Use of Transcranial Magnetic Stimulation in the Post-Operative Cognitive Dysfunction in Elderly

Postoperative Cognitive Dysfunction (POCD) is a prevalent condition with significant clinical, social, and financial impacts on patients and healthcare services. The term POCD refers to any signs of new cognitive impairment that exceed the expected time for recovery from the acute effects of surgery and anesthesia. Mild Cognitive Impairment (MCI) is among the main risk factors and is defined as a small cognitive decline from the previous level of performance in one or more cognitive domains, without interfering with daily activities. Considering the aging population linked to an increase in the number of individuals with MCI and a growing demand for surgery, the identification of interventions that can prevent the occurrence of POCD is necessary. Non-invasive brain stimulation (NIBS) techniques such as TMS (Transcranial Magnetic Stimulation) are widely used in research and clinical practice and involve the modulation of excitability and brain activity, potentially improving the individual's cognitive performance. The aim of this study is to assess the efficacy of a Theta Burst rTMS protocol with few sessions in preventing postoperative cognitive dysfunction in elderly individuals with mild neurocognitive disorder. Methodology: This will be a randomized, blinded clinical trial with volunteers aged \> 60 years, candidates for elective surgeries, who will be randomly allocated into 2 groups: the groups will receive real or sham TBS 15 days before surgery. There will be 3 intervention sessions, with a 72-hour interval between them. Outcome measures will be cognitive psychological assessment and Stroop Test cognitive task performance before and after transcranial magnetic stimulation, after surgery and at the 3-month follow-up. There will be a non-surgical control group with cognitive impairment according to the study inclusion criteria and will receive active stimulation.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Patients over 60 years old
2. Patients scheduled for elective surgeries of moderate or large scale and candidates for general or spinal anesthesia;
3. Patients who demonstrate possible or probable cognitive impairment based on pre-operative screening using the 10-CS (10-point cognitive screening) tool; - For Non-surgical Control Intervention Group, only the first and third criteria will be applied.

Exclusion Criteria:

1. Contraindications for the use of Transcranial Magnetic Stimulation (metal implants in the head, history of seizures or epilepsy, brain trauma or surgery, intracranial hypertension, and complications from exposure to magnetic fields);
2. Medical diagnosis of Major Neurocognitive Disorder (any form of dementia, regardless of the stage);
3. Indication for skull surgery;
4. Conditions that interfere with cognitive testing (presence of severe hearing and vision loss, inability to understand Portuguese);
5. Ongoing medication adjustments that affect cortical electrical activity (antidepressants, antipsychotics);
6. Difficulty attending treatment during the stipulated evaluation and follow-up period, whether due to socioeconomic or clinical reasons;
7. Anticipation of surgical scheduling;