Alzheimer’s disease (AD) is the most common type of dementia among the elderly and one of the heaviest burdens on the public health system. People with AD may suffer from progressive memory loss, aphasia, and declines in executive functions as well as neuropsychiatric symptoms including depression, hallucinations, and apathy, which seriously impact the activities of daily living and quality of life (QoL) of patients and, consequently, their caregivers [1
]. Depression and cognitive dysfunction are interdependent and associated with various adverse consequences, such as poor treatment compliance, loss of independence, and even mortality [3
]. Patients with brain disorders often perceive QoL and depressive mood as more important for their health status than disease-specific physical and mental symptoms. Therefore, improvement of these common features should become an important target in treatment of AD.
Despite advances in the pharmacopeia, there is a lack of effective treatment to lessen cognitive symptoms and modify the progression of the disease. Current medications such as acetylcholinesterase inhibitors (AChEI) and N-methyl-D-aspartic (NMDA) glutamate receptors have demonstrated a symptomatic effect on certain cognitive and non-cognitive symptoms of AD in the short term: six to twelve months in most studies [6
]. With diagnostic tools for AD becoming increasingly sophisticated, the pathology is identified at earlier stages than before, and therapies that may limit the progression of the illness and the cognitive loss associated with it are needed.
Among nonpharmacological interventions, repetitive transcranial magnetic stimulation (rTMS), with its potential to modify brain activity in targeted brain areas and related neural networks, seems to be a promising approach. This technique uses brief duration, rapidly alternating, or pulsed magnetic fields, delivered through an electromagnetic coil placed on the surface of the scalp to modulate the activity of cortical neurons underneath the application site. Its application at low frequencies (≤1 Hz) tends to suppress cortical excitability, whereas high frequency (HF) stimulation (>5 Hz) tends to enhance or facilitate cortical excitability through long-term potentiation (LTP)-like effects. When used repeatedly, such modulatory effect of cortical neural activity can persist beyond the period of stimulation, justifying the therapeutic use of rTMS. The effects of rTMS can depend on stimulation parameters that affect the electromagnetic field generated, such as coil shape, waveform, and pulses, session protocol, and on interindividual and disease-related specificities that affect the clinical response [7
In AD, there are encouraging results for the use of HF-rTMS (10–20 Hz) unilaterally, over the left dorsolateral prefrontal cortex (left dlPFC), or bilaterally [9
]. Improvements have been found in functional performance, global cognition—in domains such as episodic memory, psychomotor speed, and language skills—as well as in depressive symptoms [9
]. Another protocol applied stimulation over several brain regions bilaterally, concurrently with cognitive training for 6 weeks, finding medium to large effect size improvements (0.4–0.7) in neuropsychological, clinical and functional assessments up to 4.5 months [13
]. In spite of the accumulating evidence of positive outcomes brought by rTMS in the treatment of AD-related cognitive impairment, issues about the exact therapeutic effects and their impact on quality of life and daily functioning of the patients require further research.
We have therefore conducted an open-label uncontrolled pilot study to evaluate whether 10 HF-rTMS applied to the left dlPFC as an add-on treatment could positively affect cognition, QoL, functional ability, and psychiatric symptoms of AD patients. The primary objective was to analyze changes in global cognitive impairment one month after rTMS sessions. As secondary outcome measures, we also investigated the neuromodulatory effects on specific cognitive functions (attention/processing speed, executive function, episodic memory, and language/semantic functioning), QoL, functionality in daily activities (from both the patient’s and the caregiver’s perspectives), and depressive and anxiety symptoms. Lastly, correlation between these variables, QoL, and autonomy were also explored, both at baseline and post-treatment assessments.
This study aimed to investigate the clinical efficacy of HF-rTMS as an add-on treatment in improving cognition, QoL, and functional ability in daily life activities—from the patient’s and the caregiver’s perspective—as well as depression and anxiety rates of patients diagnosed with AD. Sessions were well tolerated and no adverse effects were reported by the participants. After treatment, a significant improvement in the patients’ semantic memory was observed in the 1-month follow-up evaluation. A significant reduction on the trait anxiety scores was as well detected, and this effect was directly correlated with an improvement on QoL. Reduction of self-reported depressive symptoms was equally associated with improvement on QoL, although the impact of treatment was marginally significant.
The World Health Organization (WHO) defines QoL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. It is a broad ranging concept incorporating in a complex way the person’s physical health, psychological state, level of independence, social relationships, personal beliefs and their relationship to salient features of the environment” [28
]. In line with this concept, the baseline data from our population suggested that the patients’ global cognition, as well as cognitive functions from all studied categories, directly impacted their QoL and autonomy in daily life activities. It is worthy noticing that the better the QoL reported by the patients, the higher they performed on the attention and memory MDRS subscales. These findings could reinforce our starting point, that cognition might be an important therapeutic target in AD in order to positively influence the patients’ perception of their QoL and the caregiver’s burden.
One month after rTMS treatment, we have found a significant improvement in the conceptualization subscale of the MDRS, which consists of tasks such as identifying the similarities between pairs of objects, identifying non-members of semantic categories, or identifying similarities and differences among simple geometric figures. The left dlPFC is mainly involved in semantic retrieval [29
], and it could be assumed that rTMS sessions targeting this region contribute to enhance the MDRS conceptualization subscale by strengthening the semantic-based treatment. Our data also showed an improvement marginally significant on participants’ visual recognition memory performance. Impaired visual memory recognition reported in 30 AD patients, and detected through the DMS-48, could be particularly related to medial temporal and perirhinal dysfunction [19
], the first regions affected in AD according to the autopsy of 83 brains of non-demented and demented individuals [30
Considering the practice (test–retest) effect is an important aspect when investigating treatment response through cognitive assessment [31
]. Scharfen and colleagues [32
] recently performed a meta-analysis and observed that, for non-clinical samples, a mere repetition of a cognitive ability test could result in an improvement of a third of a standard deviation (of the baseline model), which would reach stability after the third-fourth administration. Calamia et al. [33
] had described a similar effect, of almost a quarter of a standard deviation in a one-year interval. However, they detected that this effect was smaller in clinical populations and, according to their findings, AD patients would be expected to show an average decrease of 27.5% of a standard deviation if retested in a one-year period [33
]. Additionally, other studies have pointed out that practice effects are largely absent in patients with dementia [34
], even for those with mild AD for short test–retest intervals [37
]. Nevertheless, given that in the present study the retest interval is of one month, questions could still be raised on the influence of a practice effect regarding the results. This effect should be taken into account, adapted to the context of AD patients, in future studies with larger samples and long-term controlled follow-ups, as a careless analysis of cognitive outcomes could indeed lead to misinterpretation of the patients’ performances.
According to a recent review, positive cognitive effects of rTMS were often reported in mild AD while treatment failed to improve more advanced cases, suggesting that the efficacy may depend on the stage of the disease [7
]. Furthermore, in a meta-analysis by Chou and colleagues [11
], the included studies suggested that the significant effect of HF-rTMS over the left dlPFC of patients with AD or mild cognitive impairment would be the enhancement of memory function, and that the effects of 5–30 consecutive sessions could last for 4–12 weeks. Their results pointed out that memory improvement could as well be obtained following application of low-frequency rTMS over the right dlPFC [11
]. The left dlPFC seems to be preferentially involved in working memory and executive function, according to a literature review [39
] and a trial comparing the performance of 30 mild AD patients and 31 matched controls in an antisaccade task [40
]. In addition, a significant improvement in recognition memory has been observed after comparing sham to active neuromodulation over the left dlPFC of 10 AD patients [41
], while the familiarity component of recognition memory was found to be affected by frontal lobe lesions, due to tumor or stroke, on 24 patients [42
]. It could be hypothesized that rTMS sessions over the left dlPFC could improve the encoding phase [41
] in the context of the DMS-48 memory assessment, as well as the ability to distinguish between targets and distractor items [42
Finally, the HF-rTMS treatment significantly improved the trait anxiety (STAI-YB) scores of our sample, with a marginally significant impact on self-reported depressive symptoms (BDI). Correlation analysis on the impact of treatment showed that the decrease of depression and trait anxiety scores was associated with an improvement on QoL. The impact of rTMS on anxiety symptoms lacks further evidence on the literature [43
], especially in the context of AD. Our result could thus be seen as promising, suggesting a stable, long-term reduction of anxiety. In addition, this reasoning is also in line with the aforementioned definition of the WHO on quality of life. Although our subjects did not display a significant improvement in their QoL scores, the trait anxiety might represent an important therapeutic target in order to contribute to a better QoL. However, further investigation is still required. On the other hand, the effect on depressed mood, although marginally significant, is well reported in the literature [44
]. In this way, further studies should consider including AD patients with clinically important depressive and anxiety symptoms, and perform a more detailed assessment of QoL (e.g., one of the WHO Quality of Life instruments), as means to investigate the therapeutic potential of rTMS as an add-on treatment, and the possible long-term impact in the QoL of this population.
This study has important limitations, which are its relatively small sample size and a lack of control group. These aspects should be taken into account when interpreting our data as well as the possible influence of a test–retest effect, as mentioned above or even fluctuations in the patients’ scores. On the other hand, our trial is strengthened by well-defined inclusion/exclusion criteria, use of previously validated instruments only, and statistical correction for multiple comparisons. The results and the discussion might contribute to guide further research towards improvement of AD patients’ QoL and autonomy.