Clinical study of different modes of repetitive transcranial magnetic stimulation in the treatment of post‑stroke executive dysfunction

TIAN Geng‑run, WANG Shi‑yan, BI Ying‑li, GONG Zun‑ke✉, WANG Xiang,WANG Mi, LU Si‑han, ZHOU Hui

1.The Second Clinical School, Xuzhou Medical University, Xuzhou 221000, China

2.Rehabilitation Department, Xuzhou Central Hospital, Xuzhou 221000, China

3.Department of Neurological Rehabilitation, Xuzhou Rehabilitation Hospital, Xuzhou 221000, China

Keywords:

ABSTRACT Objective: To investigate the clinical efficacy of intermittent theta burst stimulation(iTBS) and high frequency repetitive transcranial magnetic stimulation (rTMS) on post‑stroke executive impairment(PSEI).Methods: Ninety patients with PSEI who were hospitalized in the rehabilitation department of Xuzhou Central Hospital and Xuzhou Rehabilitation Hospital from April 2021 to June 2022 were selected and divided into iTBS group, high‑frequency group and control group.All three groups of patients received routine rehabilitation training, given rTMS treatment with iTBS, 10 Hz and shame stimulation for 4 weeks.Before and after treatment,all the patients were evaluated with the Montreal cognitive assessment (MoCA), the frontal assessment battery (FAB), troop color‑word test (SCWT), shape trails test (STT), digit span test (DST) and event related potential P300.Results: After treatment, MoCA, FAB, SCWT,STT, DST scores, P300 latency and amplitude were significantly better in the three groups than before treatment (P<0.05).MoCA, FAB, SCWT, STT‑B, DST scores, P300 latency and amplitude in the iTBS group and high‑frequency group were better than in the control group,with significant differences (P<0.05).The difference between iTBS group and high‑frequency group was not statistically significant(P>0.05).Conclusion: iTBS can improve PSEI, and the efficacy is comparable to 10Hz rTMS.iTBS takes less time with better efficiency, and it is worth popularizing and applying in clinic.

1.Introduction

Post‑stroke cognitive impairment (PSCI) is one of the most common dysfunctions after stroke, including attention, memory,executive, verbal and visuospatial sub‑domains, of which executive function is one of the core cognitive domains[1].Executive function has been shown to be strongly associated with independence in stroke patients and to be an independent predictor of prognosis[2].Currently, post‑stroke executive impairment (PSEI) rehabilitation methods are less studied and less effective, and further research is needed[3].Repetitive transcranial magnetic stimulation (rTMS), a non‑invasive neuromodulation technique, has been proven to be effective in the field of the field of neurological and psychiatric rehabilitation, and is widely used in the rehabilitation of PSCI.rTMS combined with cognitive function training can improve executive function in stroke patients[4].However, conventional rTMS treatment is time‑consuming and patient compliance is poor.Intermittent theta burst stimulation (iTBS) is a newer treatment mode of rTMS, which has the advantages of high efficiency, short time consuming, and closer to the physiological rhythm of the central nervous system, and can induce more lasting excitability changes in the brain with shorter time, and regulate neuroplasticity more effectively[5].Studies have found that iTBS is effective in improving cognitive function in stroke patients[6], but there is a lack of refined studies on the treatment of PSEI.Therefore, in this study, iTBS and 10 Hz rTMS were used to treat PSEI to compare the difference in efficacy and to provide a basis for optimizing the clinical treatment plan of rTMS for PSEI.

2.Objects and Methods

2.1 General Information

Ninety patients with PSEI who were hospitalized in our hospital from April 2021 to June 2022 were selected for this study.Inclusion criteria: (1)conformed to the Chinese Medical Association criteria for diagnosis of cerebrovascular disease 2019[7]; (2)first attack,unilateral cerebral hemisphere stroke, all confirmed by imageology(CT or MRI); (3)age 35‑75 years, 2 weeks to 6 months post‑stroke,stable condition; (4) Montreal cognitive assessment scale (MoCA)and frontal assessment battery (FAB), with MoCA <26 and FAB<12 indicating executive impairment[8]; (5)no aphasia and able to complete the cognitive scale; (6)patients gave informed consent to the study and signed the informed consent form.Exclusion criteria:(1)patients with intracranial metal implants or implanted electronic devices (such as pacemakers); (2)patients with cranial defects; (3)patients with a history of epilepsy, psychiatric disorders, malignant tumors, etc; (4)patients with fever, electrolyte disturbances, severe organ dysfunction or unstable vital signs; (5)patients with visual,hearing, speech impairment or impaired movement of the healthy side of the limb who could not complete the cognitive scale; (6)patients with cognitive impairment due to other diseases (e.g.,cranial trauma, Parkinson’s, etc.).The iTBS group, HF group and control group were divided into 30 cases each using the random number table method.This study was approved by the Medical Ethics Committee of Xuzhou Central Hospital (Grant No.XZXY‑LJ‑20200812‑033).

2.2 Methods

Patients in all three groups were given conventional medication and conventional rehabilitation treatment as prescribed by the doctors,and cognitive rehabilitation training was also provided according to the results of the patients’ executive function assessment.The rehabilitation treatment was given once a day for 30 min, 5 times a week for 4 weeks.On this basis, the corresponding rTMS treatment was given daily according to the respective grouping.The Papid 2 transcranial magnetic stimulator from Magstim (UK) was used with an “8” shaped coil.The stimulation site was the dorsolateral prefrontal cortex (DLPFC) (F3/F4 of the 10‑20 international EEG recording system), and the coil was tangential to the stimulation site and the center of the coil was close to the scalp, and the stimulation intensity was 80% of the patient’s motor threshold (MT).The intensity of stimulation was 80% of the patient’s motor threshold(MT).The specific parameters of each group were as follows: (1)iTBS group: intra‑cluster frequency of 50 Hz, inter‑cluster frequency of 5 Hz, 3 pulses per cluster, 2 s interval of 8 s, 5 min for each stimulation, total 900 pulses[9]; (2)high‑frequency group: frequency of 10 Hz, 5 s interval of 25 s, 15 min for each stimulation, total 1 500 pulses; (3)control group: the same parameters as iTBS group, the coil was flipped by 90° so that the side of the coil is in contact with the patient’s scalp and the patient can hear the noise of the machine but no effect is produced.

2.3 Observed indicators

(1) Neuropsychological scales.①MoCA: a score of 30 out of 30, with 1 point added to the final total score for those with ≤12 years of education, with higher scores representing better cognitive functioning[10].②FAB: it contains 6 parts (similarity judgment test,lexical fluency test, motor sequence test, inconsistent instructions,Go‑No Go test, grasping behavior), with a total score of 18, and a score of 12 or less indicates abnormal executive function, and a higher score indicates better executive function[8].③ Stroop color‑word test (SCWT): The SCWT consists of three parts: word naming,color naming and color word interference test, in which the color word interference test requires the patient to name the printing color of Chinese characters (red, green, yellow and blue) printed in different colors as quickly and accurately as possible, instead of reading the pronunciation of the words, and the number of time spent and the number of errors in the color word interference test are recorded as the observation index.The smaller the number of time consumed and the number of errors, the better the inhibition control and the better the execution function[4].④Shape trails test (STT): STT consists of two parts, STT‑A and STT‑B.Part A requires patients to connect 25 numbers in order, while part B requires patients to connect 25 numbers in both numerical order and alternating graphic sequence; the elapsed time of both parts A and B is recorded, and STT scores reflect patients’ cognitive flexibility[11].⑤Digit span test (DST): including sequential DST and inverted DST, the subjects were asked to recite the numbers they heard in sequential or inverted order.Sequential recitation requires a certain level of immediate memory and attention, reflecting the storage function of working memory; inverted recitation reflects the working memory and information encoding ability in the executive function[12].

(2) Neurophysiological examination.Event related potential (ERP)P300[13]: the P300 was measured using a brain electrophysiology instrument (model: Z2J‑MB‑NCC08) manufactured by Shanghai Norcheng Co.The “Oddball” pure tone paradigm was used,including 2 000 Hz target stimuli of 100 ms duration and 1 000 Hz non‑target stimuli of 50 ms duration, with 20% of the target stimuli occurring randomly for a total of 50 times.In a quiet environment,the patient was asked to count the number of target stimulus appearances in the headphones silently with eyes closed, and the latency and amplitude of P300 were recorded.

2.4 Statistical processing

SPSS 26.0 software was used for statistical analysis, and the Shapiro‑Wilk test was used to test the normality of the measurement data.The measurement data conforming to normal distribution were expressed as mean ± standard deviation (±s), and one‑way ANOVA was used for comparison among the three groups, and Bonferroni method was used for comparison among the three groups when differences existed, and paired samples t‑test was used for comparison before and after treatment within the group.Data not normally distributed were expressed as median and quartiles [M(P25,P75)], and Kruskal‑Wallis H rank sum test was used for comparison among the three groups; count data were expressed as frequencies,and 2 test was used for comparison among the three groups.A statistically significant difference was considered at P<0.05.

3.Results

3.1 Comparison of general data of the three groups

Comparing the three groups of patients in terms of age, gender,years of education, nature of lesion (hemorrhagic or ischemic),disease duration, side of lesion, and lesion site differences were not statistically significant (P>0.05) and were comparable (Table 1).

Tab 1 Comparison of general information of patients in the three groups

3.2 Comparison of neuropsychological scale scores among the 3 groups

The MoCA, FAB, SCWT, STT, and DST scores of the 3 groups were significantly better than those before treatment (P < 0.05).iTBS and HF groups had better MoCA, FAB, SCWT, STT‑B, and DST scores than the control group, and the difference was statistically significant (P < 0.05).iTBS group and There was no significant difference between the HF group (P > 0.05).(Table 2‑Table 5).

3.3 Comparison of neurophysiological indexes among the three groups

Before treatment, there was no significant difference in P300 latency and wave amplitude in the three groups (P>0.05).After treatment, P300 latency was significantly shorter and wave amplitude was significantly higher in the iTBS and HF groups than in the control group (P<0.05), while there was no statistical difference in P300 latency and wave amplitude in the iTBS group compared with the HF group (P>0.05).(Table 6)

3.4 Adverse reactions

A total of 90 patients were included in this study.One patient in the iTBS group requested to withdraw from the trial due to difficulty in sleeping at night after stimulation, and one patient in the HF group requested to withdraw from the trial due to nausea after treatment,and the symptoms disappeared after the above two patients withdrew from the trial.The study was actually completed in 88 cases.

Tab 2 Comparison of MoCA and FAB scores before and after treatment in the three groups (±s)

Tab 2 Comparison of MoCA and FAB scores before and after treatment in the three groups (±s)

Note: ①Compared with before and after treatment; ②P<0.05, compared with control group; ③P>0.05, compared with HF group

Group MoCA score (scores) FAB score (scores)Before treatment After treatment t① P Before treatment After treatment t① P iTBS Group 15.52±4.36 20.66±4.36②③ ‑9.582 0.000 8.31±1.49 11.17±1.42②③ ‑10.239 0.000 HF Group 14.21±3.56 19.34±3.38② ‑9.307 0.000 8.55±1.53 11.07±1.71② ‑5.481 0.000 Control group 14.70±4.13 16.83±3.52 ‑2.874 0.008 8.77±1.30 10.10±1.35 ‑6.325 0.000 F 0.783 7.818 0.739 4.625 P 0.460 0.001 0.481 0.012

Tab 3 Comparison of SCWT scores before and after treatment in the three groups[(±s) or M(P25, P75)]

Tab 3 Comparison of SCWT scores before and after treatment in the three groups[(±s) or M(P25, P75)]

Note: ①Compared with before and after treatment; ②P<0.05, compared with control group; ③P>0.05, compared with HF group

Group SCWT elapsed time(s) Number of SCWT errors (pcs)Before treatment After treatment t① P Before treatment After treatment Z① P iTBS Group 73.57±22.87 55.01±19.10②③ 12.061 0.000 6.00(5.00,7.00) 4.00(3.00,4.00)②③ ‑4.417 0.000 HF Group 68.94±22.09 53.64±20.87② 13.312 0.000 6.00(4.00,8.50) 4.00(3.00,5.00)② ‑4.018 0.000 Control group 71.71±19.55 67.71±19.38 4.322 0.000 6.00(4.00,8.25) 5.50(4.00,8.00) ‑2.351 0.019 Test value F=0.340 F=4.558 H=0.416 H=15.817 P 0.713 0.013 0.812 0.000

Tab 4 Comparison of STT scores before and after treatment in the three groups(±s)

Tab 4 Comparison of STT scores before and after treatment in the three groups(±s)

Note: ①Compared with before and after treatment; ②P<0.05, compared with control group; ③P>0.05, compared with HF group

Group STT‑A(s) STT‑B(s)Before treatment After treatment t① P Before treatment After treatment t① P iTBS Group 156.26±62.84 149.78±53.49③ 2.711 0.011 287.72±82.75 219.96±74.19②③ 15.257 0.000 HF Group 141.19±69.69 134.54±64.01 2.734 0.011 294.18±92.67 221.57±83.61② 10.444 0.000 Control group 147.74±67.08 142.63±64.56 3.693 0.001 298.24±86.13 273.87±85.63 5.079 0.000 F 0.374 0.454 0.109 4.217 P 0.689 0.637 0.897 0.018

Tab 5 Comparison of DST scores before and after treatment in the three groups[M(P25, P75)]

Tab 6 Comparison of P300 latency and wave amplitude before and after treatment in the three groups(±s)

Tab 6 Comparison of P300 latency and wave amplitude before and after treatment in the three groups(±s)

Note: ①Compared with before and after treatment; ②P<0.05, compared with control group; ③P>0.05, compared with HF group

Group P300 latency (ms) P300 amplitude (μV)Before treatment After treatment t① P Before treatment After treatment t① P iTBS Group 384.55±36.56 348.09±20.46②③ 4.729 0.000 4.61±1.60 9.45±2.76②③ ‑7.908 0.000 HF Group 383.17±31.05 346.47±22.80② 4.848 0.000 4.35±1.67 8.36±2.36② ‑8.246 0.000 Control group 381.14±30.48 362.72±24.95 2.102 0.044 5.19±1.44 6.87±1.77 ‑5.333 0.000 F 0.081 4.553 2.212 9.216 P 0.922 0.013 0.116 0.000

4.Discussion

Current treatments for PSEI are limited, and cognitive training is limited by patient education and participation, with large individual differences in efficacy.non‑invasive brain stimulation techniques have been gradually used to improve PSEI, with rTMS being effective[3].High‑frequency rTMS is known to be effective for PSEI,but the duration of a single session is long.iTBS has also been confirmed in the literature for PSCI, but the efficacy of iTBS for PSEI lacks refinement, and comparisons with conventional high‑frequency rTMS in PSEI have rarely been reported.In this study,iTBS and high‑frequency rTMS were used in combination with conventional rehabilitation training to treat patients with PSEI, and the results showed that after 4 weeks of treatment, the MoCA, FAB,SCWT, STT, and DST scores of patients were significantly improved compared with those before treatment, and both iTBS and high‑frequency groups were better than the control group.Both iTBS and HF rTMS can promote the overall cognitive level and executive function of patients after stroke, and both have comparable efficacy and safety.

Current research on rTMS for PSEI is mostly focused on the selection of core parameters such as stimulation site and frequency.DLPFC is a key site in the Executive Control Network (ECN),which can be enhanced by modulating the excitability of this site to promote executive function recovery[4].Rektorova et al[14] found significant improvement in SCWT scores after stimulation of the left DLPFC in stroke patients using a 10 Hz high‑frequency protocol,and domestic scholars such as Yin M.Y.[4] also applied a 4‑week intervention to PSEI patients using the same frequency protocol and observed the most significant improvement in the color word interference test.Kim J et al.[15] observed that high‑frequency rTMS on the affected side improved cognitive function in stroke patients, and an increase in cis and trans DST scores was observed.It is suggested that 10Hz rTMS stimulation of DLPFC has definite efficacy on PSEI.Therefore, 10Hz rTMS acting on the affected DLPFC was also selected as a treatment parameter in this study,and the findings were consistent with the above study.The possible mechanism is that high‑frequency rTMS modulates interhemispheric cross‑inhibition[10], increases cortical excitability in the affected hemisphere, and promotes recovery of brain function.

iTBS is a new rTMS modality, named because it simulates the theta rhythm of neuronal action potential firing, which is more in line with the firing rhythm of neurons in the brain and has the advantages of short stimulation time and long‑lasting effect,which can produce a more lasting therapeutic effect with higher efficiency[5].It has been shown that iTBS has a positive effect on working memory [16], which is one of the three core components of executive function[3].There is still a lack of attention on whether iTBS has a facilitative effect on PSEI improvement and whether it is more advantageous than conventional rTMS treatment.Therefore, in this study, iTBS was selected to treat PSEI patients,and FAB, SCWT, STT, and DST were also selected to assess of executive function in patients.The significant improvement of PSEI by iTBS observed in this study is consistent with the results of a related study by Li W et al[17].ERP is an important tool to assess cognitive function, especially the P300 is now considered to be an important tool to predict functional prognosis of stroke patients and to further develop rehabilitation treatment plans[13], and the P300 was selected to objectively and sensitively assess cognitive function together with neuropsychological scales in this study.In this study,the P300 was selected to assess cognitive function objectively and sensitively together with the neuropsychological scale.In this study,patients were treated with iTBS and 10 Hz rTMS, which resulted in a reduction in P300 latency and an increase in wave amplitude, as well as an improvement in overall cognitive and executive function,which is consistent with previous studies[18].iTBS responds to the speed of recognition of external stimuli by the central nervous system, and wave amplitude represents the degree of excitation of the brain during the recognition and processing of information[19].In the present study, it was observed that iTBS and high‑frequency rTMS resulted in increased P300 wave amplitude and shortened latency in PSEI patients, with no difference between the two,suggesting comparable effects.

The specific mechanism by which iTBS improves executive function in PSEI patients is unclear and may be related to increased functional connectivity of executive function brain networks.Alkhasli et al[20] scholars using functional MRI found that subthreshold intensity iTBS stimulation increased functional connectivity between the DLPFC and the left and right caudate, demonstrating that iTBS is sufficient to increase functional connectivity in the bilateral frontal striatum.The brain regions associated with executive function include the frontal‑striatal loop and the cerebellum, which in turn includes the dorsolateral prefrontal, orbitofrontal, anterior cingulate, and basal ganglia[3].The normal maintenance of executive functions requires dynamic interactions between the DLPFC and other cortical and subcortical regions, and PSEI is associated with potential damage to the deep white matter of the brain[2, 21].The DLPFC is a core region involved in executive functions such as working memory and cognitive flexibility, and is closely related to executive functions.In the present study, we found that after iTBS stimulation of the affected DLPFC in patients with PSEI, the P300 wave amplitude increased and the latency shortened, suggesting that the excitability of the patient’s brain was altered, which may be a possible mechanism for iTBS to improve PSEI, and whether it has an effect on functional brain network connectivity still needs to be confirmed in conjunction with functional imaging studies.

The results of this study suggest that both iTBS and high‑frequency rTMS improve PSEI.However, iTBS has a short treatment time and shows a greater advantage in terms of patient compliance for some stroke patients who have difficulty in maintaining a fixed position for a long time to complete a longer period of conventional rTMS treatment due to weak core muscle strength and agitation.At the same time, iTBS is more efficient, which can improve efficiency and save medical resources, and it is worth to be promoted in the clinical application.