Abstract: “Some research suggests that 40% of people in the vegetative state are misdiagnosed. This review investigates the frequency, nature and causes of reported misdiagnosis of patients in the vegetative state, focusing on the nature of the error. It is a systematic review of all relevant literature, using references from key papers identified. The data are summarized in tables. Five clinical studies of the rate of misdiagnosis in practice were identified, encompassing 236 patients in the vegetative state of whom 80 (34%) were reclassified as having some awareness, often minimal. The studies often included patients in the recovery phase after acute injury, and were poorly reported. Five systematic reviews of signs and technologically based neurophysiological tests were identified, and they showed that most studies were small, lacked accurate or important details, and were subject to bias. Studies were not replicated. Many signs and tests did not differ between people in the vegetative state and in the minimally conscious state, and those that did were unable to diagnose an individual patient. The few single case reports suggest that failure to ensure an accurate diagnosis of the underlying neurological damage and dysfunction could, rarely, lead to significant misdiagnosis usually in patients who had brain-stem damage with little thalamic or cortical damage. Significant misdiagnosis of awareness, with an apparently ‘vegetative’ patient having good awareness, is rare. Careful neurological assessment of the cause and routine measurement of awareness using the Coma Recovery Scale – Revised should further reduce mistakes.”

Wade DT: How often is the diagnosis of the permanent vegetative state incorrect? A review of the evidence. Eur. J. Neurol. 25(4): 619-625 (2018).


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Structured Abstract


“In 1853, Sydney Whiting wrote in his classic Memoirs of a Stomach, “…and between myself and that individual Mr. Brain, there was established a double set of electrical wires, by which means I could, with the greatest ease and rapidity, tell him all the occurrences of the day as they arrived, and he also could impart to me his own feelings and impressions.” Historically, it is known that the gut must communicate with the brain, but the underlying neural circuits and transmitters mediating gut-brain sensory transduction still remain unknown. In the gut, there is a single layer of epithelial cells separating the lumen from the underlying tissue. Dispersed within this layer reside electrically excitable cells termed enteroendocrine cells, which sense ingested nutrients and microbial metabolitesLike taste or olfactory receptor cells, enteroendocrine cells fire action potentials in the presence of stimuli. However, unlike other sensory epithelial cells, no synaptic link between enteroendocrine cells and a cranial nerve has been described. The cells are thought to act on nerves only indirectly through the slow endocrine action of hormones, like cholecystokinin. Despite its role in satiety, circulating concentrations of cholecystokinin peak only several minutes after food is ingested and often after the meal has ended. Such a discrepancy suggests that the brain perceives gut sensory cues through faster neuronal signaling. Using a mouse model, we sought to identify the underpinnings of this neural circuit that transduces a sense from gut to brain.


Our understanding of brain neural circuits is being propelled forward by the emergence of molecular tools that have high topographical and temporal precision. We adapted them for use in the gut. Single-cell quantitative real-time polymerase chain reaction and single-cell Western blot enabled the assessment of synaptic proteins. A monosynaptic rabies virus revealed the neural circuit’s synapse. The neural circuit was recapitulated in vitro by using nodose neurons cocultured with either minigut organoids or purified enteroendocrine cells. This system, coupled to optogenetics and whole-cell patch-clamp recording, served to determine the speed of transduction. Whole-nerve electrophysiology, along with optical excitation and silencing, helped to uncover the neurotransmission properties of the circuit in vivo. The underlying neurotransmitter was revealed by using receptor pharmacology and a fluorescent reporter called iGluSnFR.


Single-cell analyses showed that a subset of enteroendocrine cells contains presynaptic adhesion proteins, including some necessary for synaptic adhesion. Monosynaptic rabies tracing revealed that enteroendocrine cells synapse with vagal nodose neurons. This neuroepithelial circuit connects the intestinal lumen with the brainstem in one synapse. In coculture, this connection was sufficient to transduce a sugar stimulus from enteroendocrine cells to vagal neurons. Optogenetic activation of enteroendocrine cells elicited excitatory postsynaptic potentials in connected nodose neurons within milliseconds. In vivo recordings showed that enteroendocrine cells are indeed necessary and sufficient to transduce a sugar stimulus to the vagus. By using iGluSnFR, we found that enteroendocrine cells synthesize the neurotransmitter glutamate, and pharmacological inactivation of cholecystokinin and glutamate receptors revealed that these cells use glutamate as a neurotransmitter to transduce fast, sensory signals to vagal neurons.


We identified a type of gut sensory epithelial cell that synapses with vagal neurons. This cell has been referred to as the gut endocrine cell, but its ability to form a neuroepithelial circuit calls for a new name. We term this gut epithelial cell that forms synapses the neuropod cell. By synapsing with the vagus nerve, neuropod cells connect the gut lumen to the brainstem. Neuropod cells transduce sensory stimuli from sugars in milliseconds by using glutamate as a neurotransmitter. The neural circuit they form gives the gut the rapidity to tell the brain of all the occurrences of the day, so that he, too, can make sense of what we eat.”


Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV: A gut-brain neural circuit for nutrient sensory transduction. Science 361(6408): pii: eaat5236. doi: 10.1126/science.aat5236 (2018).




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Abstract: “Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3-neocortical functional connectivity.”

Suwabe K, Byun K, Hyodo K, Reagh ZM, Roberts JM, Matsushita A, Saotome K, Ochi G, Fukuie T, Suzuki K, Sankai Y, Yassa MA and Soya H: Rapid stimulation of human dentate gyrus function with acute mild exercise. Proc. Natl. Acad. Sci. USA [Epub ahead of print, Sept. 24, 2018; doi: 10.1073/pnas.1805668115].


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Abstract: “This paper examines the effect of both cumulative and transitory exposures to air pollution for the same individuals over time on cognitive performance by matching a nationally representative longitudinal survey and air quality data in China according to the exact time and geographic locations of the cognitive tests. [The authors] find that long-term exposure to air pollution impedes cognitive performance in verbal and math tests. [They] provide evidence that the effect of air pollution on verbal tests becomes more pronounced as people age, especially for men and the less educated. The damage on the aging brain by air pollution likely imposes substantial health and economic costs, considering that cognitive functioning is critical for the elderly for both running daily errands and making high-stake decisions.”

Zhang X, Chen X and Zhang X: The impact of exposure to air pollution on cognitive performance. Proc. Natl. Acad. Sci. USA 115(37): 9193-9197 (2018).


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Vascular comorbidities are prevalent among people with multiple sclerosis and have adverse disease-related consequences. In the general population, physical activity and exercise training have proven beneficial for vascular disease risk management. People with multiple sclerosis exhibit particularly low rates of physical activity; therefore, physical activity represents a modifiable health behavior for managing vascular comorbidity risk in multiple sclerosis, and reducing disease burden. The purpose of this report was to review existing evidence linking physical activity and exercise training to potential modification of vascular comorbidities and related risk factors in people with multiple sclerosis.

Overall, 14 of the 17 observational studies identified (82.4%) reported an association between higher levels of physical activity or cardiorespiratory fitness, or decreased sedentary behavior, and better function of at least one risk factor related to vascular comorbid conditions in people with multiple sclerosis. The efficacy of exercise training in limiting vascular comorbidity risk and burden was dependent upon intervention type and duration, with 9 of 17 interventional studies (52.9%) reporting improvement in at least one relevant measure of vascular comorbidity in participants with multiple sclerosis.

The authors concluded that there is a potential relationship between physical activity and exercise and risk factors related to vascular comorbidities in people with multiple sclerosis. Physical activity and exercise training interventions may represent an effective therapeutic strategy for managing vascular comorbidities in people with multiple sclerosis, justifying further investigation.

Ewanchuk BW, Gharagozloo M, Peelen E, Pilutti LA: Exploring the role of physical activity and exercise for managing vascular comorbidities in people with multiple sclerosis: A scoping review. Mult. Scler. Relat. Disord. 26:19-32 (2018).


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How does exercise keep your brain young?

By Kelly Servick, Sep. 6, 2018.

“Stay active; age gracefully. Behind this truism, there’s a pile of unanswered scientific questions. Researchers are still sorting out what it is about physical activity that seems to lower the risk of dementia later in life. Even more uncertain is whether the effects of exercise can alter the course of diseases that cause dementia—chief among them, Alzheimer’s disease—once they’ve already taken root.

A study published today in Science offers some new clues. In mice that mimic a severe, genetic form of Alzheimer’s disease, a combination of treatments that prompt the growth of new brain cells and protect them from damage can mimic the beneficial effects of exercise (http://science.sciencemag.org/content/361/6406/eaan8821) in preventing memory decline. So could we someday bottle the effects of exercise to treat Alzheimer’s? And if so, what exactly would we need to bottle? Here’s a rundown of what we know, and what’s still controversial.

What’s the link between exercise and brain aging?

Many large studies suggest staying active and fit throughout life lowers the risk of memory problems later on. For example, a recent project tracked more than 1000 Swedish women over 4 decades and found that for those judged to have “high” cardiovascular fitness on entering the study—as measured by the maximum workload they could handle on a stationary cycle machine before exhaustion—the onset of dementia was delayed (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894933/), on average, by 9.5 years compared to those with “medium” fitness. But such studies can’t rule out all other confounding factors that might influence dementia risk—from genes to other aspects of a healthy lifestyle common in regular exercisers. And they don’t explain what exercise actually does to the brain.

Does exercise fight the effects of Alzheimer’s disease once someone has it?

Evidence for this is stronger in rodents than in humans.” …….continued….….


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Abstract summary: “Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), (Pasman and colleagues) identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2 (cell adhesion molecule 2), which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use.” The authors concluded that the study gives new insights into the etiology of cannabis use and its relation with mental health.

Pasman JA, Verweij KJH, Gerring Z, Stringer S, Sanchez-Roige S, Treur JL, Abdellaoui A, Nivard MG, Baselmans BML, Ong JS, Ip HF, van der Zee MD, Bartels M et al: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nature Neurosci. [Epub ahead of print, August 27, 2018; doi: 10.1038/s41593-018-0206-1].


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Abstract: “The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.”

Nasca C, Bigio B, Lee FS, Young SP, Kautz MM, Albright A, Beasley J, Millington DS, Mathé AA, Kocsis JH, Murrough JW, McEwen BS and Rasgon N: Acetyl-1-carnitine deficiency in patients with major depressive disorder. Proc. Natl. Acad. Sci. USA [Epub ahead of print, July 30, 2018; pii: 201801609. doi: 10.1073/pnas.1801609115 ].



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Major depressive disorder is associated with an increased risk of mortality and aging-related diseases. In this study, the authors examined whether major depression is associated with higher epigenetic aging in blood as measured by DNA methylation patterns, and whether clinical characteristics of major depression have a further impact on these patterns.

Compared with control subjects, patients with major depression exhibited higher epigenetic aging in blood and brain tissue, suggesting that they are biologically older than their corresponding chronological age. In the depression group, epigenetic aging was positively and significantly associated with childhood trauma score.

Han LKM, Aghajani M, Clark SL, Chan RF, Hattab MW, Shabalin AA, Zhao M, Kumar G,  Xie LY, Jansen R, Milaneschi Y, Dean B, Aberg KA, van den Oord EJCG, and Penninx BWJH: Epigenetic Aging in Major Depressive Disorder. Amer. J. Psychiatry 175:774–782 (2018).


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“Transgenerational epigenetic inheritance refers to the transmission of epigenetic information through the germline. While it has been observed in plants, nematodes and fruit flies, its occurrence in mammals-and humans in particular-is the matter of controversial debate, mostly because the study of transgenerational epigenetic inheritance is confounded by genetic, ecological and cultural inheritance.” In this paper, Horsthemke discusses the phenomenon of transgenerational epigenetic inheritance and the difficulties in experimental and observational studies.

Horsthemke B: A critical view on transgenerational epigenetic inheritance in humans. Nature Commun. 9(1): 2973 (2018); doi: 10.1038/s41467-018-05445-5.


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