Circuit-Based Neuromodulation Enhances Delayed Recall Ability in Patients with Mild Cognitive Impairment

Introduction

As the aging population increases, amnestic mild cognitive impairment (AMCl) is receiving more attention. AMCl is seen as an important transitional stage from normal cognitive function to dementia and is a hotspot for studying cognitive dysfunction. Currently, repetitive transcranial magnetic stimulation (rTMS) is considered a promising neuromodulation method for improving cognitive function in AMCl. Existing studies mainly focus on high-frequency or intermittent theta frequency stimulation of specific brain regions such as the dorsolateral prefrontal cortex, parietal lobe cortex, and temporoparietal cortex. However, due to the complexity of the memory process, single-target stimulation may not produce sufficient efficacy, making it necessary to explore more effective stimulation patterns and targets.

Paper Source

This study was completed by many scholars including Ma Jie, Wu Jiajia, and Xing Xiangxin, who are from Shanghai University of Traditional Chinese Medicine Affiliated Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine Rehabilitation Academy, and the Ministry of Education Intelligent Rehabilitation Engineering Research Center for Traditional Chinese Medicine. The study was published in 2024 in the Journal of Neurology, Neurosurgery & Psychiatry.

Research Method

The study is divided into three main stages:

1. Obtain white matter fiber bundle maps of the cortex-hippocampus loop in age-matched healthy volunteers using probabilistic fiber tracking and diffusion tensor imaging (DTI).

2. In AMCl patients, select the cortex-hippocampus loop significantly related to long-term delayed recall ability scores as the target for paired associative stimulation (PAS) based on the loop.

3. Randomly assign AMCl patients to either the loop-based PAS group or the sham PAS group and locate the target loop for each patient. All patients underwent 2 weeks of stimulation treatment.

In the first stage, researchers obtained white matter fiber bundle maps of the cortex-hippocampus loop in healthy elderly people using probabilistic fiber tracking and DTI technology. In the second stage, they evaluated the functional connectivity (FC) between cortex-hippocampus loops and long-term delayed recall ability in AMCl patients, selecting the loop with the highest correlation as the target for loop-based PAS. The third stage involved randomly assigning patients to the loop-based PAS group or the sham PAS group, locating the target loop for each patient, and implementing 2 weeks of stimulation treatment.

During the loop-based PAS, researchers used two liquid-cooled figure-of-eight coils to perform paired stimulation of the left prefrontal cortex and left superior parietal lobule. Each stimulation included a single pulse at 80% of the resting motor threshold to the left prefrontal cortex, immediately followed by a single pulse at 120% of the resting motor threshold to the left superior parietal lobule within 2 milliseconds. Each treatment course included 900 pairs of such paired pulses. For the sham PAS group, even though a sham coil was used that did not produce actual brain stimulation, all other aspects were the same as in the actual PAS group.

Research Findings

The results showed that compared to the baseline and the sham PAS group, the long-term delayed recall scores (AVLT_N5) in the loop-based PAS group significantly improved, increasing from 2.43 (1.43) points at baseline to 5.29 (1.98) points (P=0.003, Cohen’s d=0.97). Additionally, secondary endpoints such as AVLT total score, immediate recall total score, first immediate recall score, delayed cued recall score, and Boston Naming Test score also showed varying degrees of improvement in the loop-based PAS group.

Reanalysis found that the FC value between the left hippocampus and the left superior parietal lobule significantly decreased from baseline to the later stages of treatment in the loop-based PAS group (P=0.013). Using a generalized linear model analysis, it was found that changes in the FC value between the left hippocampus and the left superior parietal lobule were significantly correlated with improvements in AVLT_N5 scores (B=3.4, P=0.017) in the loop-based PAS group, whereas no similar correlation was found in the sham PAS group (P=0.533).

Research Significance

This study proposed a novel neuromodulation method, using individualized FC data to determine the cortex-hippocampus loop as the target and employing a paired stimulation pattern inspired by Hebbian theory, to enhance the long-term delayed recall function in AMCl patients. The results preliminarily confirmed the effectiveness of this method and found that changes in FC between the left hippocampus and the left superior parietal lobule might be the central mechanism for improving long-term delayed recall function in AMCl patients.

The innovations in this study include combining brain structure and function to construct a “hippocampus-cortex” network related to symptoms, which is used as the target for neuromodulation treatment. Additionally, the study introduced a paired stimulation pattern inspired by Hebbian theory, which contrasts sharply with existing single-target stimulation. The results provide new directions and clues for individualized neuromodulation treatment of cognitive impairments like AMCl, potentially advancing clinical practice and policy formulation in this field.

Highlights of the Paper

1. For the first time, a loop-based paired stimulation treatment model was proposed, contrasting sharply with existing single-target stimulation.

2. Combined brain structure and function data to construct a “hippocampus-cortex” network highly related to AMCl symptoms as the treatment target.

3. Innovatively adopted a paired stimulation pattern inspired by Hebbian theory for neuromodulation and preliminarily confirmed its effectiveness in enhancing long-term delayed recall function in AMCl patients.

4. Found that changes in FC between the left hippocampus and the left superior parietal lobule might be the central mechanism for improving long-term delayed recall function, providing new clues for the study of AMCl pathological mechanisms.

5. The results provide new ideas for individualized neuromodulation treatment of cognitive impairments like AMCl and are expected to advance clinical practice and policy formulation in this field.

This study proposed a novel loop-based neuromodulation treatment model and preliminarily confirmed its potential for enhancing long-term delayed recall function in AMCl patients, opening new paths for individualized treatment of cognitive dysfunction.