Postoperative Cognitive Dysfunction (POCD) is a highly prevalent condition with
significant clinical, social, and financial impacts for patients and their communities.
Postoperative (PO) cognitive impairments have generally been divided into short- and
long-term disturbances. Delirium, a short-term disorder, is defined according to the
Diagnostic and Statistical Manual of Mental Disorders V (DSM-V) as impairment in
attention, awareness, and cognition, fluctuating throughout the day and affected by
endogenous and exogenous factors. It has an incidence of 37-46%, differing depending on
the type of surgical procedure performed, with reports of up to 51%. In contrast, the
term POCD has been used to refer to any new signs of cognitive impairment that exceed the
expected time for recovery from the acute effects of surgery and anesthesia, being
considered long-term. Among hospitalized PO patients aged 60 years or older, rates of up
to 40% have been observed. Considering the aging population linked to a growing demand
for surgery, identifying factors that increase the risk of POCD is necessary, as age is
the biggest risk factor. Mild Cognitive Impairment (MCI) is one of the main risk factors
and is defined as cognitive decline from a previous level of performance in one or more
cognitive domains (complex attention, executive function, learning and memory, language,
perceptual-motor, or social cognition), based on the concern of the individual,
caregiver, or clinician. However, these changes do not interfere with the ability to be
independent in daily activities. The conversion rate from MCI to dementia is 10 to 15%
per year, regardless of any possible influence from anesthesia and surgery. However,
there is evidence that anesthesia and surgery may exacerbate the pathological mechanisms
of Alzheimer's disease, which could potentially increase this conversion rate.
Pre-existing brain, heart, or vascular diseases, low educational levels, and alcohol use
are also frequent risk factors. Iatrogenic factors also seem to contribute to POCD. Some
articles speculate that POCD in the elderly is attributable to the use of benzodiazepines
(BZDs) and anticholinergics (ACs), while others suggest that POCD is independent of the
type of surgery or anesthesia used and would result from pre-existing brain fragility.
Although a transient fluctuation in cognition during the postoperative period is often
not considered concerning, it is important to note that POCD predicts the onset of future
dementia and may contribute to chronic neurodegeneration, particularly with repeated
surgical procedures.PO cognitive changes can clearly lead to a loss of autonomy in the
elderly, prolong hospital stays, generate high medical costs, and increase mortality,
making it a serious health and social problem that cannot be ignored. Current theories on
the underlying mechanisms of POCD highlight the role of inflammation and immune
activation. Surgery itself induces inflammatory processes, localized and systemic
expression of pro-inflammatory cytokines, and signaling molecules. Tissue damage after
surgery triggers the release of IL-1 and TNF- from endothelial cells and phagocytes,
whose elevated levels induce the production of IL-6, increasing the extent of tissue
trauma and triggering a cascade of events. The formed inflammatory cascade and cytokine
release reach the central nervous system and have a direct relationship with the
hippocampus. This brain region contains the highest number of cytokine receptors, has the
highest density of IL-1 receptors, and although physiological levels of this cytokine are
essential for optimal memory and learning processes in the hippocampus, excessive levels
have been associated with decreased cognitive function in animal models. The hippocampus
seems especially vulnerable to the harmful effects of systemically elevated inflammatory
mediators due to the high density of TNF- receptors and numerous other receptors on the
surface of endothelial cells in this brain region. The mechanism underlying impaired
learning and memory resulting from excessive levels of IL-1 and other inflammatory
mediators in the hippocampus involves harmful effects on long-term potentiation (LTP) and
neurogenesis in this brain region, as demonstrated in several animal models. The
cognitive reserve is a protective factor for the development of PO cognitive changes and
that its increased levels are strongly protective for the incidence of dementia;
including higher levels of education, greater occupational complexity, premorbid IQ, and
a preference for mentally stimulating leisure activities. Studies in cognitively healthy
humans have also shown that physical exercise improved global cognition and was
associated with increased gray matter volume, while cognitive exercise was associated
with reduced memory loss. Non-invasive brain stimulation (NIBS) techniques are widely
used in research and clinical practice, involving the modulation of brain excitability
and activity, which can increase or decrease depending on the parameters used, such as
transcranial magnetic stimulation (TMS). Numerous in vitro and in vivo experimental
models provide evidence that repetitive TMS (rTMS) can enhance long-term potentiation
(LTP). LTP is a lasting increase in signal transmission between two neurons resulting
from synchronous stimulation. It is one of several phenomena contributing to synaptic
plasticity. Memory is thought to be encoded by modifying synaptic strength, so LTP is
widely considered one of the main cellular mechanisms underlying learning and memory.
These improvements in neural plasticity are observed alongside enhanced performance on
hippocampal-dependent cognitive measures. The fundamental basis for brain function is
brain oscillations in various frequency ranges. Several studies provide evidence
supporting the idea that modulating specific frequency oscillations can alter cognition
in healthy individuals. Additionally, rTMS has been used to improve cognitive function
through the same mechanism. Particularly, several studies suggest that focal rTMS may
promote the alteration and synchronization of human brain oscillations and reveal changes
in cognition. According to Hoy and colleagues, neural synchrony refers to the coordinated
firing of connected brain regions, which is considered essential for the integration of
neural networks and cognitive performance. In other words, rTMS may be an effective
oscillatory alteration approach with the potential to improve specific cognitive
functions such as attention and perception. New forms of rTMS have recently been
developed, including Theta Burst Stimulation (TBS), a new accelerated form of stimulation
that more closely mimics the brain's natural firing patterns and may have greater effects
on cognitive performance. TBS sessions usually last only 3-10 minutes, compared to
conventional rTMS sessions. Faster daily treatments with TBS can allow for increased
treatment capacity and reduced costs per session. Improvements in cognitive function
using intermittent Theta Burst (iTBS) compared to those using traditional rTMS have been
found and may be due to endogenous oscillations. It is important to note that theta and
gamma bands have been linked to working memory processes. Oscillations play a critical
role in integrating the different brain regions necessary for working memory, with
synchronous activity between prefrontal and posterior parietal regions associated with
successful working memory encoding. Current findings are promising, revealing a more
substantial effect of iTBS compared to the best conventional rTMS protocol investigated
so far. These findings indicate that iTBS may be a more suitable and accelerated protocol
for cognitive promotion in patients diagnosed with cognitive deficits related to diseases
such as Alzheimer's disease and vascular cognitive impairment. However, further
patient-based studies with cognitive deficits are needed to explore the effects of iTBS
on cognition in real-world settings and different patients. Therefore, the goal of this
project is to explore new approaches to postoperative cognitive dysfunction, focusing on
its prevention using brain magnetic stimulation techniques. So far, no pre- and
postoperative intervention studies have shown robust results in preventing this clinical
condition.