Is There a Brain Microbiome?

Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”

Vagus Nerve Stimulation Ameliorates Cognitive Impairment and Increased Hippocampal Astrocytes in a Mouse Model of Gulf War Illness

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Engineering Safer Psychedelics for Treating Addiction

Addiction is best described as a disorder of maladaptive neuroplasticity involving the simultaneous strengthening of reward circuitry that drives compulsive drug seeking and weakening of circuits involved in executive control over harmful behaviors. Psychedelics have shown great promise for treating addiction, with many people attributing their therapeutic effects to insights gained while under the influence of the drug. However, psychedelics are also potent psychoplastogens—molecules capable of rapidly re-wiring the adult brain. The advent of non-hallucinogenic psychoplastogens with anti-addictive properties raises the intriguing possibility that hallucinations might not be necessary for all therapeutic effects of psychedelic-based medicines, so long as the underlying pathological neural circuitry can be remedied. One of these non-hallucinogenic psychoplastogens, tabernanthalog (TBG), appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction. Here, we discuss the implications of these results for the development of addiction treatments, as well as the next steps for advancing TBG and related non-hallucinogenic psychoplastogens as addiction therapeutics.

The Carbamate, Physostigmine does not Impair Axonal Transport in Rat Cortical Neurons

Among the various chemicals that are commonly used as pesticides, organophosphates (OPs), and to a lesser extent, carbamates, are most frequently associated with adverse long-term neurological consequences. OPs and the carbamate, pyridostigmine, used as a prophylactic drug against potential nerve agent attacks, have also been implicated in Gulf War Illness (GWI), which is often characterized by chronic neurological symptoms. While most OP- and carbamate-based pesticides, and pyridostigmine are relatively potent acetylcholinesterase inhibitors (AChEIs), this toxicological mechanism is inadequate to explain their long-term health effects, especially when no signs of acute cholinergic toxicity are exhibited. Our previous work suggests that a potential mechanism of the long-term neurological deficits associated with OPs is impairment of axonal transport (AXT); however, we had not previously evaluated carbamates for this effect. Here we thus evaluated the carbamate, physostigmine (PHY), a highly potent AChEI, on AXT using an in vitro neuronal live imaging assay that we have previously found to be very sensitive to OP-related deficits in AXT. We first evaluated the OP, diisopropylfluorophosphate (DFP) (concentration range 0.001-10.0 µM) as a reference compound that we found previously to impair AXT and subsequently evaluated PHY (concentration range 0.01-100 nM). As expected, DFP impaired AXT in a concentration-dependent manner, replicating our previously published results. In contrast, none of the concentrations of PHY (including concentrations well above the threshold for impairing AChE) impaired AXT. These data suggest that the long-term neurological deficits associated with some carbamates are not likely due to acute impairments of AXT.

Glut1 deficiency syndrome: New and emerging insights into a prototypical brain energy failure disorder

Considering its small size relative to the rest of the body, the mammalian brain has a disproportionately high energy requirement. This energy is supplied to the brain mainly in the form of glucose through the principal cerebral glucose transporter, Glut1. Inactivation of even a single copy of the Glut1 gene, SLC2A1, has dire consequences for the brain, starving cerebral neurons of energy and triggering the debilitating neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). Considering the monogenic nature of Glut1 DS, the disease serves as an excellent paradigm to study the larger family of brain energy failure syndromes. Here we review how studies of Glut1 DS are proving instructive to the brain’s energy needs, focusing first on the requirements, both spatial and temporal of the transporter, second, on proposed mechanisms linking low Glut1 to brain dysfunction and, finally on efforts to treat the disease and thus restore nutritional support to the brain. These studies promise not only to inform mechanisms and treatments for the relatively rare Glut1 DS but also the myriad other conditions involving the Glut1 protein.

Hearing Impaired Participants Improve More Under Envelope-Transcranial Alternating Current Stimulation When Signal to Noise Ratio Is High

An issue commonly expressed by hearing aid users is a difficulty to understand speech in complex hearing scenarios, that is, when speech is presented together with background noise or in situations with multiple speakers. Conventional hearing aids are already designed with these issues in mind, using beamforming to only enhance sound from a specific direction, but these are limited in solving these issues as they can only modulate incoming sound at the cochlear level. However, evidence exists that age-related hearing loss might partially be caused later in the hearing processes due to brain processes slowing down and becoming less efficient. In this study, we tested whether it would be possible to improve the hearing process at the cortical level by improving neural tracking of speech. The speech envelopes of target sentences were transformed into an electrical signal and stimulated onto elderly participants’ cortices using transcranial alternating current stimulation (tACS). We compared 2 different signal to noise ratios (SNRs) with 5 different delays between sound presentation and stimulation ranging from 50 ms to 150 ms, and the differences in effects between elderly normal hearing and elderly hearing impaired participants. When the task was performed at a high SNR, hearing impaired participants appeared to gain more from envelope-tACS compared to when the task was performed at a lower SNR. This was not the case for normal hearing participants. Furthermore, a post-hoc analysis of the different time-lags suggest that elderly were significantly better at a stimulation time-lag of 150 ms when the task was presented at a high SNR. In this paper, we outline why these effects are worth exploring further, and what they tell us about the optimal tACS time-lag.

Alzheimer’s and Consciousness: How Much Subjectivity Is Objective?

Does Alzheimer Disease show a decline in cognitive functions that relate to the awareness of external reality? In this paper, we will propose a perspective that patients with increasing symptoms of AD show a change in the awareness of subjective versus objective representative axis of reality thus consequently move to a more internal like perception of reality. This paradigm shift suggests that new insights into the dynamicity of the conscious representation of reality in the AD brain may give us new clues to the very early signs of memory and self-awareness impairment that originates from, in our view the microtubules. Dialog between Adso and William, in Umberto Eco’s The Name of the Rose, Third Day: Vespers. “But how does it happen,” I said with admiration, “that you were able to solve the mystery of the library looking at it from the outside, and you were unable to solve it when you were inside?” “Thus, God knows the world, because He conceived it in His mind, as if it was from the outside, before it was created, and we do not know its rule, because we live inside it, having found it already made.”

Progression of Cognitive Impairment to Alzheimer’s Disease: Through the Lens of Salivary Extracellular Vesicles

The elusiveness encircling around the domain of cognition, its impairment, and the poor prognosis of Alzheimer’s disease has made early diagnosis a necessity. The noticeable symptoms in these conditions appear years later after the neuropathological changes occur in the brain. Exosomes, a small-sized extracellular vesicle facilitate intercellular communication of disease pathologies and their cargo can provide molecular information about its place of origin. The study titled “A novel approach to correlate the salivary exosomes and their protein cargo in the progression of cognitive impairment into Alzheimer’s disease” was an attempt toward understanding the role of salivary small-sized extracellular vesicular (EV’s) cargo in monitoring the progression. Outcomes of the study represent, that the salivary small-sized EV’s (ssEV’s) levels were higher in the cognitively impaired and Alzheimer’s diseased as well the differential expression of the protein in the cargo correlates well with the disease severity staging. Thus, it can help in the development of an early non-invasive screening method.

Adaptive Immune Responses Associated with the Central Nervous System Pathology of Gulf War Illness

Gulf War Illness is a multisymptomatic condition which affects 30% of veterans from the 1991 Gulf War. While there is evidence for a role of peripheral cellular and humoral adaptive immune responses in Gulf War Illness, a potential role of the adaptive immune system in the central nervous system pathology of this condition remains unknown. Furthermore, many of the clinical features of Gulf War Illness resembles those of autoimmune diseases, but the biological processes are likely different as the etiology of Gulf War Illness is linked to hazardous chemical exposures specific to the Gulf War theatre. This review discusses Gulf War chemical–induced maladaptive immune responses and a potential role of cellular and humoral immune responses that may be relevant to the central nervous system symptoms and pathology of Gulf War Illness. The discussion may stimulate investigations into adaptive immunity for developing novel therapies for Gulf War Illness.