Ketamine is a promising alternative to traditional pharmacotherapies for major depressive disorder, treatment-resistant depression, and other psychiatric conditions that heavily contribute to the global disease burden. In contrast to the current standard of care medications for these disorders, ketamine offers rapid onset, enduring clinical efficacy, and unique therapeutic potential for use in acute, psychiatric emergencies. This narrative presents an alternative framework for understanding depression, as mounting evidence supports a neuronal atrophy and synaptic disconnection theory, rather than the prevailing monoamine depletion hypothesis. In this context, we describe ketamine, its enantiomers, and various metabolites in a range of mechanistic actions through multiple converging pathways, including N-methyl-D-aspartate receptor (NMDAR) inhibition and the enhancement of glutamatergic signaling. We describe the disinhibition hypothesis, which posits that ketamine’s pharmacological action ultimately results in excitatory cortical disinhibition, causing the release of neurotrophic factors, the most important of which is brain-derived neurotrophic factor (BDNF). BDNF-mediated signaling along with vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) subsequently give rise to the repair of neuro-structural abnormalities in patients with depressive disorders. Ketamine’s efficacious amelioration of treatment-resistant depression is revolutionizing psychiatric treatment and opening up fresh vistas for understanding the underlying causes of mental illness.

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.

The human brain is an extraordinarily complex organ responsible for all aspects of cognition and control. Billions of neurons form connections with thousands of other neurons, resulting in trillions of synapses that create a vast and intricate network. This network is subjected to continuous remodeling that adapts to environmental and developmental changes. The resulting neuroplasticity is crucial to both healthy states and many forms of mental illness and neurodegeneration. This narrative review comprehensively examines N,N-dimethyltryptamine (DMT), a naturally occurring hallucinogen and psychedelic compound, focusing on its implications in promoting neuroplasticity via neuritogenesis. We examine DMT’s pharmacology, including its interaction with serotonergic, sigma-1, and trace amine-associated receptors and their associated signaling pathways. The therapeutic potential of DMT in both animal models and clinical trials is discussed with impacts on perception, cognition, emotion, and consciousness. We uniquely focus on current directions centered on unveiling the direct mechanisms of DMT’s therapeutic effects that demonstrate transformative effects on mental well-being, particularly for conditions like depression, anxiety, and post-traumatic stress disorder. We discuss the connection between DMT and neuroplasticity, offering the potential for forming new neural connections, improving learning, memory, and aiding recovery from brain injuries, including neurorehabilitation and neuroregeneration. The ultimate potential of DMT’s therapeutic efficacy to enhance neurogenesis, especially for neurodegenerative conditions, is also discussed.

Objectives: Transcranial alternating current stimulation (tACS) can enhance primary motor cortex (M1) excitability and improve motor skill when delivered unilaterally to the dominant hemisphere. However, the impact of tACS on contralateral M1 excitability both during and after application has not been studied. The purpose of this study was to examine the effects of tACS delivered to the dominant left M1 on the excitability of the unstimulated contralateral non-dominant right M1. Methods: This study implemented a double-blind, randomized, SHAM-controlled, within-subjects, crossover experimental design. Eighteen young adults completed a tACS condition and a SHAM condition on two different days in counterbalanced order with a week washout period between days. Transcranial magnetic stimulation (TMS) was utilized to assess excitability of the contralateral right M1 while tACS was delivered to the left M1. TMS was administered in five test blocks (termed Pre, D5, D10, D15, and Post) relative to a 20 min application of tACS (70 Hz, 1 mA current strength). The Pre and Post TMS test blocks were conducted before and immediately after tACS was applied to the left M1, whereas the TMS test blocks performed during tACS were completed at time points starting at the 5, 10, and 15 min marks of the 20 min stimulation period. The primary dependent variable was the 1 mV motor evoked potential (MEP) amplitude. MEP data were analyzed with a 2 condition (tACS, SHAM) × 5 test (Pre, D5, D10, D15, Post) within-subjects ANOVA. Results: The main effect for condition (p = 0.704) and condition × test interaction (p = 0.349) were both non-statistically significant. There was a significant main effect for test (p = 0.003); however, post hoc analysis indicated that none of the pairwise comparisons were statistically significant. Conclusions: Overall, the findings indicate that tACS applied to the left M1 does not significantly modulate contralateral right M1 excitability during or immediately after stimulation, at least when utilizing the present tACS parameters.

Background: Transcranial direct current stimulation (tDCS) applied unilaterally to the cerebellum (c-tDCS) can improve several aspects of human motor performance. The purpose of the study was to examine the influence of dual source tDCS delivered bilaterally over the cerebellar cortices (dsc-tDCS) on the time to task failure (TTF) of a fatiguing contraction in young adults. Methods: The study utilized a double-blind, randomized, SHAM-controlled, within-subjects, crossover design, and participants were given either dsc-tDCS or SHAM stimulation in two different experiments held 7 days apart in a fully counterbalanced order. Every aspect of the two experiments was the same except the type of stimulation (dsc-tDCS or SHAM) delivered during the fatiguing contraction. The fatiguing contraction was executed with a precision grip at 15% of the maximum voluntary contraction (MVC) force, and participants were instructed to maintain the contraction for as long of time as possible. Results: The TTF and fatigue index were both similar for the dsc-tDCS and SHAM stimulation conditions. In addition, the electromyographic (EMG) activity, force error, and standard deviation (SD) of force measured during the fatiguing contraction were also not statistically different between the dsc-tDCS and SHAM stimulation conditions. Conclusions: The findings suggest that dsc-tDCS does not decrease the rate of progression of muscle fatigue.