Thalamocortical Physiological disturbances in sleep and TDP-43
Disruption of normal sleep oscillations, such as cortical slow oscillations, hippocampal ripples and thalamocortical spindles impairs declarative memory and memory consolidation \cite{Salfi2020} . The elderly and patients diagnosed with neurodegenerative disorders, such as ALS, are particularly prone to sleep disruptions. 
C9of72 is a ubiquitously expressed protein in the brain that contains a hexanucleotide sequence which, in 95% of people without neurodegenerative disease, occurs less than 11 times, whereas it is expanded to greater than 30 times in a large number of patients with ALS and FTD with TDP-43 pathology (FTD-TDP), curiously, only in Europe and North American but not Asia \cite{Balendra_2018}. detected in 50% of fALS, 10% of sALS and 25% of patients with   \cite{Dedeene2019} . The C9orf72 expansion is also involved in p-TDP-42 and dipeptide repeat protein (DPR) inclusions \cite{Dedeene2019}.  From the C9orf72 expansion region, translation occurs that is not started at the ATG codon (called repeat-associated non-ATG,RAN ), producing five known types of DPRs (poly-GA, poly-GR poly-PR poly-AP and poly-GP) of which two are the particularly implicated in neurotoxicity (Poly-GR and poly-PR)  \cite{Gittings_2019} .  
In patients with rapid eye movement sleep disorders, including TDP-43opathies, such as FTD and ALS, the G4C2 C9orf72 repeat expansion may be involved. The suprachiasmatic nucleus (SCN) (in the hypothalamus) and the pineal gland, which synthesizes melatonin and serves as the main executor of the SCN, are two principle brain regions that govern circadian sleep/wake cycles. The SCN suppresses or stimulates the pineal synthesis of melatonin according to the light/dark cycle, leading to a decreased or increased tendency to sleep \cite{Dedeene2019}.   In pinealocytes and SCN neurons from C9orf72 cases,  DPR inclusions were numerous, while pTDP-43 pathology was not observed  \cite{Dedeene2019} . However, in Drosophila, in a comparison between flies expressing either wild type or mutant variants of TDP-43 in motor neurons or glia, total sleep is decreased in TDP-43 mutant variants, while ALS-linked mutant TDP-43 variants have more frequent sleep bouts \cite{Estes_2013}, which seems to implicate TDP-43 in sleep aberrations, although perhaps in brain regions other than the primary regions that regulate the sleep cycle (SCN and pineal). Interestingly, it was recently reported that targeting the poly-GR of the C9orf72 gene with antisense oligonucleotides suppressed aberrant poly-GR gain-of-function and inhibited cytoplasmic TDP-43 aggregate formation in stress granules as well as neurodegeneration in a C9orf72  ALS transgenic mouse model which has a number of behavior disturbances, including hyperactivity and anxiousness \cite{Chew2015}.  In a behavioral disorder that occurs during sleep, patients with Rapid eye movement (REM) sleep behavior disorder (RBD) present with vocalizations and sometimes injurious or violent behaviors while sleeping, and, although rare, have nearly a 90% risk of developing a neurodegenerative disorder, predominantly PD, and RBD has been treated with low-dose clonazepam or high-dose melatonin taken at bedtime  \cite{Howell_2015}
 Dietary molecular interventions: Ketone Bodies and Medium Chain Triglycerides (MCT)
It has been reported that in ALS there is a decrease in energy uptake  \cite{Ahmed2016} while energy expenditure is increased  \cite{Bouteloup_2009} leading to imbalances in energy supply and demand, metabolic failure, and neuronal cell death  \cite{Vandoorne2018} . Additionally, several mitochondrial respiratory-chain complexes have been shown to be decreased in AD, HD and PD brain tissue \cite{Pathak2013}. It has also been proposed that underlying many neurological diseases are metabolic deficiencies which lead to the degeneration of susceptible neuronal subtypes (such as long range projection neurons,  CA1 with high firing rates Fast-Fatigable motor neurons with large axons)  as well as glia and vasculature cells \cite{Muddapu2020}, beginning in subcortical regions (e.g. striatal,  hippocampal or spinal motor neurons, varies depending on disease) and ultimately processing the cortex \cite{Zhou2012}.    

Complementary and alternative medicine (CAM) approaches for the treatment of ALS

N-acetylcysteine (NAC)
 Mucuna pruriens (common name Velvet Bean) and Withania somnifera (common name  Ashwagandha )
Two Ayurvedic medicines in widespread use, Mucuna pruriens (Mpe) and Withania somnifera  (Wse), have reported utility in the treatment of neurodegenerative diseases  \cite{Maccioni2018}\cite{Katzenschlager2004}\cite{Dar2015}.  In a partial TDP-43 protein depletion Drosophila model of ALS (achieved through the GAL4-Upstream Activation Sequence system in which knockdown TAR DNA-binding protein-43 homolog was targeted in motoneurons), both  Mpe and Wse (supplemented in food at 0.1% w/w) ameliorated ALS associated disease phenotypes. Mpe and Wse improved the hyperactive anomalies in ambulation and climbing behavior, dysregulated sleep (in two age cohorts, 3–6 or 10–15 day-old male flies), and corrected evoked post-synaptic potential (ePSP) following electrical stimulation of the dorsal longitudinal muscle (DLM) neuromuscular junction in TDP-43 mutant flies and the mutant flies showed a significant decrease in amplitude and an increase in latency  \cite{Maccioni2018}.  
 IMS-088 by ImStar Therapeutics is an Wse analogue,
Huolingshengji Formula (HLSJ) Clinical 200 ml, p.o., 12 weeks (explain briefly)
Dihuang Yinzi (DHYZ):  Clinical Decoction, p.o., twice daily, 12 years Dihuang Yinzi, a Classical Chinese Herbal Prescription, for Amyotrophic Lateral Sclerosis: A 12-Year Follow-up Case Report (Cai & Yang, 2019)⁠
Berberine may have therapeutic value in ALS. Berberine is an mTOR inhibitor that increases autophagy. As autophagy is the major mechanism by which pathogenic TDP-43 aggregates are removed from the cell, it has been proposed as a possible target for ALS. (Chang et al., 2016)
Standard of Care medications
Edaravone (MCI-186, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan)
Edaravone is a free radial scavenger that has been approved for the treatment of acute cerebral infarction in 2001 \cite{Takei_2017}.  Yoshino et al conducted a six month open-label study of edaravone at two doses (30 mg, n=5 and 60mg n=15) by IV drip once daily \cite{Yoshino_2006}. This study concluded that edaravone shows potential in slowing ALS progression based upon the primary endpoint of change in ALSFRS-R score and the secondary endpoint of 3-nitrotyrosine (3NT) in the cerebrospinal fluid (CSF). However, in the first placebo-controlled, double-blind study that was designed to evaluate edaravone for efficacy and safety, conducted over a 36-week period (with a 12 week pre-treatment observational period to include only patients with an ALSFRS-R score that changed by -1 to -4),  was not able to demonstrate that edaravone was efficacious for ALS \cite{Abe_2014}.  Yet, in a 24-week intervention trial, Abe et al reported that there was a decrease in the progressive decline in ALS based on the ALSFRS-R in the patients receiving edaravone (−5.70 ± 0.85, n=102) compared to those receiving the placebo, showing edaravone's superiority ( −6.35 ± 0.84, n=104), while the adverse events were similar between the edaravone and placebo groups. The second phase-3 trial (NCT01492686 ) was conducted based on the inclusion criteria that identified, through post-hoc analysis of the Abe study,  a potential sub-population of patients that may benefit from edaravone treatment \cite{Takei2017}.
 Riluzole  
Riluzole, the first FDA-approved medication for ALS, is an anti-glutamatergic compound belonging to a class of medicines called benzothiazoles \cite{Lacomblez_1996}\cite{Jaiswal_2018}.  Lacomblez et al. reported that riluzole has  neuroprotective activity and that it prolonged survival in patients in a dose dependent manner, but with the best cost/benefit ratio afforded to those receiving 100mg/day vs placebo (HR 0·55, 95% CI 0·36–0·83; log-rank p=0·037). In a retrospective analysis, it was determined that the prolongation of survival in ALS with riluzole was derived with treatment in ALS stage 4, a late disease stage, just before death (stage 5) in which there is dysphagia-induced weight loss, and nutritional and respiratory failure \cite{Fang_2018}.