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Contemporary Problems with Methods in Basic Brain Science Impede Progress in ASD Research and Treatments
Published in Elizabeth B. Torres, Caroline Whyatt, Autism, 2017
As of today, coverage of sensory-motor-oriented therapies in ASD is not possible. This lacking impedes the type of diversification in therapies needed to tackle the disorder’s heterogeneity and implementation of personalized approaches to address problems in each child. In this regard, we hope that the proposed neuromotor control taxonomy (Torres 2011) helps define different subtypes of ASD. This taxonomy also maps different levels of phylogenetically appearing control with different levels of somatic motor variability. Under such scheme, it may be possible to provide a classification system evaluating the functioning of different nerve groups (e.g., efferent-motor vs. afferent-sensory), and within those subgroups further separate facial versus bodily maps (as in Figure 12.7). An important component in this regard is the level of deliberate autonomy of the brain over the body. When paired with genetics, such taxonomy would also be amenable to map different types of synaptic noise (Figure 12.8) with corresponding signatures of somatic motor noise along the facial and bodily maps (in Figure 12.7). If the autonomic nervous systems, or the level of involuntary motions, overpower deliberate autonomy of the brain over the body, we may be able to classify autism based on the quantification of such interference with volitional control and agency of the brain over the physical body.
Role of the NTS in the Medullary Respiratory Network Producing Respiratory Movements
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
Armand L. Bianchi, Laurent Grélot
Vagal afferents including pulmonary slowly adapting stretch receptors (PSR) and rapidly adapting irritant receptors (RAR) terminate onto neurons of the NTS.31-35 These receptors are involved in various situations, including pulmonary volume changes which result in excitatory and inhibitory respiratory reflexes. Activation of PSR by moderate lung inflation induces inhibition of inspiration, which is revealed by an inflation test. On the basis of their responses to such a test, inspiratory neurons can be differentiated in two categories, i.e., inspiratory neurons not excited by lung inflation, the alpha inspiratory neurons, and inspiratory neurons excited by lung inflation, the beta inspiratory neurons.36 The synaptic connectivity mediating the excitation of beta inspiratory neurons has been elucidated as being monosynaptic by the construction of cross-correlograms between spike discharges of the PSR and medullary neuronal activity,37 by using the spike discharge of the PSR as a trigger to average the extracellular potentials of nerve terminals within the medulla,38 or by the intracellular synaptic noise recorded from inspiratory neurons.39,40 It has been assumed that the beta inspiratory neurons play the role of interneurons mediating inhibition to alpha inspiratory neurons.36 However, this hypothesis was strongly questioned by the existence of a direct synaptic action of beta inspiratory neurons onto phrenic motoneurons.41,42 This is consistent with the inspiratory excitatory effect of lung inflation on phrenic discharge,43 and the possible projection of rapidly adapting pulmonary receptors on beta inspiratory neurons.44,45 Thus, as stated by Davies et al.,46 it seems that “even though alpha and beta inspiratory neurons can be separated on the basis of inflation test, the cells share many other properties so that the division is more quantitative than qualitative”.
Receptor Binding Studies: General Considerations
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Radiolabeled probes can be used to measure the interaction of drugs with specific macromolecules which do not represent classical receptors, in the sense that they do not normally initiate a physiological response subsequent to interaction with an endogenously released ligand. As with classical receptors, radiotracer binding techniques cannot be fully utilized until the physiological and pharmacological properties of drug interaction with the site have been documented independently. An example of the identification of such a binding site is the ion channel associated with nicotinic acetylcholine receptors of neuromuscular junctions or the electric organs of certain fish, such as the electric rays, Torpedo. Acetylcholine and other cholinergic agonists interact with the receptor thereby initiating a rapid, depolarizing influx of cations (chiefly sodium) across the postsynaptic membrane via an ion channel. The relationship between the receptor and ion channel is not clear; they may represent different functions of the same macromolecule, be located on separate polypeptide chains in the same protein or be separate, interacting entities. The distinction between drugs which influence neurotransmission at the neuromuscular junction through interactions with the receptor as opposed to its associated ion channel has been accomplished only relatively recently.20 Drugs which interact directly with the ion channel cause characteristic changes in the time course of end plate currents and the opening and closing of single ionic channels as revealed by synaptic noise analysis.21 In these studies, it was shown that several drugs which had been thought to interact with the receptor actually interact with the ion channel. Electrophysiological evidence suggested that two compounds, perhydrohistrionicotoxin and phencyclidine, might serve as biochemical probes of the channel, and, in fact, saturable binding components were detected with the tritiated analogues of both compounds. Moreover, this binding was inhibited by a large number of known ion channel blockers. Further detailed studies indicate that the histrionicotoxin and phencyclidine sites are not identical.35 That the measured binding actually involves sites on the ion channel receives strong support from the observation that receptor activators strongly potentiate the binding of the histrionicotoxin and phencyclidine to the channel.22 The rate of channel probe binding is increased by up to several hundred-fold in the presence of receptor agonists. This increase is attenuated, although not eliminated, by receptor antagonists. Moreover, preincubation of the receptors with agonists decreases the degree of agonist-mediated enhancement of channel binding. Thus, several conformational states of the receptor-ion channel complex (i.e., resting, “activated” and “desensitized” states) can be detected by monitoring only the binding of radiolabeled probes to the channel. These interactions provide a convenient means for identification of ion channel binding sites and suggest more purely biochemical (as opposed to physiological or pharmacological) criteria for the in vitro identification of sites on the receptor-channel complex.
Pharmacotherapeutic combinations for the treatment of Alzheimer’s disease
Published in Expert Opinion on Pharmacotherapy, 2022
Tomoyuki Nagata, Shunichiro Shinagawa, Shinichiro Nakajima, Yoshihiro Noda, Masaru Mimura
The Alzheimer’s Disease Management Council Clinical Consensus Panel algorithm advocates starting with a low dose and gradually titrating up to the maximum dose of one approved symptomatic anti-dementia drug (any ChEI or memantine), depending on the severity of dementia in AD [15]. In moderate to severe levels of AD, any ChEI or memantine monotherapy is recommended as a first-line treatment [15]. If use of the selected drug must be discontinued because of adverse events or a lack of efficacy, combination treatment (one ChEI and memantine) is recommended as the next treatment step [15]. The ‘lack of efficacy’ of any anti-dementia drug was not defined in the previous guidelines, and the timing of combination therapy remains unclear. In the longitudinal course of neurocognitive deterioration, a ‘lack of efficacy’ may be defined by the score reduction slope between two-point phases using neurocognitive assessment scales such as the Mini-Mental State Examination (MMSE). In a previous large sample study, an average annual reduction in the MMSE score, which is representative of the neurocognitive status, was about 3 points or more in patients with AD who had not received treatment (ChEIs or memantine) [15,16]. Thus, combination therapy using approved anti-dementia drugs could be recommended based on a certain score reduction slope (e.g. a reduction of 3 MMSE points per year) during the long-term course of symptomatic therapy. The effectiveness of add-on combination therapy has been discussed for about 20 years, and meta-analyses have concluded that combination therapy for patients with moderate to severe AD is superior to monotherapy in terms of efficacy and tolerability when cognitive function, neuropsychiatric symptoms (NPSs), ADL, and global assessments are considered [17,18]. On the other hand, for patients with mild to moderate stages, combination therapy showed no additional benefit, compared with monotherapy [18]. However, when each combination therapy for AD was compared, the combination of galantamine and memantine was superior to that of donepezil and memantine [19]. The pharmacological mechanism of combination therapy using ChEI and memantine has been discussed for a long time, and memantine is thought to suppress the ‘synaptic noise’ of a glutamate background, which is a pathophysiological characteristic of AD, while ChEI enhances the physiological signal level at the post-synapse of cholinergic neurons, possibly leading to an improvement in symptoms [7,20].