Improvement of poststroke cognitive impairment by intermittent theta bursts: A double-blind randomized controlled trial

Background and Objective

  • Intermittent theta burst stimulation (iTBS) has shown promise in improving cognitive impairment in Alzheimer’s and Parkinson’s diseases.
  • This study investigates the efficacy of iTBS on poststroke cognitive impairment (PSCI).
  • Objective: To assess the effect of left dorsolateral prefrontal cortex (DLPFC) iTBS on cognitive function in stroke patients.

Methods

  • Fifty-eight patients with PSCI were randomly divided into iTBS (n = 28) and sham stimulation groups (n = 30).
  • Both groups received routine cognitive rehabilitation.
  • The iTBS group received iTBS intervention of the left DLPFC, while the sham stimulation group received sham stimulation at the same site for 2 weeks.
  • Outcome measures: mini-mental state examination (MMSE), Oxford cognitive screen (OCS), and event-related potential P300, assessed at baseline (T0) and immediately after the intervention (T1).

Results

  • No significant differences in baseline clinical characteristics between the two groups.
  • After intervention, both groups showed significant increases in MMSE scores and P300 amplitude, as well as a significant reduction in the P300 incubation period.
  • The iTBS group exhibited a significantly higher change value than the sham stimulation group (p < 0.05).
  • Compared to the sham stimulation group, the iTBS group had more significant changes in semantic comprehension and executive function (p < 0.05).

Conclusion

  • iTBS can effectively and safely improve overall cognitive impairment in stroke patients, including semantic understanding and executive function, and it also has a positive impact on memory function.
  • Future randomized controlled studies with large samples and long-term follow-up should be conducted to further validate the results of the present study.

Introduction

  • Poststroke cognitive impairment (PSCI) is a common complication of stroke, with 24%−75% of stroke survivors experiencing persistent cognitive impairment that can worsen to poststroke dementia (Aben et al., 2018; K. Wang et al., 2021).
  • PSCI patients suffer from dysfunction of attention, executive function, memory, thinking, and language, which negatively affects their rehabilitation, increases disability rates and medical costs, and reduces their ability to live independently (Mchutchison et al., 2020; Rohde et al., 2019).
  • Current PSCI treatments include drug therapy, such as cholinesterase inhibitors (donepezil) and N-methyl-D-aspartic acid receptor antagonists (carpalatin) (Gorelick et al., 2011; Kim et al., 2020; K. Wang et al., 2021).
  • While these drugs can improve cognitive functioning, they are often accompanied by adverse reactions (Farooq et al., 2017; Sun, 2018).
  • Nondrug therapies like cognitive training and psychological intervention have unclear meta-analysis results (Elliott & Parente, 2014; Merriman et al., 2019).
  • Repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability and synaptic structure to promote functional recovery in stroke patients (Rossini et al., 2015).
  • High-frequency rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) can effectively and safely improve cognition impairment in Alzheimer’s disease (X. Wang et al., 2020) and stroke (Waldowski et al., 2009; Yin et al., 2020), and improve cognition in healthy individuals (Patel et al., 2020).
  • Intermittent theta burst stimulation (iTBS) is an optimized mode of rTMS with low stimulus intensity, short stimulation cycle, and long-term benefit (Nowak et al., 2010).
  • iTBS patterns improve overall cognitive function in healthy volunteers (Hoy et al., 2016; Wu et al., 2021) and patients with Parkinson’s disease (Trung et al., 2019).
  • iTBS reduces inhibitory control of cone cells, increases excitatory output, and induces/enhances neuroplasticity and excitability of the brain.
  • Cognitive function improvement is mediated by the association of DLPFC with the caudate nucleus and the stimulation-induced increase in neurotransmitter release (Hoy et al., 2016; Trung et al., 2019; Wu et al., 2021).
  • iTBS has shown positive improvement in PSCI, but sample sizes are small and cognitive scope is too single (Szaflarski et al., 2011; Vuksanović et al., 2015).
  • This study is a randomized double-blind single-center pseudo-controlled trial to investigate the short-term effects of iTBS on patients with PSCI.

Methods - Subjects

  • Patients with PSCI admitted to rehabilitation at the medicine department of the Affiliated Hospital of North Sichuan Medical College from January 10, 2020 to April 30, 2021 were recruited.
  • Inclusion criteria:
    • Meets diagnostic criteria outlined in the Diagnostic points of various cerebrovascular diseases.
    • Confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) and diagnosed as ischemic or hemorrhagic stroke.
    • 18−65 years old with stroke duration between two and three months.
    • PSCI diagnosis consistent with the diagnostic criteria of expert Consensus on the Management of PSCI (2017): mini-mental state examination (MMSE) score: illiteracy ≤17, primary school education ≤20, junior high school and above education ≤24.
    • No serious visual or hearing impairment and can complete relevant assessment and testing.
    • Donepezil was administered 2 weeks after stroke to improve cognitive function.
    • Stable vital signs.
    • Signed informed consent of patients and their families for iTBS treatment.
  • Exclusion criteria:
    • Cognitive dysfunction caused by craniocerebral trauma or neurological diseases other than stroke.
    • Patients with aphasia, unstable arrhythmias, or other serious physical conditions.
    • Patients with contraindications of magnetic stimulation, such as wearing a pacemaker or intracranial metal.
    • Patients with a history of seizures.
    • Patients in critical condition with fever, infection, or vital organ failure.
    • Postoperative patients with left cerebral hemorrhage.

Methods - Experimental Design

  • This prospective single-center randomized double-blind pseudo-controlled trial was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College (approval no. 2021ER066-1).
  • Fifty-weight patients were randomly divided into the iTBS group (n = 28) and the sham stimulation group (n = 30).
  • Each subject received 10 consecutive rounds of iTBS or pseudo-stimulation of DLPFC over 2 weeks once a day from Monday to Friday.
  • All subjects received the same conventional cognition-related medication and rehabilitation training, including donepezil 10 mg orally before bedtime and rehabilitation training.
    • Directional force training.
    • Attention training.
    • Computing power training.
    • Memory training.
    • Executive training.
  • All subjects were not aware of their grouping, and MMSE, Oxford cognitive screen (OCS), and P300 were assessed by the same professional therapist who was also unaware of grouping before treatment began. At the end of the last session, MMSE, OCS, and P300 were reassessed by the same professional therapist who did not know the grouping.

Intervention

  • Measurement of the resting motor threshold
    • Stimulation was performed using a transcranial magnetic stimulation system (nagneuro60 type stimulator, Nanjing Vishee Medical Technology Co., Nanjing, China) and a figure-eight coil.
    • The recording electrode was attached to the muscle abdomen of the abductor pollicis brevis on the normal side of the patient, and the reference electrode was placed at the tendon roughly 2 cm away from the recording electrode. The pole was placed proximal to the ipsilateral forearm.
    • The coil was placed in the motor cortex of the healthy hemisphere with the coil tangent to the scalp and the patient sitting relaxed in a chair.
    • The coils were shifted systematically in the primary motor cortex (M1) until a maximum and consistent motor-evoked potential response was recorded from the abductor pollicis brevis on the normal side.
    • The resting motor threshold (RMT) of the subjects was the minimum stimulus intensity that elicited at least a 50-mV motor-evoked potential in 5/10 consecutive cycles.
  • Stimulation plan
    • The left DLPFC (F3 point) was located according to the international 10/20 system, and the stimulus intensity was set to 100% RMT.
    • iTBS parameters included three continuous pulses at 50 Hz repeated at 5 Hz (2 s on, 8 s off) for a total of 192 s and 600 pulses.
    • In the sham stimulation group, the stimulation coil was rotated 90◦ perpendicular to the target area to generate minimum stimulation, and the stimulation parameters and sites were consistent with those of the iTBS group.

Outcome indicators

  • Cognitive function was assessed by MMSE, OCS, and event-related potential (ERP) P300 before intervention (T0) and immediately after the last intervention (T1).
  • The MMSE scale covers multiple cognitive areas, measuring orientation, memory, attention, computation, language, and visual ability (Ghafar et al., 2019; T. Zhang & Zhao, 2017).
  • For MMSE, the higher the score, the better the cognitive function. Scores ranged from 0 to 30. Cognitive impairment scores: illiteracy ≤17, primary school education ≤20, junior middle school or above ≤24.
  • MMSE had good sensitivity (0.924) and specificity (0.806) in the assessment of cognitive impairment (Sleutjes et al., 2020).
  • OCS: memory, language, number, practice, attention, and executive function.
  • ERP: response of the brain to external stimuli, reflecting electrophysiological changes in the brain’s attention and memory, used as an effect index of iTBS to improve cognitive function (Pinto et al., 2018).
  • P300: reflects processing speed and is an important tool in studying memory, its delay can be used as a marker of cognitive deterioration (Magnano et al., 2006).

Statistical analysis

  • All statistical analyses were performed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA).
  • The Shapiro–Wilk test was utilized to assess if the scores conformed a normal distribution.
  • For quantitative data that conformed to a normal distribution, the mean ± standard deviation (\bar{x} ± s) was used.
  • For quantitative data that did not conform to a normal distribution, interquartile range was used.
  • The change value “Δ” was figured out to assess the differences of cognitive function scores along therapy timeline.
  • For quantitative data conforming to normal distribution, one-way analysis of variance (ANOVA) was used for comparison, for quantitative data not conforming to normal distribution, nonparamet- ric test was used for comparison, and for count data, the chi-square test was used for comparison.
  • The Cohen’s d and Morris ppc2 were used to assess effect size of all the variables.
  • The significance level was set at 0.05.

Results - Demographic and clinical characteristics

  • A total of 60 subjects were included. In the iTBS group, two subjects withdrew from the intervention due to private reasons unrelated to the study. Accordingly, 58 subjects completed the study.
  • At baseline, there were no significant differences between the two groups in age, sex, stroke duration/type, the location of the lesion, hemiplegic limb, education level, MMSE, and P300 latency and amplitude (p > .05).
  • At the end of the treatment, the subjects were asked if they knew they were in the iTBS or pseudo-stimulation condition, and all said no.
  • One subject in the iTBS group had sneezing symptoms during stimulation and the symptoms disappeared immediately after the stimulation was stopped, and no serious adverse events were recorded in remaining subjects.

Comparison of clinical outcomes between the two groups

  • After treatment, MMSE scores (media difference = 17; 95% confidence interval [CI]: 1.00–6.00; effect size:0.644; p = .045) increased compared with baseline with statistically significant change.
  • For OCS, there were statistical differences in semantic (media difference = 4; 95% confidence interval [CI]: 0.00–1.00; effect size:0.497;p = .028) and imitation (media difference = 12; 95% confidence interval [CI]: 0.00–2.00; effect size:0.746; p = .006) between groups at T1.
  • Suggest significant differences in executive function scores (media difference = 0; 95% CI: −1.00–0.00; effect size:0.811;p = .003), while imitative function (media difference = 0; 95% CI: 0.00–1.00; p = .069) and semantic (media difference = 3; 95% CI: 0.00–1.00; p = .207) scores become insignificant.

Event related potentials (ERPs)—P300 assessments

  • For P300, there was a significant increase in the latency of P300 (mean difference = 345.71; 95% CI: −31.49–7.88; effect size: 0.947; p = .001) after intervention, but the amplitude (mean differ- ence = 0.85; 95% CI: −0.03–1.72; effect size: 0.978; p = .057) showed no significant difference.
  • There were statistical differences in the changes both in the latency (media difference = −37.5; 95% CI: −14.9–9.00; effect size: 1.295; p < .001) and amplitude (media difference = 4.5; 95% CI: 0.50–1.90; effect size: 0.984; p = .001) of P300.

Discussion

  • This randomized controlled double-blind trial provides initial evidence for the potential of iTBS to treat PSCI. In multiple assessments of neuroelectrophysiological and neuropsychological tests, iTBS stimulation of the left DLPFC improved overall cognitive function, with significant improvements in executive function.
  • Mild cognitive impairment after stroke is a key therapeutic target as it can slow down the process of cognitive degeneration and prevent its development to vascular dementia (Gorelick et al., 2011). This study confirmed the regulation and recovery effect of iTBS with respect to cognitive function and further consolidated the potential efficacy of noninvasive brain stimulation technology on PSCI.
  • Synaptic plasticity is the most important biological mechanism leading to learning and memory, and long-term potentiation (LTP) is a major neurophysiological factor related to learning and memory (Di Lorenzo et al., 2019).
  • Studies have shown that rTMS has a direct effect on the stimulation-target region and can increase blood flow, promote the expression of neurotrophic factors, and improve the release of neurotransmitters (Anderkova & Rektorova, 2014; Chou et al., 2020).
  • DLPFC, as a core region involved in executive functions such as working memory and cognitive flexibility, is a key node of the central executive network and is closely related to the regulation of executive functions (Baker et al., 2014).

Limitations

  • iTBS is rarely used in the treatment of PSCI, and its parameters require further study, for example, stimulation frequency/duration and total number of pulses/courses.
  • In this study, a treatment time of 2 weeks was used, the patients were followed up after treatment, and the evaluation of long-term iTBS efficacy on PSCI was lacking.
  • There was no clear classification of lesion location and lesion size of patients in this cohort.
  • The sample size of this study is small, so a multi-center randomized controlled study with a large sample is required to further explore the efficacy of iTBS in improving PSCI.

Conclusion

  • This randomized controlled trial provided evidence for the efficacy and tolerability of iTBS for the left DLPFC in the treatment of PSCI. After iTBS intervention, overall cognitive function improved, especially executive function, and there were improvements in memory function. Only one patient developed irritation-related sneezing symptoms during treatment, and none of the remaining patients reported any adverse events.