Our results indicate that glial cells decode ongoing synaptic competition and, hence, are poised to influence its outcome.

Perisynaptic glia discriminate patterns of motor nerve activity and influence plasticity at the neuromuscular junction.

In the nervous system, the induction of plasticity is coded by patterns of synaptic activity. Glial cells are now recognized as dynamic partners in a wide variety of brain functions, including the induction and modulation of various forms of synaptic plasticity. However, it appears that glial cells are usually activated by stereotyped, sustained neuronal activity, and little attention has been given to more subtle changes in the patterns of synaptic activation. To this end, we used the mouse neuromuscular junction as a simple and useful model to study glial modulation of synaptic plasticity. We used two patterns of motor nerve stimulation that mimic endogenous motor-neuronal activity. A continuous stimulation induced a post-tetanic potentiation and a phasic Ca(2+) response in perisynaptic Schwann cells (PSCs), glial cells at this synapse. A bursting pattern of activity induced a post-tetanic depression and oscillatory Ca(2+) responses in PSCs. The different Ca(2+) responses in PSCs indicate that they decode the pattern of synaptic activity. Furthermore, the chelation of glial Ca(2+) impaired the production of the sustained plasticity events indicating that PSCs govern the outcome of synaptic plasticity. The mechanisms involved were studied using direct photo-activation of PSCs with caged Ca(2+) that mimicked endogenous plasticity. Using specific pharmacology and transgenic knock-out animals for adenosine receptors, we showed that the sustained depression was mediated by A1 receptors while the sustained potentiation is mediated by A(2A) receptors. These results demonstrate that glial cells decode the pattern of synaptic activity and subsequently provide bidirectional feedback to synapses.