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. 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.         
melatonin 
oxytocin

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

 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, 0.1% w/w), ameliorated 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 (which 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)

Future Directions (half page) (fig3)

Many potential therapeutic treatments for ALS that reach the clinical trial stage, fail to demonstrate clinical efficacy using the ALSFRS-R scale, which quantifies respiratory and motor function.

Conclusions (10-15 lines)

Acknowledgements:

The author wishes to express her gratitude for the kind reading and discussion of the manuscript with Dr. Manoj Kumar Jaiswal.  

Conflicts of Interests:

The author declares that no competing interests exist and warrants that there are no financial or personal interests, motivations or affiliations that would potentially cause a conflict in the judgments and opinions expressed in this chapter review.  The views and opinions expressed herein do not necessarily reflect the views and opinions of the James J. Peters VA Medical Center or the Icahn  School of Medicine at Mount Sinai. This work is original, non-redundant and has not been duplicated or published elsewhere.

Author Contributions:

This manuscript was conceived, drafted and written exclusively by Pasha Apontes.

Abbreviations:

ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; FTD, frontotemporal dementia; transactive response DNA-binding protein gene;  TDP-43, Transactive response DNA-binding protein 43; CTD, C-terminal domain (CTD); NTD, N-terminal domain; NLS, nuclear localization signal; fALS, familial amyotrophic lateral sclerosis; sALS sporatic amyotrophic lateral sclerosis; DSB, double strand break;  RRMI and RRM2, RNA recognition motifs 1 and 2, respectively.