Multiple frequencies in the basal ganglia in Parkinson's disease

In recent years, the authors have developed what appears to be a very successful phenomenological model for analyzing the role of deep brain stimulation (DBS) in alleviating the symptoms of Parkinson's disease. In this paper, we extend the scope of the model by using it to predict the generation of new frequencies from networks tuned to a specific frequency, or indeed not self-oscillatory at all. We have discussed two principal cases: firstly where the constituent systems are coupled in an excitatory-excitatory fashion, which we designate by ``+/+''; and secondly where the constituent systems are coupled in an excitatory-inhibitory fashion, which we designate ``+/-''. The model predicts that from a basic system tuned to tremor frequency we can generate an unlimited range of frequencies. We illustrate in particular, starting from systems which are initially non-oscillatory, that when the coupling coefficient exceeds a certain value, the system begins to oscillate at an amplitude which increases with the coupling strength. Another very interesting feature, which has been shown by colleagues of ours to arise through the coupling of complicated networks based on the physiology of the basal ganglia, can be illustrated by the root locus method which shows that increasing and decreasing frequencies of oscillation, existing simultaneously, have the property that their geometric mean remains substantially constant as the coupling strength is varied. We feel that with the present approach, we have provided another tool for understanding the existence and interaction of pathological oscillations which underlie, not only Parkinson's disease, but other conditions such as Tourette's syndrome, depression and epilepsy

The Use of Personal Projects Analysis to Enhance Occupational Therapy Goal Identification

Background: Client-centered occupational therapy begins with the identification of personally-relevant patient goals. This study aimed to determine whether the elicitation module of Personal Projects Analysis (PPA) could help patients in an acquired brain injury day hospital program identify more meaningful goals than those identified using the Canadian Occupational Performance Measure (COPM) alone. Method: Ten patients completed the COPM. They rated the importance of each goal and their confidence that they could attain each goal. During the next session, using the elicitation module of PPA, they identified personal projects just prior to their brain injuries, current personal projects, and future desired personal projects. They were then invited to revise their COPM goals and re-rate them for importance and confidence. Results: Following completion of the elicitation module of PPA, seven participants changed at least one goal. Of the goals that were changed, half were revised to include the mention of another person. There were no significant changes in average goal importance or perceived attainability. Occupational therapists reported that the elicitation module of PPA helped them get to know their patients better and identify potential therapeutic occupations. Discussion: The elicitation module of PPA may help people develop goals that are more embedded in their social contexts

Abnormal Trafficking of Endogenously Expressed BMPR2 Mutant Allelic Products in Patients with Heritable Pulmonary Arterial Hypertension

More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations

Exploration of the Generation and Suppression of Pathological Oscillatory Neural Activity in a Model of Deep Brain Stimulation in Parkinsons disease

21st Bioengineering in Ireland Conference (BINI) 2015, Carton House, Maynooth, Co. Kildare, Ireland, 16-17 January 2015This study explores possible mechanisms for the generation of pathological neural oscillatory activity associated with Parkinson’s disease in theoretical models. The suppression of the model oscillations with high frequency stimulation, analogous to the use of deep brain stimulation (DBS) in the treatment of Parkinson's disease, is also examined. The relationship between oscillation amplitude and the amplitude of the applied stimulation is explored theoretically and then compared with experimental data recorded in patients.Science Foundation Irelan

Microglia shape presynaptic properties at developing glutamatergic synapses

Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+ /Mg2+ ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron-microglia interactions profoundly influence the functional maturation of excitatory presynaptic function

A Pro-Drug Approach for Selective Modulation of AI-2-Mediated Bacterial Cell-to-Cell Communication

The universal quorum sensing autoinducer, AI-2, is utilized by several bacteria. Analogs of AI-2 have the potential to modulate bacterial behavior. Selectively quenching the communication of a few bacteria, in the presence of several others in an ecosystem, using analogs of AI-2 is non-trivial due to the ubiquity of AI-2 processing receptors in many bacteria that co-exist. Herein, we demonstrate that when an AI-2 analog, isobutyl DPD (which has been previously shown to be a quorum sensing, QS, quencher in both Escherichia coli and Salmonella typhimurium) is modified with ester groups, which get hydrolyzed once inside the bacterial cells, only QS in E. coli, but not in S. typhimurium, is inhibited. The origin of this differential QS inhibition could be due to differences in analog permeation of the bacterial membranes or ester hydrolysis rates. Such differences could be utilized to selectively target QS in specific bacteria amongst a consortium of other species that also use AI-2 signaling

Hard-wired epimysial recordings from normal and reinnervated muscle using a bone-anchored device

Background: A combined approach for prosthetic attachment and control using a transcutaneous bone-anchored device and implanted muscle electrodes can improve function for upper-limb amputees. The bone-anchor provides a transcutaneous feed-through for muscle signal recording. This approach can be combined with targeted muscle reinnervation (TMR) to further improve myoelectric control. Methods: A bone-anchored device was implanted trans-tibially in n = 8 sheep with a bipolar recording electrode secured epimysially to the peroneus tertius muscle. TMR was carried out in a single animal: the peroneus tertius was deinnervated and the distal portion of the transected nerve to the peroneus muscle was coapted to a transected nerve branch previously supplying the tibialis anterior muscle. For 12 weeks (TMR) or 19 weeks (standard procedure), epimysial muscle signals were recorded while animals walked at 2 km·h−1. Results: After 19 weeks implantation following standard procedure, epimysial recording signal-to-noise ratio (SNR) was 18.7 dB (± 6.4 dB, 95% CI) with typical recordings falling in the range 10–25 dB. Recoveries in gait and muscle signals were coincident 6 weeks post-TMR; initial muscle activity was identifiable 3 weeks post-TMR though with low signal amplitude and signal-to-noise ratio compared with normal muscle recordings. Conclusions: Following recovery, muscle signals were recorded reliably over 19 weeks following implantation. In this study, targeted reinnervation was successful in parallel with bone-anchor implantation, with recovery identified 6 weeks after surger

Fostering implementation of health services research findings into practice: a consolidated framework for advancing implementation science

Abstract Background Many interventions found to be effective in health services research studies fail to translate into meaningful patient care outcomes across multiple contexts. Health services researchers recognize the need to evaluate not only summative outcomes but also formative outcomes to assess the extent to which implementation is effective in a specific setting, prolongs sustainability, and promotes dissemination into other settings. Many implementation theories have been published to help promote effective implementation. However, they overlap considerably in the constructs included in individual theories, and a comparison of theories reveals that each is missing important constructs included in other theories. In addition, terminology and definitions are not consistent across theories. We describe the Consolidated Framework For Implementation Research (CFIR) that offers an overarching typology to promote implementation theory development and verification about what works where and why across multiple contexts. Methods We used a snowball sampling approach to identify published theories that were evaluated to identify constructs based on strength of conceptual or empirical support for influence on implementation, consistency in definitions, alignment with our own findings, and potential for measurement. We combined constructs across published theories that had different labels but were redundant or overlapping in definition, and we parsed apart constructs that conflated underlying concepts. Results The CFIR is composed of five major domains: intervention characteristics, outer setting, inner setting, characteristics of the individuals involved, and the process of implementation. Eight constructs were identified related to the intervention (e.g., evidence strength and quality), four constructs were identified related to outer setting (e.g., patient needs and resources), 12 constructs were identified related to inner setting (e.g., culture, leadership engagement), five constructs were identified related to individual characteristics, and eight constructs were identified related to process (e.g., plan, evaluate, and reflect). We present explicit definitions for each construct. Conclusion The CFIR provides a pragmatic structure for approaching complex, interacting, multi-level, and transient states of constructs in the real world by embracing, consolidating, and unifying key constructs from published implementation theories. It can be used to guide formative evaluations and build the implementation knowledge base across multiple studies and settings.http://deepblue.lib.umich.edu/bitstream/2027.42/78272/1/1748-5908-4-50.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/2/1748-5908-4-50-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/3/1748-5908-4-50-S3.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/4/1748-5908-4-50-S4.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/5/1748-5908-4-50.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78272/6/1748-5908-4-50-S2.PDFPeer Reviewe