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The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Background: Phonological working memory is key to vocabulary acquisition, spoken word recognition, real-time language processing, and reading. Transcranial direct current stimulation, when coupled with behavioral training, has been shown to facilitate speech motor output processes, a key component of nonword repetition, the primary task used to assess phonological working memory. In this study, we examined the efficacy of combining overt nonword repetition training with anodal high-definition transcranial direct current stimulation (HD tDCS) to the presupplementary motor area (preSMA) to enhance nonword repetition. Objective: This study investigated whether 20 min of active or sham anodal HD tDCS targeting preSMA concurrently with a nonword repetition task differentially impacted nonword repetition ability. Method: Twenty-eight neurotypical college-age adults (18-25 years; 19 females, eight males, one nonbinary) completed a 20-min nonword repetition training task where they received either active or sham 1-mA anodal HD tDCS to the preSMA while overtly repeating a list of four-, five-, six-, and seven-syllable English-like nonwords presented in a random order. Whole nonword accuracy and error patterns (phoneme and syllable) were measured prior to and following training. Results: Following training, both groups showed a decrease in nonword repetition accuracy. The drop in performance was significantly greater for the active stimulation group compared to the sham stimulation group at the four-syllable nonword length. Discussion: The findings suggest that targeting the speech motor component of nonword repetition through overt training and HD tDCS to the preSMA does not enhance phonological working memory ability.

Pain perception is the consequence of a complex interplay between activation and inhibition. Noradrenergic pain modulation inhibits nociceptive transmission and pain perception. The main source of norepinephrine (NE) in the central nervous system is the Locus Coeruleus (LC), a small but complex cluster of cells in the pons. The aim of this study is to review the literature on the LC-NE inhibitory system, its influence on chronic pain pathways and its frequent comorbidities. The literature research showed that pain perception is the consequence of nociceptive and environmental processing and is modulated by the LC-NE system. If perpetuated in time, nociceptive inputs can generate neuroplastic changes in the central nervous system that reduce the inhibitory effects of the LC-NE complex and facilitate the development of chronic pain and frequent comorbidities, such as anxiety, depression or sleeping disturbances. The exact mechanisms involved in the LC functional shift remain unknown, but there is some evidence that they occur through plastic changes in the medial and lateral pathways and their brain projections. Additionally, there are other influencing factors, like developmental issues, neuroinflammatory glial changes, NE receptor affinity and changes in LC neuronal firing rates. [ABSTRACT FROM AUTHOR]