A mouse model of oxycodone reward following its oral self-administration in a sweetened solution.

According to the World Health Organization, more than 50 million individuals were living with dementia in 2019; this number is expected to increase to 139 million in 2050 (). The financial burden associated with dementia is also likely to more than double from the US$1.3 trillion per year recorded in 2019 to US$2.8 trillion by 2030 (). Neurocognitive disorders, including mild cognitive impairment (MCI) and dementia, are a challenge not only for those affected but also for their families. Because of a set of cognitive impairment-related symptoms involving both functional decline and increased dependency, caring for individuals with dementia and cognitive impairment is associated with a high financial and care burden. Family caregivers are required to care for individuals with dementia and handle unexpected situations such as behavioral problems and changes in patient characteristics; studies have indicated that in general, 57% of unpaid caregivers of individuals with Alzheimer disease (AD) provide care for an average of 9 h per day over ≥4 years (; ). As dementia progresses, each instance of a decrease in physical activity function can result in nearly 5 additional hours of monthly caregiving. Caregivers often experience increased care burdens, stress, and negative emotions or mental health problems (eg, depression) due to the duration of care (). In consideration of this, effective intervention strategies that mitigate dementia progression and alleviate the major physical and psychological problems related to the caregiving process must be identified. Scientific and medical advancements have enabled research on novel, innovative technological care models. For example, noninvasive brain stimulation (NIBS) techniques can be used to induce neuronal plasticity in the brain through the modulation of cortical neuron excitability (). Non-invasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), rTMS induces neuronal firing through repetitive magnetic pulses (), whereas tDCS alters resting membrane potentials using weak direct electrical currents (; ). Through long-term potentiation (LTP)- and long-term depression (LTD)-like mechanisms, both approaches have demonstrated potential benefits for memory and cognitive function in individuals with cognitive impairment. Compared with tDCS, rTMS directly evokes neuronal activity and may produce more focal neuromodulatory effects, whereas tDCS primarily modulates neuronal excitability in a simpler and more portable manner (; ; ). Although a meta-analysis revealed that NIBS efficacy in 6 cognitive domains of patients with Parkinson disease (PD) may be limited (), another meta-analysis reported that rTMS and tDCS significantly improved memory functions in patients with mild cognitive impairment (MCI), with rTMS having a more substantial effect than that of tDCS (). In addition, in their meta-analysis, Teselink et al. reported that NIBS techniques significantly improve global cognition but that most subgroup analyses on their cognitive function effects have focused on rTMS and patients with AD, without considering tDCS or patients with MCI (). In total, 11 meta-analyses on the effects of rTMS in patients with AD have reported significant improvements in global cognitive function (; ; ; ; ; ; ; ; ; ; ). Only one study revealed no significant improvement in cognition, as measured using the Mini-Mental State Examination (MMSE) (). Three meta-analyses on the effects of tDCS in patients with AD indicated a significant improvement in overall cognition (; ; ). One study, however, reported that these effects did not remain significant over the long term (). In general, clinical trials have provided inconsistent results with respect to the effects of NIBS techniques on cognitive outcomes in patients with AD. NIBS techniques may also be used in combination with various nonpharmaceutical modalities, such as cognitive training (CT) and aerobic exercise, to achieve a synergistic effect. CT involves a set of standard tasks designed to reflect specific cognitive functions involving cognitive domains such as memory, attention, and executive processing, with the tasks tailored to an individual’s level of ability (). It can be delivered to an individual or group, with training on pencil and paper or through the Internet (). A meta-analysis focused on NIBS combined with CT revealed a significant positive short-term effect of tDCS combined with CT in patients with MCI and AD (). Another meta-analysis on NIBS combined with CT reported a significant positive immediate effect of rTMS combined with CT in patients with MCI and AD on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and MMSE; over the follow-up period, the positive effect was retained on the ADAS-Cog but not on the MMSE (). Thus, additional controlled studies providing robust, evidence-based insights into the effec