Background: Neuropsychiatric disorders are a significant cause of death and disability worldwide. The mechanisms underlying these disorders include a constellation of structural, infectious, immunological, metabolic, and genetic etiologies. Advances in next-generation sequencing techniques have demonstrated that the composition of the enteric microbiome is dynamic and plays a pivotal role in host homeostasis and several diseases. The enteric microbiome acts as a key mediator in neuronal signaling via metabolic, neuroimmune, and neuroendocrine pathways. Objective: In this review, we aim to present and discuss the most current knowledge regarding the putative influence of the gut microbiome in neuropsychiatric disorders. Methods: We examined some of the preclinical and clinical evidence and therapeutic strategies associated with the manipulation of the gut microbiome. Results: targeted taxa were described and grouped from major studies to each disease. Conclusions: Understanding the complexity of these ecological interactions and their association with susceptibility and progression of acute and chronic disorders could lead to novel diagnostic biomarkers based on molecular targets. Moreover, research on the microbiome can also improve some emerging treatment choices, such as fecal transplantation, personalized probiotics, and dietary interventions, which could be used to reduce the impact of specific neuropsychiatric disorders. We expect that this knowledge will help physicians caring for patients with neuropsychiatric disorders.
Transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCRE), tripolar TFS, is proposed to treat pharmacoresistant epilepsy. We determined the effect of tripolar TFS on electrical amygdaloid kindling (AK) in freely moving cats. Fifteen cats were bilaterally implanted with electrodes in the amygdala (AM) and prefrontal cortex and assigned to three groups: the control group, which only received AK; the tripolar TFS before AK group, in which TCREs were placed over the vertex and tripolar TFS (300 Hz, 200 μs biphasic equal charge, square pulses) was delivered for 40 min just prior to AK; and the tripolar TFS after AK group, in which the TCREs were placed over the temporal bone ipsilateral to the kindled AM, while tripolar TFS was administered for 2 min just after AK onset for 40 days, and, thereafter, only AK was applied. AK was applied daily until all animals reached kindling stage VI. A three concentric spheres finite element cat head model was developed to analyze the electric fields caused by tripolar TFS. Tripolar TFS after AK inhibited kindling development. Animals with tripolar TFS after AK remained at the focal seizure stages for 20 days after tripolar TFS cessation and required 80.0 ± 15.42 AK stimulations to reach stage VI, significantly higher than TFS before AK, and control (P < .001). Tripolar TFS before AK did not show signs of protection against epileptogenesis. The finite modeling of tripolar TFS showed that the electric field is >0.3 mV/mm at depths less than approximately 12.6 mm in the cat brain, which should be strong enough to alter brain activity. In conclusion, tripolar TFS applied via a TCRE over the ipsilateral temporal area significantly delayed AK. This taken together with other reports of tripolar TFS aborting seizures in acute seizure models suggests that tripolar TFS is a promising new modality that should be considered for further testing.
Accumulation of amyloid‐beta (Aβ) in temporal lobe structures, including the hippocampus, is related to a variety of Alzheimer's disease symptoms and seems to be involved in the induction of neural network hyperexcitability and even seizures. Still, a direct evaluation of the pro‐epileptogenic effects of Aβ in vivo, and of the underlying mechanisms, is missing. Thus, we tested whether the intracisternal injection of Aβ modulates 4‐aminopyridine (4AP)‐induced epileptiform activity, hippocampal network function, and its synaptic coupling. When tested 3 weeks after its administration, Aβ (but not its vehicle) reduces the latency for 4AP‐induced seizures, increases the number of generalized seizures, exacerbates the time to fully recover from seizures, and favors seizure‐induced death. These pro‐epileptogenic effects of Aβ correlate with a reduction in the power of the spontaneous hippocampal network activity, involving all frequency bands in vivo and only the theta band (4–10 Hz) in vitro. The pro‐epileptogenic effects of Aβ also correlate with a reduction of the Schaffer‐collateral CA1 synaptic coupling in vitro, which is exacerbated by the sequential bath application of 4‐AP and Aβ. In summary, Aβ produces long‐lasting pro‐epileptic effects that can be due to alterations in the hippocampal circuit, impacting its coordinated network activity and its synaptic efficiency. It is likely that normalizing synaptic coupling and/or coordinated neural network activity (i.e., theta activity) may contribute not only to improve cognitive function in Alzheimer's disease but also to avoid hyperexcitation in conditions of amyloidosis.
Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro. Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro. Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.
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