Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core ...feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2–5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.
•Young transgenic α-syn mice exhibit network hyperexcitability in the hippocampus in vitro.•Young transgenic α-syn mice have increased locomotor activity in an open field test.•Hippocampal pyramidal cells are more depolarised in young transgenic α-syn mice.•Increased mitochondrial cytochrome c oxidase (complex IV) function in PV+ interneurons in young transgenic a-syn mice.
•Age-dependent impairment in hippocampal gamma frequency activity in A30P mice.•Gamma oscillations in slices from A30P mice show greater sensitivity to rotenone.•Age-dependent impairment in ...mitochondrial function in A30P.
Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P). We found an age-dependent reduction in the power of the gamma (20–80 Hz) frequency oscillations in slices taken from mice aged 9–16 months (9+A30P), that was not present in either young 2–6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of α-syn. These findings provide mechanistic insights into the consequences of over-expression of α-syn which might contribute to cognitive decline.
The basolateral amygdala (BLA) has a fundamental role in affective processing. In vivo studies have revealed rhythmic population activity of a similar type to that seen in the hippocampus and ...cortical areas during learning tasks. The amygdala contains densely interconnected networks of inhibitory interneurons similar to those responsible for fast network activity generation in the hippocampus and other cortical structures. Here we report that neuronal networks of the BLA in isolation generate persistent, gamma frequency (30–80 Hz) oscillations upon kainate receptor activation with kainic acid. We show that, like other cortical structures, BLA oscillations are completely dependent upon γ‐aminobutyric acid (GABA)ergic inhibition. GABAA receptor blockade abolished all oscillations, and the activity was also sensitive to the barbiturate, pentobarbital. Blockade of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors or N‐methyl‐d‐aspartate (NMDA) receptors had no significant effect on gamma activity. However, the GluR5‐containing kainate receptor‐specific antagonist (S)‐1‐(2‐amino‐2‐carboxyethyl)‐3‐(2‐carboxybenzyl) pyrimidine‐2,4‐dione (UBP302) abolished oscillations–evidence that glutamatergic receptor involvement is predominantly kainate receptor mediated. The mixed AMPA/kainate receptor antagonist 6‐nitro‐7‐sulphamoylbenzofquinoxalone‐2,3‐dione disodium (NBQX) abolished all oscillatory activity in 8/14 of slices tested. In the remaining slices, gamma frequency activity was abolished to reveal a low‐amplitude, NMDA receptor‐dependent, beta frequency (10–20 Hz) oscillation. Gamma oscillations are abolished by gap junction blockade. While these data show the BLA capable of generating gamma rhythms in common with other cortical areas studied to date, the network mechanisms appear to be different, suggesting a unique network structure underlies amygdala rhythmogenesis. Understanding how BLA networks produce synchronous activity is paramount to understanding how the BLA executes influence on important cognitive processes such as emotional learning.
Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) ...scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies.
•Electrophysiology probes Alzheimer's and drug effects on neurons/networks.•Electrophysiology biomarkers measure channelopathy, synaptic neurotransmission and neural network dynamics, synchronization, and connectivity.•Spatial scale ranges from microscopic (μm) to macroscopic (cm) measures.•Temporal scale ranges from microseconds to hours (e.g., sleep).•Electrophysiology markers translate from clinical to preclinical research.
The sparse connectivity within the striatum in vivo makes the investigation of individual corticostriatal synapses very difficult. Most studies of the corticostriatal input have been done using ...electrical stimulation under conditions where it is hard to identify the precise origin of the cortical input. We have employed an in vitro dissociated cell culture system that allows the identification of individual corticostriatal pairs and have been developing methods to study individual neuron inputs to striatal neurons. In mixed corticostriatal cultures, neurons had resting activity similar to the system in vivo. Up/down states were obvious and seemed to encompass the entire culture. Mixed cultures of cortical neurons from transgenic mice expressing green fluorescent protein with striatal neurons from wild-type mice of the same developmental stage allowed visual identification of individual candidate corticostriatal pairs. Recordings were performed between 12 and 37 days in vitro (DIV). To investigate synaptic connections we recorded from 69 corticostriatal pairs of which 44 were connected in one direction and 25 reciprocally. Of these connections 41 were corticostriatal (nine inhibitory) and 53 striatocortical (all inhibitory). The observed excitatory responses were of variable amplitude (-10 to -370 pA, n = 32). We found the connections very secure - with negligible failures on repeated stimulation (approximately 1 Hz) of the cortical neuron. Inhibitory corticostriatal responses were also observed (-13 to -314 pA, n = 9). Possibly due to the mixed type of culture we found an inhibitory striatocortical response (-14 to -598 pA, n = 53). We are now recording from neurons in separate compartments to more closely emulate neuroanatomical conditions but still with the possibility of the easier identification of the connectivity.
In the preceding article in this issue, Paul Vanden Berghe and colleagues describe how euthanasia has come to be incorporated into palliative care provision in Flanders and, to some extent, in the ...whole of Belgium. Here, Fiona Randall offers a critique of the situation described and questions many of the assumptions behind the Belgian model. Commentary on: Assisted dying - the current situation in Flanders: euthanasia embedded in palliative care by Paul Vanden Berghe, Arsène Mullie, Marc Desmet and Gert Huysmans. European Journal of Palliative Care 20:6 p273-276 1 reference
Cerebrospinal and structural‐molecular neuroimaging in‐vivo biomarkers are recommended for diagnostic purposes in Alzheimer’s disease (AD) and other dementias; however, they do not explain the ...effects of AD neuropathology on neurophysiological mechanisms underpinning cognitive processes. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer’s Association reviewed the field literature and reached consensus on the event‐related electroencephalographic oscillations (EROs) that show consistent abnormalities in patients with significant cognitive deficits due to Alzheimer’s, Parkinson’s (PD), Lewy body (LBD), and cerebrovascular diseases. Converging evidence from oddball paradigms showed that, as compared to cognitively unimpaired (CU) older adults, AD patients had lower amplitude in widespread delta (>4 Hz) and theta (4–7 Hz) phase‐locked EROs as a function of disease severity. Similar effects were also observed in PD, LBD, and/or cerebrovascular cognitive impairment patients. Non‐phase‐locked alpha (8–12 Hz) and beta (13–30 Hz) oscillations were abnormally reduced (event‐related desynchronization, ERD) in AD patients relative to CU. However, studies on patients with other dementias remain lacking. Delta and theta phase‐locked EROs during oddball tasks may be useful neurophysiological biomarkers of cognitive systems at work in heuristic and intervention clinical trials performed in AD patients, but more research is needed regarding their potential role for other dementias.
A multidisciplinary Expert Panel reviewed the literature and reached a consensus on the event‐related electroencephalographic oscillations (EROs) showing consistent abnormalities in patients with significant cognitive deficits due to Alzheimer’s, Parkinson’s (PD), Lewy body (LBD), and cerebrovascular diseases. Delta and theta phase‐locked EROs during oddball tasks may be useful as neurophysiological biomarkers of cognitive systems at work in AD patients, although those EEG measures were unspecific in relation to the other dementing disorders mentioned above.
Background
The body's natural defences are breached during invasive procedures conducted during paramedic clinical care. Despite the complexity of these procedures, asepsis is a clinical goal for all ...invasive procedures. In doing so, it is critical that ‘key-parts’ and ‘key-sites’ are protected to decrease the risk of transmitting healthcare-associated infections (HAIs). Although a national framework in Australia for the prevention of HAIs exists, this advice needs adapting to the field of paramedicine to account for variation in practice setting and clinical practice. This project aimed to reach consensus among experts regarding how to maintain asepsis in paramedic practice.
Method
A modified Delphi process was used with four iterative online rounds. Participants were sought nationally using a snowball (bias) technique and included professionals within healthcare who met the inclusion criteria of extensive experience in one or more of three areas: paramedicine, infection prevention and control, and evidence-based policy development.
Results
Eleven experts in the field of IPC and paramedicine contributed to a consensus project regarding how to maintain asepsis in paramedic practice.
Conclusion
This project provides a consensus statement that will allow operational procedures to be reviewed, techniques specific to paramedic practice to be developed and implemented, and scientific research to be conducted.
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