Increased white matter connectivity in euthymic bipolar patients: diffusion tensor tractography between the subgenual cingulate and the amygdalo-hippocampal complex

Bipolar disorder has been associated with anatomical as well as functional abnormalities in a brain network that mediates normal and impaired emotion regulation. Previous brain imaging studies have highlighted the subgenual cingulate (SC) and the amygdalo-hippocampal (AH) complex as core regions of this network. Thus we investigated white matter (WM) fiber tracts between the SC and the AH region, the uncinate fasciculus, as well as between two control regions (pons and cerebellum), using diffusion tensor imaging tractography in 16 euthymic bipolar patients (BP) and 16 sex-, age- and handedness-matched controls. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the reconstructed fiber bundle and the number of virtual reconstructed fibers were compared between groups. The tractography results revealed a significantly increased number of reconstructed fibers between the left SC and left AH in BP as compared to healthy controls. FA and ADC of the reconstructed fiber tract did not differ significantly between the groups. Furthermore, no significant group differences were observed neither for reconstructed fiber tracts between the right SC and right AH nor between the control regions. The present results suggest an altered WM pathway between the left SC and AH region and thus extend previous findings of anatomical and functional modifications in these structures in BP.     

In vitro quantitative light-induced fluorescence to measure changes in enamel mineralization

A sensitive, quantitative method for investigating changes in enamel mineralization of specimens subjected to in vitro or in situ experimentation is presented. The fluorescence-detecting instrument integrates a Xenon arc light source and an object positioning stage, which makes it particularly suitable for the nondestructive assessment of demineralized or remineralized enamel. We demonstrate the ability of in vitro quantitative light-induced fluorescence (QLF) to quantify changes in mineralization of bovine enamel discs that had been exposed in vitro to a demineralizing gel (n=36) or biofilm-mediated demineralization challenges (n=10), or were carried in situ by three volunteers during a 10-day experiment (n=12). Further experiments show the technique's value for monitoring the extent of remineralization in 36 specimens exposed in vitro to oral multispecies biofilms and document the repeatability of in vitro QLF measurements (n=10) under standardized assay conditions. The validity of the method is illustrated by comparison with transversal microradiography (TMR), the invasive current gold standard for assessing experimental changes in enamel mineralization. Ten discs with 22 measurement areas for comparison demonstrated a positive correlation between TMR and QLF (r=0.82). Filling a technological gap, this QLF system is a promising tool to assay in vitro nondestructively localized changes in mineralization of enamel specimens.     

Reduction of neuromuscular activity is required for the rescue of motoneurons from naturally occurring cell death by nicotinic-blocking agents.

Spinal motoneurons (MNs) in the chick embryo undergo programmed cell death coincident with the establishment of nerve-muscle connections and the onset of synaptic transmission at the neuromuscular junction. Chronic treatment of embryos during this period with nicotinic acetylcholine receptor (nAChR)-blocking agents [e.g., curare or alpha-bungarotoxin (alpha-BTX)] prevents the death of MNs. Although this rescue effect has been attributed previously to a peripheral site of action of the nAChR-blocking agents at the neuromuscular junction (NMJ), because nAChRs are expressed in both muscle and spinal cord, it has been suggested that the rescue effect may, in fact, be mediated by a direct central action of nAChR antagonists. By using a variety of different nAChR-blocking agents that target specific muscle or neuronal nAChR subunits, we find that only those agents that act on muscle-type receptors block neuromuscular activity and rescue MNs. However, paralytic, muscular dysgenic mutant chick embryos also exhibit significant increases in MN survival that can be further enhanced by treatment with curare or alpha-BTX, suggesting that muscle paralysis may not be the sole factor involved in MN survival. Taken together, the data presented here support the argument that, in vivo, nAChR antagonists promote the survival of spinal MNs primarily by acting peripherally at the NMJ to inhibit synaptic transmission and reduce or block muscle activity. Although a central action of these agents involving direct perturbations of MN activity may also play a contributory role, further studies are needed to determine more precisely the relative roles of central versus peripheral sites of action in MN rescue.     

Pigment epithelium-derived factor promotes the survival and differentiation of developing spinal motor neurons.

Pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitor (serpin) superfamily that has been shown previously to promote the survival and/or differentiation of rat cerebellar granule neurons and human retinoblastoma cells in vitro. However, in contrast to most serpins, PEDF has no inhibitory activity against any known proteases, and its described biological activities do not appear to require the serpin-reactive loop located toward the carboxy end of the polypeptide. Because another serpin, protease nexin-1, has been shown to promote the in vivo survival and growth of motor neurons, the authors investigated the potential neurotrophic effects of PEDF on spinal cord motor neurons in highly enriched cultures and in vivo after injury. Here, it is shown that native bovine and recombinant human PEDF promoted the survival and differentiation (neurite outgrowth) of embryonic chick spinal cord motor neurons in vitro in a dose-dependent manner. A truncated form of PEDF that lacks approximately 62% of the carboxy end of the polypeptide comprising the homologous serpin-reactive loop also exhibited neurotrophic activities similar to those of the full-length protein. Furthermore, the data here showed that PEDF was transported retrogradely and prevented the death and atrophy of spinal motor neurons in the developing neonatal mouse after axotomy. These results indicate that PEDF exerts trophic effects on motor neurons, and, together with previous reports, these findings suggest that this protein may be useful as a pharmacologic agent to promote the development and maintenance of motor neurons. J. Comp. Neurol. 412:506-514, 1999. Published 1999 Wiley-Liss, Inc.     

Characterization of spinal motoneuron degeneration following different types of peripheral nerve injury in neonatal and adult mice

Experimental lesions have been used widely to induce motoneuron (MN) degeneration as a model to test the ability of different trophic molecules to prevent lesion-induced alterations. However, the morphological mechanisms of spinal MN death following different types of lesions is not clear at the present time. In this study, we have characterized the morphological characteristics of MN cell death by examining DNA fragmentation and the ultrastructural and light microscopic morphological features of MNs following different types of spinal nerve injury (i.e., axotomy and avulsion) in the developing and adult mouse. In neonatal mice, axotomy induced cell death as well as the atrophy of MNs that survived the injury. DNA fragmentation could be detected by using the terminal deoxynucleotidyl transferase (TUNEL) method during the cell death process following neonatal axotomy, whereas TUNEL labeling was not observed following either neonatal or adult avulsion. However, with the exception of TUNEL labeling, the morphological characteristics of MN death following neonatal axotomy and avulsion were similar, and both resembled most closely the form of programmed cell death termed cytoplasmic or type 3B, which exhibits similarities as well as differences with currently accepted definitions of apoptosis. By contrast, adult avulsion resulted in a type of degeneration that resembled necrosis more closely. However, even there, the morphology was mixed, showing characteristics of both apoptosis and necrosis. These results indicate that the mode of MN degeneration is complex and is related to developmental age and type of lesion. J. Comp. Neurol. 396:158–168, 1998. © 1998 Wiley-Liss, Inc.     

Progressive grey matter alterations in bipolar disorder across the life span – A systematic review

Objectives

To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD patients.

Methods

Eleven studies with 329 BD patients and 277 controls met our PICOS criteria (participants, intervention, comparison, outcome and study design): BD diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD individuals over ≥1-year interval between scans.

Results

The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in adolescent patients, whereas it increased in healthy adolescents. Adult BD patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD.

Conclusions

The evidence collected suggests that the progression of BD impairs adolescent brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in adolescent BD suggest that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain development across the lifespan promises a deeper understanding of the progression of BD patients through different developmental episodes.     

Electrophysiological study prior to planned pulmonary valve replacement in patients with repaired tetralogy of Fallot

Aim

Ventricular arrhythmias (VAs) are the most common cause of death in patients with repaired Tetralogy of Fallot (rTOF). However, risk stratifying remains challenging. We examined outcomes following programmed ventricular stimulation (PVS) with or without subsequent ablation in patients with rTOF planned for pulmonary valve replacement (PVR).

Methods

We included all consecutive patients with rTOF referred to our institution from 2010 to 2018 aged ≥18 years for PVR. Right ventricular (RV) voltage maps were acquired and PVS was performed from two different sites at baseline, and if non-inducible under isoproterenol. Catheter and/or surgical ablation was performed when patients were inducible or when slow conduction was present in anatomical isthmuses (AIs). Postablation PVS was undertaken to guide implantable cardioverter-defibrillator (ICD) implantation.

Results

Seventy-seven patients (36.2 ± 14.3 years old, 71% male) were included. Eighteen were inducible. In 28 patients (17 inducible, 11 non-inducible but with slow conduction) ablation was performed. Five had catheter ablation, surgical cryoablation in 9, both techniques in 14. ICDs were implanted in five patients. During a follow-up of 74 ± 40 months, no sudden cardiac death occurred. Three patients experienced sustained VAs, all were inducible during the initial EP study. Two of them had an ICD (low ejection fraction for one and important risk factor for arrhythmia for the second). No VAs were reported in the non-inducible group (p < .001).

Conclusion

Preoperative EPS can help identifying patients with rTOF at risk for VAs, providing an opportunity for targeted ablation and may improve decision-making regarding ICD implantation.