Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that involves demyelination and axonal degeneration. Although substantial progress has been made in drug development for relapsing-remitting MS, treatment of the progressive forms of the disease, which are characterized clinically by the accumulation of disability in the absence of relapses, remains unsatisfactory. This unmet clinical need is related to the complexity of the pathophysiological mechanisms involved in MS progression. Chronic inflammation, which occurs behind a closed blood-brain barrier with activation of microglia and continued involvement of T cells and B cells, is a hallmark pathophysiological feature. Inflammation can enhance mitochondrial damage in neurons, which, consequently, develop an energy deficit, further reducing axonal health. The growth-inhibitory and inflammatory environment of lesions also impairs remyelination, a repair process that might protect axons from degeneration. Moreover, neurodegeneration is accelerated by the altered expression of ion channels on denuded axons. In this Review, we discuss the current understanding of these disease mechanisms and highlight emerging therapeutic strategies based on these insights, including those targeting the neuroinflammatory and degenerative aspects as well as remyelination-promoting approaches.
Faissner S, Plemel JR, Gold R and Yong VW: Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nature Rev. Drug Discov. 18(12): 905-922 (2019).
Abbreviated Abstract: Adverse childhood experiences such as early life adversity or stress and childhood trauma have a lifelong impact on mental and physical health. Childhood trauma has been associated with posttraumatic stress disorder (PTSD), anxiety, depression, bipolar disorder, diabetes, and cardiovascular disease. However, the heritability of adverse childhood-related phenotypes such as PTSD, depression, and resilience is low to moderate, and is very variable for a given phenotype, which implies that gene by environment interactions (such as through epigenetic modifications) may be involved in the onset of these phenotypes.
Currently, there is increasing interest in the investigation of epigenetic contributions to adverse childhood-induced differential health outcomes. In this review, the basic concepts of epigenetic modifications (such as methylation) and the function of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response are outlined. Examples of specific genes undergoing methylation in association with adverse childhood-induced differential health outcomes are provided. Limitations in this field are reviewed, with suggestions for advances using new technologies and novel research directions.
Jiang S, Postovit L, Cattaneo A, Binder EB and Aitchison KJ: Epigenetic Modifications in Stress Response Genes Associated with Childhood Trauma. Frontiers Psychiatry 2019 Nov 8;10:808. doi: 10.3389/fpsyt.2019.00808. eCollection 2019.
Abstract: “Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.”
Satizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL et al: Genetic architecture of subcortical brain structures in 388,851 individuals. Nature Genetics 51(11):1624-1636 (2019).
In the current longitudinal study, Saarikivi and colleagues investigated the development of working memory in musically trained and nontrained children and adolescents, aged 9–20. Working memory was measured with the Digit Span (DS) forwards and backwards tests (N = 106) and the Trail-Making A and B (TMT-A and B; N = 104) tests three times, in 2011, 2013, and 2016. Younger musically trained participants outperformed their nontrained peers in the TMT-A, TMT-B and DS forwards tests. These tests all primarily require active maintenance of a rule in memory or immediate recall. In contrast, there were no group differences in the backwards test that requires manipulation and updating of information in working memory. The authors suggest that musical training is more strongly associated with heightened working memory capacity and maintenance than enhanced working memory updating, especially in late childhood and early adolescence.
Saarikivi KA, Huotilainen M, Tervaniemi M and Putkinen V: Selectively Enhanced Development of Working Memory in Musically Trained Children and Adolescents. Front. Integr. Neurosci., 06 November 2019 | https://doi.org/10.3389/fnint.2019.00062
Abstract: “Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABAA receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABAA receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment.”
Neumann S, Boothman-Burrell L, Gowing EK, Jacobsen TA, Ahring PK, Young SL, Sandager-Nielsen K and Clarkson AN: The Delta-Subunit Selective GABAA Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism. Frontiers in Neurosci., 29 October 2019 | https://doi.org/10.3389/fnins.2019.01133.
Journal Club: “The presentation and development of psychiatric illnesses is affected by interindividual variability in brain morphology and genetics. Epigenetic factors and early life experiences can also alter brain development and influence psychiatric illness susceptibility. For example, interactions between genetic and environmental factors may alter gene expression, resulting in neuroplastic and functional modifications that lead to anxiety and depression. …”
Vonderwalde I: DNA Methylation within the Amygdala Early in Life Increases Susceptibility for Depression and Anxiety Disorders. J. Neurosci. 39 (45) 8828-8830 (2019).
The present study provides evidence for a prodromal phase of multiple sclerosis, with implications for studying disease aetiology and underscoring the limitations of therapies that solely target inflammation. The findings also suggest an opportunity to apply secondary prevention strategies at the very earliest stages of the disease. Specifically, the authors studied whether serum neurofilament light chain (sNfL) levels are elevated before clinical multiple sclerosis onset. Results indicated that levels of sNfL were increased 6 years before clinical multiple sclerosis onset, indicating that multiple sclerosis may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
Bjornevik K, Munger KL, Cortese M, Barro C, Healy BC, Niebuhr DW, Scher Al, Kuhle J and Ascherio A: Serum Neurofilament Light Chain Levels in Patients with presymptomatic Multiple Sclerosis. JAMA Neurol. [Epub ahead of print, Sept. 13, 2019; doi: 10.1001/jamaneurol.2019.3238.].
Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain’s energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. An increasing amount of evidence suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. The authors describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data, and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. The authors consider potential mechanisms by which metabolic abnormalities could generate attacks and highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions.
- Prevalent triggers of migraine attacks can all be linked to unbalanced cerebral energy metabolism and/or oxidative stress.
- Magnetic resonance spectroscopy studies have shown that mitochondrial phosphorylation potential and ATP are decreased in the brains of people with migraine between attacks. Glucose (and lipid) metabolism and mitochondrial functions are abnormal in the peripheral blood.
- Among patients with migraine, various single nucleotide polymorphisms are present in non-coding mitochondrial DNA and nuclear-encoded mitochondrial proteins; common variants associated with migraine are functionally involved in mitochondrial metabolism.
- Metabolic enhancers, such as riboflavin and coenzyme Q10, and dietary or pharmacological ketogenesis improve migraine but novel, more efficient metabolic strategies are needed.
- Experimental studies indicate a link between cerebral energy disequilibrium and cortical spreading depression and/or trigeminovascular system activation; calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide could also help restore energy homeostasis.
- Migraine can be regarded as a conserved, adaptive response that occurs in individuals with a genetic predisposition and a mismatch between the brain’s energy reserve and workload.
Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J: The metabolic face of migraine – from pathophysiology to treatment. Nature Rev. Neurol. [Epub ahead of print, Oct. 4, 2019; doi: 10.1038/s41582-019-0255-4].
To analyze music preferences in human subjects, Gold and colleagues built a computer model to analyze songs quantitatively. The researchers fed the model a large musical repertoire, including Canadian and German folk songs and Bach compositions. This training allowed the model to measure a trait that the researchers call ‘complexity’, which includes qualities such as how surprising a song would sound to listeners accustomed to Western music.
The results showed that the human brain favors songs that are neither too simple nor too complex. Surprising twists and turns in a piece of music can influence its appeal to the brain. The researchers asked people to rate how much they liked various musical clips, including excerpts from Georges Bizet’s opera ‘Carmen’ and the Japanese traditional song ‘Sakura’. Participants preferred songs of medium complexity to simple and highly complex tunes. When participants were uncertain about how a song would unfold, they preferred fewer surprises. But if people thought they knew what would happen next in a song, they enjoyed being surprised.
The results support existing theories that in many types of art, intermediate complexity maximizes curiosity and enjoyment.
Gold BP, Pearce MT, Mas-Herrero E, Dagher A and Zatorre RJ: Predictability and uncertainty in the pleasure of music: a reward for learning? J. Neurosci. [Epub ahead of print, 21 October 2019; 0428-19; DOI: https://doi.org/10.1523/JNEUROSCI.0428-19.2019].
Previous studies identified several separate risk factors for stress-induced disorders. The authors of the present study tested whether they could use an integrated approach to predict susceptibility or resilience to social defeat stress (SDS) in mice and whether administration of acetyl-L-carnitine promoted resilience in the SDS paradigm.
Their findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The co-presence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, they provided initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience in the SDS paradigm.
They feel that these results provide the starting point for in vivo models which predict development of neurobiological and behavioral deficits after stress exposure. This approach may lead to novel therapeutic strategies which promote resilience in susceptible individuals.
Nasca C, Menard C, Hodes Gm Bigio B, Pena C, Lorsch Z, Zelli D, Ferris A, Kana V, Purushothaman I, Dobbin J, Nassim M, DeAngelis P, Merad M, Rasgon N, Meaney M, Nestler EJ, McEwen BS and Russo SJ: Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress. Biol. Psychiatry 86 (6): 483-491 (2019).