A Scoping Review Of Neuromodulation Techniques in Neurodegenerative Diseases: A Useful Tool For Clinical Practice? Part 1

Abstract: 

Background and Objectives: Neurodegenerative diseases that typically affect the elderly such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia are usually characterised by significant cognitive impairment that worsens significantly over time. 

Neurodegenerative diseases are common diseases that affect the physical health of the elderly, and the most common of these diseases is Alzheimer's disease. This disease affects the cognitive ability and memory of the elderly, making it difficult for them to complete daily tasks and life, and even require care. Although this phenomenon is very common in our society, we need to look at this issue positively.

First, although Alzheimer's disease affects the memory of the elderly, it does not necessarily mean that their quality of life will be reduced. People with dementia are usually still able to be active members of their daily lives. There may be some activities that require special care or help, but these challenges can be overcome. Moreover, studies have shown that people with Alzheimer's disease can get great comfort and happiness by recovering their memories and returning to past experiences.

Second, Alzheimer's disease is not always irreversible. We now know that certain factors can slow or prevent its development. For example, staying physically fit, exercising regularly, eating a healthy diet, and participating in social activities can significantly reduce the risk of developing Alzheimer's disease. These simple habits can also improve memory, strengthen mental health, and improve the quality of life.

Finally, we need to realize that dementia is not the fault of relatives or patients. Although this disease may bring challenges to some families, it can also be seen as an opportunity for family members to interact and help each other. Through external support and care, we can help patients better adapt to the disease and achieve a meaningful life.

In short, although elderly neurodegenerative diseases may affect people's memory, through a positive attitude, preventive measures and support from family members, patients can have a meaningful life in their lives and receive the right care and spiritual attention. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

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To date, viable pharmacological options for the cognitive symptoms in these clinical conditions are lacking. Various recent studies have employed neuromodulation techniques to try and contrast patients' decay. 

Materials and Methods: We conducted an in-depth literature review of the state-of-the-art of the contribution of these techniques across neurodegenerative diseases. 

Results: The present review reports that neuromodulation techniques targeting cognitive impairment do not allow to drawing yet any definitive conclusion about their clinical efficacy although preliminary evidence is very encouraging. 

Conclusions: Further and more robust studies should evaluate the potentialities and limitations of the application of these promising therapeutic tools to neurodegenerative diseases.

Keywords: Alzheimer's disease; cognitive impairment; frontotemporal dementia; neuropsychology; Parkinson's disease; rehabilitation; stimulation.

1. Introduction

Neurodegenerative diseases targeting the elderly are a public health priority throughout the world with significant medical, psychological and economic repercussions. 

The most common disorders are Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). Their prevalence and incidence have dramatically increased with age over the last decades, and they are expected to continue to grow due to the continuous increase in the average length of life in most countries. 

Neurodegenerative diseases are not homogeneous in their clinical profiles and underlying pathophysiology, although they are typically characterised by significant cognitive impairment. 

Time and accuracy of diagnosis are crucial factors, as they would allow the planning of timely and appropriate clinical management. 

As no effective pharmacological treatments for cognitive and motor symptoms are currently available, in recent years various studies have started to investigate the potential contribution of neuromodulation techniques (such as non-invasive brain stimulation techniques, NIBS) in contrasting patients' decay. 

After a presentation of the most prominent epidemiological and clinical features of each disorder, the present in-depth review reports the state-of-the-art neuromodulation techniques studies targeting cognitive impairment in neurodegenerative diseases. 

Our twofold aim is to show the preliminary evidence currently available in the field and to suggest that further research should evaluate the potentialities and limitations of these promising therapeutic options.

1.1. Clinical Profiles of Neurodegenerative Diseases

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder that represents more than 60% of dementia diagnoses among the elderly [1]. The neurophysiology of AD is mainly characterised by the extracellular accumulation of amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles containing phosphorylated tau protein on cortical and sub-cortical regions [2,3]. 

These local abnormalities challenge large-scale cerebral integrity, causing global white and grey matter atrophy involving the frontal regions, cingulate and temporal cortex and precuneus, selective hippocampal atrophy and increased ventricular volume [4–6]. 

Large-scale neural circuitry damages are likely to underlie clinical symptoms in AD as treatments aimed to reduce amyloid accumulation are revealed to be ineffective in the reduction of cognitive and memory decline [7]. 

These neurophysiological manifestations precede the onset of behavioural and psychiatric clinical symptoms, so their early detection is a crucial diagnostic factor [8]. The first noticeable cognitive changes involve progressive memory loss, impaired retrieval of semantic knowledge, reduced visuospatial attention and topographical disorientation [9–11], especially in early-onset AD [12]. 

Then, the disease progression spreads the abnormalities on a large-scale level involving long-range networks [3], causing severe impairment to executive functions [13] and anterograde amnesia [14]. 

A definitive cure for AD has not been found yet, since the aetiology is still unknown and the pathogenesis is unclear (for a review see [15]). For this reason, the main therapeutic protocols can only try to attenuate disease progression by reducing symptoms or delaying their onset to maintain a sufficient level of physical, psychological and social functioning [16]. 

Frontotemporal dementia (FTD) is a neurodegenerative disorder which shares different commonalities with AD but, differently from AD does not involve hippocampal deterioration, thus preserving episodic and autobiographical memories [17,18]. 

Clinical manifestations of FTD are heterogeneous, but it is possible to identify two main variants: the behavioural variant (bvFTD) and the primary progressive aphasia (PPA) which is in turn divided into a semantic variant (svPPA), a non-fluent variant (nfvPPA) and a logopedic variant (lvPPA). 

The behavioural variant (bvFTD) is characterised by the deterioration of frontal and prefrontal cortices which determine behavioural abnormalities and impairments of executive functions and working memory [19] as well as attentional deficits, perseverative behaviours and mental rigidity [20,21]. 

In the latter stages of disease progression, the involvement of the DLPFC leads to significant deficits in planning and organization abilities [22]. The semantic variant (svPPA) is characterised by degeneration of the left anterior, middle and inferior temporal cortices [23,24] which is related to loss of word meaning [19]. 

Core symptoms of svPPA include loss of semantic memory in both verbal and non-verbal domains, difficulties in recognising the names and faces of known people, anomia, and reading and spelling difficulties. 

Impairment in performing non-verbal tasks suggests that svPPA is a disease which affects the integrity of semantic knowledge rather than a purely language-related condition [25]. 

The non-fluent/agrammatic variant (nfvPPA) is characterised by cortical atrophy in the left inferior frontal gyrus, premotor cortex and anterior insula [26]. This atrophy causes agrammatic speech, deficits in the comprehension of syntactically complex sentences and apraxia of speech while the semantic meaning of single words is usually preserved [18,27]. 

The third type of PPA is called logopenic PPA (lvPPA). This form is characterised by atrophy of the left posterior temporal cortex and inferior parietal lobe, resulting in anomia, dysfluency, impaired repetition of sentences, simplified yet preserved grammar and impairments at the phonological and syntactic level of lexical processing [18]. 

Parkinson's disease (PD) is classically characterised by a series of motor impairments that include tremor, akinesia, rigidity and postural instability. It has also been extensively demonstrated that cognitive decline is a major, and often even more debilitating, symptom of PD [28]. 

In many cases, impairment in the cognitive domain could be typically classified as full-blown mild cognitive impairment (MCI) [29]. 

Neuropsychological examination of the cognitive functions in PD patients usually reveals mild to moderate deficits in the visuospatial domain, attention, working memory (WM), emotional processing [30] and a general decrease in executive functions [31].

1.2. Neurostimulation Techniques Overview

Technological achievements have recently made available potentially useful innovative tools to researchers and clinicians. For the aim of the present review, we will now focus on neurostimulation techniques. 

Neuroplasticity is one of the main targets of different cognitive, physical, pharmacological and neurostimulation protocols [32]. Neuroplasticity can be induced through direct stimulation of target brain regions through different noninvasive brain stimulation techniques (NIBS). 

These techniques can stimulate the brain by providing magnetic stimulation (TMS) or direct current (tDCS) and alternating current (tACS) from outside the skull. Because of their power to directly modulate cerebral activity, NIBS techniques have been widely used in treatments of neurological diseases involving disruption or aberration of cerebral activity [33–35]. 

As we already observed, these techniques can be adopted in conjunction with other cognitive training or with electric neurofeedback protocol to modulate specific brain regions' activities [36]. Transcranial magnetic stimulation (TMS) is a technique based on the perturbation of neurophysiological activity inducing a current through a non-invasive magnetic pulse over the skull [37]. 

TMS can be applied by adopting different approaches, such as delivering single pulses, paired pulses or multiple pulses. Another way of stimulating brain plasticity is via "transcranial electrical stimulation" which refers to transcranial direct current stimulation (tDCS) and transcranial alternating-current stimulation (tACS). 

These two techniques are based on the same principle: current flow from one electrode to another inducing electrophysiological modulation in the targeted brain region [38]. 

The difference between tDCS and tACS is that the former provides a stable current over time and its excitatory or inhibitory modulation of the membrane potentials' excitability threshold depends on which electrode (anodal or cathodal, respectively) is located over the target region [39], while the latter provides a current that varies rhythmically above and below zero over time with a specific amplitude and frequency stimulating oscillatory activity. However, to date, little is known about the precise electrophysiological correlates and the specific mechanism underlying tACS effects. 

Two currently accepted hypotheses suggest that tACS directly entrains underlying brain oscillations and/or that tACS leads to synaptic changes via spike-timing-dependent plasticity mechanisms [40].

2. Methods

An EBSCO-, Google Scholar- and PubMed-based literature review on neuromodulation studies targeting neurodegenerative diseases was conducted. Combinations of keywords entered for enquiries were: "transcranial magnetic stimulation" OR "transcranial direct current stimulation" OR "brain stimulation" AND "Alzheimer's disease" OR "Frontotemporal dementia" OR "Parkinson's disease". 

The review was further extended by considering all of the relevant articles reported in the references of each paper. Analysis has been primarily focused on methods regarding brain stimulation, patients' characteristics, presence/absence of cognitive symptoms, study design and experimental protocols, quantification of stimulation parameters of interest and brain imaging data, where available. 

We excluded research on healthy subjects only and/or conducted in non-human animals. As this field of applied clinical research is innovative and thus one cannot expect to find several large randomized controlled clinical trials to be assessed in terms of their efficacy, we also included in our review well-conducted small-scale studies that represent the majority of studies conducted so far. 

3. State-of-the-Art

3.1. Alzheimer's Disease

Considering its incidence and prevalence, AD is one of the most studied neurodegenerative disorders. A vast literature addressing possible therapeutic options to reduce patients' cognitive impairment is thus available. 3.1.1. 

Transcranial Magnetic Stimulation-TMS Single-pulse TMS (spTMS) is commonly used to probe the circuit or understand plasticity and physiological response. 

For clinical purposes, it has been mostly used for the early detection of AD [41], early diagnosis of dementias and MCI [42,43] and to predict the progression of cognitive decline [44,45]. 

However, since it is limited in its ability to elicit long-term modulation of cortical excitability, it is not commonly used for therapeutic purposes. Repetitive TMS (rTMS) is a protocol in which trains of multiple magnetic pulses are delivered at specific frequencies and time delays to produce long-lasting perturbation of cerebral activity [46]. 

Theta burst stimulation is a specific type of TMS that can be applied using different (e.g., continuous or intermittent) protocols, and it is reasonably assumed to represent neural learning in a Hebbian form of long-term synaptic plasticity. 

The modulatory effect of this kind of cerebral stimulation depends on the coil shape, which affects the depth of the stimulated location [47] together with the intensity, duration and frequency at which pulses are delivered [48,49]. 

The currently most used rTMS protocol for long-lasting modulation of cerebral excitability is the high-frequency rTMS (HF-rTMS; for a review, see [50]), which consists of the delivery of one or more trains of stimuli at frequencies greater than 1 Hz. The HF-rTMS protocol showed greater efficacy and duration over time when compared to the low-frequency (LF; <1 Hz) rTMS [51]. 

However, the difference in effectiveness observed between these two kinds of rTMS protocols could depend on the stimulated hemisphere, since excitatory HF-rTMS and inhibitory LF-rTMS activity could be used differentially on the two hemispheres to compensate for dysbalanced interhemispheric interactions. Since most of the cognitive functions impaired in AD are related to memory recall, problem-solving, reasoning and emotional control, prefrontal regions are the main targets of NIBS. 

Turriziani et al. [52] stimulated the right dorsolateral prefrontal cortex (DLPFC) with LF-rTMS for 10 min before a non-verbal recognition memory task. They observed improved memory performances following the real stimulation on the right DLPFC compared to the right-sham stimulation. In contrast, no improvement has been observed in the stimulation of the left DLPFC. 

In a second crossover experiment, they stimulated the right DLPFC five days/week for two weeks and found that improvements persisted for at least four weeks after the end of the treatment. A recent systematic review [53] showed the effects of HF-rTMS prolonged administration for the treatment of different neurological and psychiatric disorders, including AD. 

Two studies explored the clinical effect of HF-rTMS at 20 Hz over the DLPFC, stimulating only the left hemisphere for 20 sessions [54] or left and right DLPFC for 13 sessions [55]. 

In the first case, post-training improvement at the behavioural level has been observed on the Behavioral Pathologies in Alzheimer's Disease Rating Scale (BEHAVE-AD) as well as improvement in cognitive functions assessed with the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) [54]. In the second case, they did not observe any significant improvements at the end of the four weeks of training, but they observed improvements in Montreal Cognitive Assessment (MoCA) scores during weeks two and three [55]. 

Most studies have been conducted using an eight-shape coil, which can only stimulate the superficial part of the cerebral cortex, while other coils can stimulate brain regions located deeper by a factor of three [56]. 

This kind of deep stimulation is named deep TMS (dTMS). Avirame et al. [57] used dTMS at 10 Hz to stimulate deep prefrontal bilateral hub regions in 20 sessions in patients with moderate to severe AD. 

The cognitive assessment has been performed before and after the treatment using a computerised cognitive test (Minsdtreams; NeuroTrax Corp., Bellaire, TX, USA) and the Addenbrooke Cognitive Examination (ACE). 

Pre and post-comparisons showed near-threshold improvements in both assessments, but only patients who obtained lower scores on ACE (<50) showed significant improvements at the end of the training. 

Moreover, changes in ACE scores were negatively correlated with baseline scores, suggesting that dTMS bilateral intervention could be particularly valuable in patients showing severe impairments.

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