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Mandeep Kaur,1 Marsal Sanches2 1Department of Behavioral Medicine, Cone Health, Greensboro, NC, USA; 2UT Health Center of Excellence on Mood Disorders, Faillace Department of Psychiatry & Behavioral Sciences, McGovern Medical School, Houston, TX, USACorrespondence: Mandeep KaurGeneral, Child and Adolescent Psychiatrist Department of Behavioral Medicine, Cone Behavioral Health Hospital, 700 Walter Reed Drive, Greensboro, North Carolina, 27410, USATel +1 (713) 540-2469Email mandy.drmandeep@gmail.comAbstract: Treatment-Resistant Depression (TRD) patients remain a challenging sub-division of patients with Major Depressive Disorder (MDD) in day to day clinical practice. As with any diagnostic condition, comprehensive evaluation, exclusion of other psychiatric conditions, assessment of co-morbid medical and psychiatric illnesses and psychosocial stressors are the keys to appropriate diagnosis and subsequent management. There are various management options available for the treatment of MDD, however, about 30% of the patients fail to achieve full remission of symptoms despite multiple trials and belong to this sub-category of MDD. This article brings forth discussion of other non-conventional medication and non-medication treatment alternatives that merit exploration of their efficacy in TRD. Many of the proposed novel medications and other treatment modalities such as Deep Brain Stimulation, exercise, yoga are already used for other medical and psychiatric disorders and have some evidence suggesting their potential benefits in TRD in conjunction with conventional medications or even as monotherapy. Nevertheless, more research is needed in this direction to establish effectiveness.Keywords: major depressive disorder, treatment-resistant depression, anti-depressants, pharmacology, deep brain stimulation, HPA axis, psychedelic agents

Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)—a tract important to induce PAS-LTP—were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]