Pathophysiology of oral pharyngeal apraxia and mutism following posterior fossa tumor resection in children

Journal ArticleMutism following posterior fossa tumor resection in pediatric patients has been previously recognized, although its pathophysiology remains unclear. A review of the available literature reveals 33 individuals with this condition, with only a few adults documented in the population. All of these patients had large midline posterior fossa tumors. To better understand the incidence and anatomical substrate of this syndrome, the authors reviewed a 7-year series of 110 children who underwent a posterior fossa tumor resection. During that time, nine (8.2%) of the 110 children exhibited mutism postoperatively. They ranged from 2.5 to 20 years of age (mean 8.1 years) and became mute within 12 to 48 hours of surgery. The period of mutism lasted from 1.5 to 12 weeks after onset: all children had difficulty coordinating their oral pharyngeal musculature as manifested by postoperative drooling and inability to swallow. Further analysis of these cases revealed that all children had splitting of the entire inferior vermis at surgery, as confirmed on postoperative magnetic resonance studies. Lower cranial nerve function was intact in all nine patients. Current concepts of cerebellar physiology emphasize the importance of the cerebellum in learning and language. The syndrome described resembles a loss of learned activities, or an apraxia, of the oral and pharyngeal musculature. To avoid the apraxia, therefore, the inferior vermis must be preserved. For large midline tumors that extend to the aqueduct, a combined approach through the fourth ventricle and a midvermis split may be used to avoid injuring the inferior vermis

Quantitative Methods for Tracking Cognitive Change 3 Years After Coronary Artery Bypass Surgery

Background: The analysis and interpretation of change in cognitive function test scores after Coronary Artery Bypass Grafting (CABG). Longitudinal studies with multiple outcomes present considerable statistical challenges. Application of hierarchical linear statistical models can estimate the effects of a surgical intervention on the time course of multiple biomarkers. Methods: We use an analyze then summarize approach whereby we estimate the intervention effects separately for each cognitive test and then pool them, taking appropriate account of their statistical correlations. The model accounts for dropouts at follow-up, the chance of which may be related to past cognitive score, by implicitly imputing the missing data from individuals’ past scores and group patterns. We apply this approach to a study of the effects of CABG on the time course of cognitive function as measured by 16 separate neuropsychological test scores, clustered into 8 cognitive domains. The study includes measurements on 140 CABG patients and 92 nonsurgical controls at baseline, and 3, 12, and 36 months. Including a nonsurgical control group allows comparison of changes in cognition over time between the surgery group and patients with similar risk factors, controlling for potential effects of aging and vascular disease. Results: We find that CABG patients have very longitudinal changes from baseline in cognitive function similar to those observed for nonsurgical controls. Any small differences tend to favor greater improvement in CABG patients than in the nonsurgical controls. Conclusions: The methods used have application to a wide range of intervention studies in which multiple biomarkers are followed over time to quantify health effects. Software to implement the methods in commonly used statistical packages is available from the authors at http://www.biostat.jhsph.edu/research/software.shtml

Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration

AbstractThe coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA–CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway

Cyclophilin D deficiency rescues Aβ-impaired PKA/CREB signaling and alleviates synaptic degeneration

The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cyclophilin D (CypD), an integral part of mitochondrial permeability transition pore (mPTP), is involved in amyloid beta (Aβ)-instigated mitochondrial dysfunction. Blockade of CypD prevents Aβ-induced mitochondrial malfunction and the consequent cognitive impairments. Here, we showed the elimination of reactive oxygen species (ROS) by antioxidants probucol or superoxide dismutase (SOD)/catalase blocks Aβ-mediated inactivation of protein kinase A (PKA)/cAMP regulatory-element-binding (CREB) signal transduction pathway and loss of synapse, suggesting the detrimental effects of oxidative stress on neuronal PKA/CREB activity. Notably, neurons lacking CypD significantly attenuate Aβ-induced ROS. Consequently, CypD-deficient neurons are resistant to Aβ-disrupted PKA/CREB signaling by increased PKA activity, phosphorylation of PKA catalytic subunit (PKA C), and CREB. In parallel, lack of CypD protects neurons from Aβ-induced loss of synapses and synaptic dysfunction. Furthermore, compared to the mAPP mice, CypD-deficient mAPP mice reveal less inactivation of PKA–CREB activity and increased synaptic density, attenuate abnormalities in dendritic spine maturation, and improve spontaneous synaptic activity. These findings provide new insights into a mechanism in the crosstalk between the CypD-dependent mitochondrial oxidative stress and signaling cascade, leading to synaptic injury, functioning through the PKA/CREB signal transduction pathway

Abnormal mitosis in reactive astrocytes

Although abnormal mitosis with disarranged metaphase chromosomes or many micronuclei in astrocytes (named “Alzheimer I type astrocytes” and later “Creutzfeldt-Peters cells”) have been known for nearly 100 years, the origin and mechanisms of this pathology remain elusive. In experimental brain insults in rats, we show that abnormal mitoses that are not followed by cytokinesis are typical for reactive astrocytes. The pathology originates due to the inability of the cells to form normal mitotic spindles with subsequent metaphase chromosome congression, which, in turn may be due to shape constraints aggravated by cellular enlargement and to the accumulation of large amounts of cytosolic proteins. Many astrocytes escape from arrested mitosis by producing micronuclei. These polyploid astrocytes can survive for long periods of time and enter into new cell cycles

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

Objective. Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. Approach. We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400-micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. Main results. Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. Significance. Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area