White matter disorders and their neurobehavioural consequences While initially thought that cortical dysfunctions played a major role in pathodysfunctions, it was noted that lesions to the basal ganglia and thalamus subcortically could disrupt cognition and emotion. White matter connects the grey matter through white matter tracts, which are abundant in myelinated axons. While much of the focus is on grey matter and it's pathology, white matter disorders come with a range of neurobehavioural sequale. Cognitive slowing is a major symptom, forgetfulnesss coupled with personality and affective changes seen in the subcortical dementias. Here, the “fundamental” functions of arousal, attention, motivation, and mood that provide for the timing and activation of cortical processes are disrupted [1]. The spectrum of white matter involvement is diverse. In significant white matter involvement it may involve inattention, executive dysfunction, confusion, memory loss, personality change, depression, somnolence, lassitude, or fatigue: - language is usually normal or only mildly affected because the language-related cortex is spared - white matter contributes to cognitive and emotional functions, and lesions of white matter disconnect these networks to produce neurobehavioral syndromes. Neuropsychologically, there is a sustained attention deficit, executive dysfunction, memory- retrieval deficit, visuospatial impairment, psychiatric dysfunction, and normal language; extrapyramidal function; and procedural memory. Sustained attention deficits, executive dysfunction, and memory-retrieval deficits may be especially salient. These problems are typical in patients with white matter disorders and relate to a slowing of cognition-what is often referred to neuropsychologically as impaired speed of information processing - Neuroanatomically, these disturbances are all closely associated with frontal lobe dysfunction, and most white matter disorders show a predilection for the frontal white matter 1 White matter tracts (Filley) General anaesthesia through volatile anaesthetics has the ability to induce neurotoxicity through white matter disruptions where oligodendrocyte function may be disrupted, coupled with a background of neuroinflammation. Diverse changes, including cognitive impairment are noted where post-operative cognitive impairment can be noted from even breif medically-controlled exposures. In toxic exposures of volatile solvents, eg toluene, toxic leukoencepalopathy can develop with widespread white matter involvement. Toluene primarily affects cortical white matter with associated neuropsychological deficits in processing speed, sustained attention, memory retrieval and executive functioning. In heavy exposures, it is likened to a subcortical dementia, specifically a white matter dementia Diffuse leukoencepalopathy from chronic toluene exposure resulting in dementia (Filley) Volatile anaesthesia affects biologic processes which also are affected in Alzheimer’s disease. Anaesthetics can cause widespread neuronal apoptosis and may alter neurobiological processes by inducing apoptosis and Aβ formation 2 Hope for recovery? Ketogenic interventions have been implemented in cognitive impairment, where ketone uptake into white matter tracts predicts cognitive improvement, particularly related to cognitive processsing speed. As ketone levels are directly correlated to cognitive processing speed and functional connectivity, along with neurorestorative aspects (eg. neurotrophic, remyelination) they seem to be a promising intervention therapeutically. 3 Efforts to promote cognitive recovery in brain injuries have been centred around improving levels of consciousness and increasing complexity eg amantadine for ABI (zolpidem, ketamine etc have been proposed to enhance brain complexity in disorders of consciousness) or modulating neurotrophic pathways. Other symptomatic treatments have been suggested, eg pharmacologically addressing cognitive processing speed with psychostimulants eg methylphenidate. Remyelinating therapies and specifically targeted myeloprotection have been suggested as therapeutic options. There is no consensus across randomised control studies in order to support recommendation of a specific diet or dietary component for remyelination. "An ideal therapeutic strategy would be both anti-inflammatory and would enhance neural repair with minimal side effects" Repair usually occurs by promoting the secretion of neurotrophins (NGF, BDNF) which can promote oligodendrocyte precursor cell proliferation and repair of the nervous system. Natural products have the potential to increase the survival rate of neural stem cells and promote the differentiation of neural stem cells into oligodendrocytes, which promotes the formation of myelin sheath, then contributing to remyelination. Remyelination could potentially be facilitated by the modulation of the inflammatory environment and glutathione/redox regulation have a critical role in myelination processes and white matter maturation. Voluntary exercise can promote both neuroprotection and neuroregeneration Fasting/calorie restriction resulted in more complete remyelination Omega-3 PUFAs were demonstrated to promote, in vivo, the expression of myelin-related 4 proteins Vitamin D3 supplementation decreases the magnitude of white matter demyelination Dietary polyphenols could mitigate demyelination by modulating the immune response, limiting demyelination, reducing neuroinflammation, and downregulating immune functions Ensuring diet contains plenty of B vitamins, Vitamin E and choline may help Spirulina promoted white matter regeneration, C-Phycocyanin and Phycocyanobilin having a potent remyelinating action Some natural products with proposed myelo-restorative actions include: - H. erinaceus had a regulatory effect on the process of myelin genesis - Hesperidin - Diosgenin - 18β - Glycyrrhetinic acid and glycyrrhizic acid directly enhanced remyelination rather than via immunomodulation. It is proposed to be an anti-inflammatory and neural repair agent, especially at later stages when when axonal damage and neuron loss have already occurred - Scutellarin - Cannabidiol - Matrine - Icariin - Resveratrol - Oligomeric proanthocyanidin reduced demyelination and increased expression of myelin basic protein whilst inhibiting inflammatory factors Anything that strongly reduces inflammation generally helps promote subsequent myelination in the white matter. Melatonin is one effective option. A mixture of anthocyanins and phenolics promotes myelination in a rodent in vitro model Intriguing once again is spirulina, this is being pre-clinically studied for multiple conditions such as MS. It is not only anti-oxidative, neuroprotective etc but also modulated the expression of genes related to remyelination, gliogenesis and axon-glia processes. Also re- jigs the damaged dopaminergic systems, helps tame microglial activation, oxidative stress etc in one study. Upping things like flavonoids like quercetin could remarkably improve both cognition performance and myelination in the context of induced brain injury by promoting the 5 proliferation of oligodendrocyte progenitor cells and strengthening survival of oligodendrocytes in vivo Diosgenin is also really promising, diosgenin can promote oligodendrocyte progenitor cell differentiation and accelerate remyelination. It dose-dependently reduced central nervous system inflammation and demyelination. We also found that diosgenin treatment can significantly inhibit the activation of microglia and promote remyelination. Diosgenin-rich yam extract treatment appeared to safely enhance cognitive function in healthy adults. References: [1] The behavioral neurology of white matter. Christopher M. Filley. — 2nd ed. [2] https://doi.org/10.1038/s41598-020-66122-6 [3] http://dx.doi.org/10.2174/1871527322666230508123558 6