A Scoping Review Of Neuromodulation Techniques in Neurodegenerative Diseases: A Useful Tool For Clinical Practice? Part 2

The DLPFC is the main but not the only target region for rTMS. Precuneus is a ventral superior parietal region involved in episodic memory, visuospatial processing, and global state of consciousness since it is a functional core of the default mode network (DMN; [58]). 

Episodic memory is the ability to store a specific experience or scene in our brain. This kind of memory is often used in our lives, such as remembering the route to a place, the scene at a party, the face of a person, etc. Memory is the ability of our brain to store information, including the process of learning, remembering, understanding, and applying information.

Episodic memory and memory are inseparable. First of all, episodic memory requires the support of memory. If we do not have a certain memory reserve, we cannot store the experienced scene in the brain. Secondly, episodic memory can train and improve memory. By constantly improving the observation of scenes and the memory of details, we can enhance the brain's ability to store and extract information, thereby improving our memory.

And how to improve our episodic memory and memory? It is very simple. We can achieve our goals through some exercises and training. For example, look at and observe the scenes and things you have experienced more, and pay attention to discovering the details and differences in them; at the same time, we should also use more notes, drawings, simulations, and other methods to help memory. Then, we can also improve our memory through learning and thinking. For example, learning new knowledge and skills, solving problems, and thinking logically can exercise our brains and improve our memory.

In short, episodic memory and memory promote and support each other. Only through continuous exercise and training can we master better episodic memory and memory, and make our brains more flexible and healthy. I believe that as long as we persist and persevere, we will achieve satisfactory results! It can be seen that we need to improve memory, and Cistanche can significantly improve memory, because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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Connectivity alteration in the DMN and other networks has been observed during early-stage AD [59]. Koch et al. [60] used TMS to stimulate the precuneus in 14 early-stage AD patients using 20 Hz HF-rTMS on the left precuneus for a total of 20 sessions in two weeks. 

At the end of the training, they observed a selective improvement in episodic memory comparing real stimulation to a sham condition. Some studies explored the effect of rTMS on different locations that are thought to underlie cognitive functions involved in AD symptomatology. 

Lee et al. [61] stimulated 27 probable AD patients in different brain regions for six weeks using 10 Hz-rTMS combined with a cognitive task. Locations of stimulation were divided into two clusters composed of three regions each, and their stimulation was alternated during each of the six weeks. 

This kind of protocol has been implemented in a dedicated system for the administration of rTMS combined with computerized cognitive training (CCT) named NeuroAD System (Neuronix Ltd., Tel Aviv, Israel). 

This system integrates neuronavigated TMS and CCT and is revealed to be an effective low-risk therapeutic instrument. Cognitive tasks were chosen for each session according to the cognitive function subtended by the stimulated brain regions. 

After the training, patients showed significant improvement in memory, language, and especially in the overall ADAS-Cog score. Similar results with a similar approach have also been observed by Rabey and Dobronevsky [62]. 

In a recent study, the stimulation of similar regions on different daily sessions was adopted by Sabbagh et al. [63] in a large sample of AD patients including 131 participants. 

After 30 sessions of 10 Hz HF-rTMS with CCT, they observed improvements in ADAS-Cog and Clinical Global Impression of Change scale (CGIC) scores not immediately after training but five weeks after the end of the treatment. Their results showed that their protocol was particularly effective with mild AD patients showing baseline ADAS-Cog scores < 30. 

Finally, the long-term effects of rTMS have been explored by Nguyen et al. [64]. In their study, they used the aforementioned NeuroAD system combined with additional rTMS trains of pulses provided at 10 Hz during a memory task. 

They observed an improvement in the ADAS-Cog scale immediately after the end of the training. However, at a six-month follow-up, this improvement was maintained by only the five patients who showed greater post-training improvements. 

In a subsequent open-label study, they recruited five patients who showed fewer improvements at the six-month follow-up and administered another two weeks of rTMS [65]. 

This additional intervention led to a reduction of cognitive decline and a decrease in behavioral symptoms such as apathy. This study suggests that, in some patients, five to six weeks of rTMS combined with CT could lead to cognitive improvements lasting for one year. Table 1 contains the main information about the studies reviewed.

3.1.2. Transcranial Direct Current Stimulation-tDCS

The most used transcranial electrical stimulation technique in AD treatment is the tDCS in its anodal configuration. However, most of these studies are single-case or pilot studies that show encouraging but necessarily preliminary results [76,77]. 

Some of the first evidence for the potential therapeutic benefits of tDCS comes from a study employing anodal tDCS on bilateral temporal regions for 30 min daily for five days [78]. 

In this study, an improvement in visual recognition memory performance persisted for one month after the treatment had been observed. More recently, another study adopting ten sessions of anodal tDCS for 20 min on the left and right temporoparietal regions showed improvements in mini-mental state examination (MMSE), in the clock-drawing test and the MoCA scores only in the real-tDCS group, together with an improvement in Cornell Depression Scale scores in both real-tDCS and sham-tDCS groups [79]. 

Finally, the application of home-based anodal tDCS has been adopted by Im et al. [80]. In this study, anodal tDCS was administered for a prolonged period of six months to patients divided into a real stimulation group and a sham group. 

After this period, MMSE scoring and the Boston naming test performance were observed. Moreover, a marginal stabilization of performance in some executive functions was observed compared to a general decline observed in the sham group. 

However, the causal effect of tDCS has not been confirmed across all studies. For example, Cotelli et al. [81] studied the effect of tDCS on the left DLPFC for 25 min in 10 sessions. They divided the sample into three groups: one with real tdCS + CCT memory task, one with placebo tDCS + CCT memory task, and a tDCS + motor training. 

Their results showed an improvement in face-name association test performances in both groups performing CCT memory tasks regardless of the tDCS protocol, showing no additive effect of real tDCS application. 

Another study adopting six sessions of anodal tDCS on the left DLPFC for 20 min in two weeks failed to observe significant differences between real tDCS and sham in apathy scores, neuropsychiatric inventory (NPI), ADAS-Cog and Cornell depressive scale [82]. 

Authors suggested that the lack of significant results could be mainly caused by the moderate AD stage of their patients which could impair neuroplasticity mechanisms [83,84] together with the limited number of tDCS sessions adopted in the study. Similar inconclusive results have been observed by Bystad et al. [85] stimulating the left temporal lobe for 30 min over 10 sessions. 

Despite an observed tendency of enhanced delayed recall performance in the real tDCS group compared to placebo, in general, they failed to find significant differences in memory performances between the groups. 

This result may be caused by individual differences such as skull thickness, which can influence treatment effectiveness [86], and because their sample was composed of patients with AD in an advanced stage which seems to reduce positive therapeutic outcomes [87]. 

Despite some encouraging evidence, results of tDCS-based treatments are not always consistent across studies, highlighting the need for a larger sample size, integration with precise neurophysiological measures to better define the target of the treatments, and more coherence in experimental designs in terms of the duration and number of stimulation sessions and uniformity of clinical outcomes to obtain a clearer picture of tDCS efficacy in AD [88,89]. 

Table 2 contains the main information about the studies reviewed.

3.1.3. Transcranial Alternating Current Stimulation-tACS

Although tACS showed potential in entraining specific frequency bands resulting in the modulation of cognitive functions in healthy subjects, only recently, a few efforts have been employed in the administration of this technique to AD patients. 

It is known that gamma oscillatory activity is abnormal in AD patients [106]. Gamma activity has been linked to cortico-cortical communication, multisensory processing, and integration across different brain regions [66,107]. For this reason, Naro et al. [108] stimulated six different regions in the left hemisphere using tACS to evaluate gamma frequency entraining in AD, MCI, and healthy participants. 

Results showed that AD patients did not show any tACS modulatory effect compared to MCI and healthy participants. Interestingly, MCI patients with AD-similar gamma profiles developed AD within two years from the end of the training, suggesting that gamma tACS could be used as a potential early diagnostic tool for AD. 

Some optogenetic studies suggested that externally driven gamma activity could reduce Aβ depositions and p-Tau levels [109]. In a recent study, Dhaynaut et al. [90] used tACS in the gamma frequency range (40 Hz) for 20 sessions (one session) on bilateral temporal lobes. After the tACS treatment, a trend of a decrease of intracerebral p-Tau has been observed, especially on temporal lobes, suggesting a potential novel therapeutic approach for neurophysiological AD manifestation.

3.1.4. Other Neurostimulation Techniques

Besides TMS as mentioned above and tDCS and tACS, other less diffused novel NIBS techniques can directly or indirectly modulate cerebral activity such as the radio-electric asymmetry conveyer (REAC), focused ultrasound (FU) and transcranial pulse stimulation (TPS) with ultrasounds. 

The radio-electric asymmetry conveyer (REAC) is a biomedical device that allows the induction of a small current in a portion of biological tissue through the emission of very weak microwaves in the Wi-Fi frequency range [110]. 

These microwaves can induce small changes in cerebral activity that can last for a prolonged time after stimulation. These new non-invasive neurostimulation techniques have also been used in AD patients through stimulation of the ear lobe with a series of 500 ms radiofrequency bursts. Patients underwent two cycles of treatment consisting of 18 sessions each cycle, with an average time delay of six months between cycles. 

After the first cycle, there was an improvement in all the cognitive and behavioral functioning indices (i.e., MMSE; NPI; activity of daily living, ADL; and instrumental activity of daily living, IADL). 

Further improvements in all these indices, except ADL, have been observed after the second cycle of treatment [111]. One of the most limiting factors of pharmacological treatments is that most of the chemical particles in the blood flow are not able to pass the brain-blood barrier, a regulatory interface that determines the entrance of substances into the brain [91]. 

Focused ultrasound (FU) is a non-invasive stimulation that can selectively, transiently, and safely force the opening of the blood-brain barrier to increase the blood flow in specific brain regions and allow the passage of drugs. Recently, some studies successfully adopted FU to open the brain-blood barrier in human AD patients [112–114]. 

Two of these studies demonstrated that the application of FU on the white matter in the right prefrontal cortex could safely cause an opening of the brain–blood barrier lasting for 24 h [113] and a reduced resting-state functional connectivity in the ipsilateral frontoparietal network lasting for the same time [112]. The other study reported a selective opening of the brain–blood barrier in the hippocampal and entorhinal cortex, demonstrating that it is possible to modulate the brain–blood barrier permeability in the very specific structure of the human brain to deliver pharmacological treatments directly to target regions without observing significant clinical worsening and aversive side-effects. 

However, the adoption of such techniques and their potential therapeutic implications need many more studies to provide precise and reliable therapeutic protocols. Finally, among the ultrasound-based brain stimulation techniques, there is also a clinical sonication technique based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS). 

This was recently used in a study by Beisteiner et al. [115] in which ultrasound brain stimulation and first observations of long-term effects are presented. In this study, the authors included simulation data, laboratory measurements with rat and human skulls and brains, and finally, in vivo modulations of somatosensory-evoked potentials in healthy subjects (sham-controlled) and 35 patients with Alzheimer's disease acquired in a multicenter setting. The results showed large safety margins and dose-dependent neuromodulation. 

A high treatment tolerability and no major side effects were reported. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network, as revealed by fMRI data. 

These results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham-controlled clinical studies. Table 3 contains the main information about the studies reviewed.

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