Can Alzheimer’s Disease Be Prevented? First Evidence from Spinal Stimulation Efficacy on Executive Functions

Abstract

Background:

Recently, a growing body of evidence has shown that, from the early stage of impairment, Alzheimer’s patients (AD) present difficulties on a variety of tasks mostly relying on executive functions. These strongly impact their daily life activities causing a severe loss of independency and autonomy.

Objective:

To evaluate the efficacy of transpinal direct current stimulation (tsDCS) combined with cognitive trainings for improving attentional and executive function abilities in a group of AD patients.

Methods:

In a randomized-double blind design, sixteen AD patients underwent different cognitive trainings combined with tsDCS. During the treatment, each subject received tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: 1) anodal, and 2) sham while performing three computerized tasks: alertness, selective attention, and executive functions. Each experimental condition was run in ten consecutive daily sessions over two weeks.

Results:

After anodal tsDCS, a greater improvement in executive functions compared to sham condition was found. More importantly, the follow-up testing revealed that these effects lasted over 1 month after the intervention and generalized to the different neuropsychological tests administered before, after the treatment and at one month after the end of the intervention. This generalization was present also in the attentional domain.

Conclusion:

This evidence emphasizes, for the first time, that tsDCS combined with cognitive training results efficacious for AD patients. We hypothesize that enhancing activity into the spinal sensorimotor pathways through stimulation improved cognitive abilities which rely on premotor activity, such as attention and executive functions.

Keywords

Alzheimer’s disease cognitive training neuromodulation transpinal stimulation tsDCS

INTRODUCTION

Over the past decades, current neurobiological theories have clearly indicated that the human brain works as a network of interconnected components in which spatially distributed but functionally linked regions support cognition and behavior [1 –5]. In line with these theories, a growing body of evidence points to sensorimotor processes as not just a supporter for the different cognitive domains but rather as a foundation for all mental activities [6]. Examples of relevant domains are language comprehension and production [7 –10], autobiographical memory [11, 12, 11, 12], gestures [13], and decision making [6]. Simulation based sensorimotor mechanisms have also been demonstrated in problem solving involving spatial working memory [14, 15] and in executive functions tasks [16 –18]. Indeed, a central aspect of executive functions is to control and plan motor actions and goals [16 –18]. Thus, one exciting new direction in cognitive rehabilitation research is understanding how cognitive processes and sensorimotor systems interact. Indeed, despite the availability of several standardized strategies [19], cognitive disorders are increasing in incidence as many societies deal with the demographic reality of an aging population [20].

Among the most severe neurological diseases, Alzheimer’s disease (AD), the most prevalent type of dementia, frequently occurs in the elderly population [21]. It affects millions of people [22] by causing a progressive cognitive decline which interferes with the essential activities of daily life [23, 24]. The typical symptoms of dementia involve different cognitive domains, such as memory, spatial and temporal orienting, language and learning, comprehension, and communication skills [20]. A growing body of literature has also recently pointed out that, from the early stage of impairment, AD patients present difficulties on a variety of tasks mostly relying on executive functions [25 –27], primarily due to degeneration of prefrontal cortex [28]. This “umbrella term” includes verbal reasoning, problem solving, working memory, planning, and the ability to cope with novelty [25, 29].

Thus, because executive deficits interfere with the performance of daily life activities, by worsening the quality of life of AD individuals [25], is essential to take this cognitive dimension into account when planning a rehabilitation protocol aimed at preventing and/or delaying the progression of AD. Among the most recent proposals, transcranial direct current stimulation (tDCS) is a well-documented technique which induces changes in the excitability of underlying neural tissue [30].

tDCS is a non-invasive brain stimulation technology that involves the application of a weak direct electrical current (1–2 mA) through anodal or cathodal electrodes placed on the scalp. Depending on the electrical polarity, it is generally assumed that the anode induces a depolarization of the neuronal resting membrane potential, while the cathode decreases cortical excitability in the brain region under and around the placement. These effects are generally compared with a sham (or placebo) condition, in which the stimulator is turned off after 30 s [30, 31]. Previous evidence has already emphasized that tDCS is efficacious in improving AD abilities in different cognitive domains [32 –36] such as memory [37 –40] and general performance measured through the Mini-Mental State Examination (MMSE) and the Wechsler’s Intelligence scale [41]. Moreover, after anodal tDCS, an increased metabolism in the prefrontal cortices was observed which was correlated with subjective satisfaction and improvement in memory functioning [42].

Given that sensorimotor processes act as a basis for cognitive activities related to executive functions [6 , 43–45], the hypothesis might be advanced that stimulation over the sensorimotor network would result efficacious for improving these cognitive abilities in AD. Indeed, previous work by our research group and others has found that modulation over the motor cortex or the cerebellum improves language recovery, visuospatial memory, and executive functions [46 –51]. It has also been recently pointed out that the spinal cord takes part in the recovery of language and, in particular, for those aspects related to sensorimotor properties ([52, 53] and Pisano et al., unpublished data). Indeed, anodal transpinal direct current stimulation (tsDCS) over the thoracic vertebrae combined with language training improved action verbs and word articulation in different aphasic groups ([52, 53] and Pisano et al., unpublished data). More importantly, after anodal tsDCS, significant functional connectivity changes were found in a cerebellar-cortical network which recruited regions such as the cerebellum and the premotor cortex known to be involved in sensorimotor processing [53]. Thus, this evidence emphasized, for the first time, that the neural response due to tsDCS combined with cognitive training exerts supraspinal effects by specifically influencing the sensorimotor network.

Given that previous evidence has shown that tsDCS exerts its influence at the cortical level [55 –58] and, in particular, over the sensorimotor areas ([53], see also [57, 58]), we might assume that enhancing activity into the spinal sensorimotor pathways would improve cognitive abilities which rely on premotor activity, such as executive functions [28].

As previously stated, a deficit in executive functions heavily interferes with the performance of daily life activities, by worsening the quality of life of AD individuals and, thus, their autonomy [25 –27].

To our knowledge, to date, no study has explored the potential of tsDCS combined with cognitive training for improving executive functions in AD.

MATERIALS AND METHODS

Participants

Sixteen patients suffering from AD (9 females, age: mean 78.25; SD 6.18) participated in the present study. Patients were all enrolled by the Behavioural Neurology Laboratory of the IRCCS Santa Lucia in Rome. The demographic and clinical characteristics of the enrolled subjects are summarized in Table 1. All participants were subsequently admitted to the Unit for the Diagnosis of Dementia at IRCCS Foundation Santa Lucia to be evaluated according to the clinical criteria established by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association [59]. According to the Alzheimer Dementia Association [60] and to the conventional cut-off score for dementia (≤23.8) at the MMSE [61], our AD group included 8 patients with moderate dementia (13–20 MMSE) and 8 patients with mild dementia (21–24 MMSE) (see Table 2). The exclusion criteria were the history of severe untreated medical, neurological, and psychiatric diseases, drug or alcohol abuse, comorbidities related to spinal cord, presence of pacemakers or brain capsules.

Table 1

Clinical and demographic characteristics of Alzheimer’s patients (mean score±SD values)

Age (y)	78.25±6.18
Sex (female:male)	9 : 7
Right Handedness	16
Education (y)	10.5±4.46
MMSE	20.06±1.88
ADL	4.31±0.79
IADL	5.06±0.85

MMSE, Mini-Mental State Examination; ADL, Activities of Daily Living; IADL, Instrumental Activities of Daily Living.

Table 2

Neuropsychological assessment in AD patients at Baseline (T0), at the End of Treatment (T10) and at Follow-up (FU) for the anodal and sham condition, respectively (in bold scores above the cut-off)

P	C	MMSE	Clock Test (TOT)	TMT (B-A) (s)	Phonological Fluency	Semantic Fluency	Visual Search	FAB	WEIGL	TOL	BADS
		T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU	T0 T10 FU
		(cut- off ≤23.8)	(cut- off ≤42.16)	(cut-off >186)	(cut-off ≤16)	(cut-off ≤10,8)	(cut-off ≤30)	(cut-off ≤13,5)	(cut-off ≤4,25)		(cut-off ≤10,78)
Real First
1	Real	20 22 22	57 57 57	70 32^∧ 32	36 46^∧ 45	13 20^∧ 18	45 44 44	16 15 15	13 14 14	23 29^* 29	8 11^* 11
	Sham	22 22 22	57 56 56	32 38 36	46 40 40	20 14 14	44 45 44	15 15 15	14 11 11	27 29^∧ 29	11 11 11
3	Real	20 20 20	22 22 22	257 106^* 109	25 27^∧ 27	8 9 9	42 49^∧ 47	12 16^* 15	3 5^* 5	n.a	8 14^* 13
	Sham	20 20 20	22 23 22	106 170 173	27 31^∧ 28	9 6 6	49 43 43	16 16 15	5 5 5	14 12 12
5	Real	21 26^* 25	41 58^* 56	188 107^* 107	45 44 44	15 18^∧ 18	53 53 53	19 18 18	12 11 11	29 29 29	10 13^* 13
	Sham	26 24 24	58 54 54	107 110 110	44 47^∧ 45	18 18 18	53 54 53	18 19 18	11 12 12	29 30 29	13 13 13
7	Real	23 26^* 25	45 53^∧ 52	102 102 102	26 27 27	10 16^* 15	46 53^∧ 53	7 8 8	9 10 10	n.a	7 12^* 12
	Sham	26 26 25	53 50 50	102 102 102	27 27 27	16 15 15	53 53 53	8 7 7	10 9 9	12 11 11
9	Real	21 23 22	19 18 18	n.a.	24 25 24	16 15 15	24 39^* 38	6 10 10	7 7 7	0 16 16	7 6 6
	Sham	23 22 22	18 19 18	25 21 21	15 13 13	39 36 36	10 10 10	7 8 7	16 20 19	6 6 6
11	Real	21 25^* 24	22 26 25	n.a.	40 40 40	16 17 17	48 45 45	12 15^* 15	11 13^∧ 13	20 29^* 29	7 7 7
	Sham	25 24 24	26 24 24	40 40 40	17 17 17	45 45 45	15 15 15	13 13 13	29 28 28	7 7 7
13	Real	19 23 23	22 54^* 53	181 115^∧ 115	33 31 31	9 11^* 11	48 50^∧ 50	14 14 14	10 8 8	28 29^* 29	8 11^* 11
	Sham	23 24^∧ 23	54 50 50	115 100^∧ 110	31 31 31	11 11 11	50 48 48	14 14 14	8 7 7	29 29 29	11 11 11
15	Real	18 19 19	26 35 35	n.a.	1 5 4	4 4 4	6 8 7	5 6 6	n.a.	n.a.	n.a.
	Sham	19 19 19	35 32 32	5 3 3	4 4 4	8 4 4	6 7 6
Sham First
2	Sham	17 19 19	26 17 17	n.a.	15 15 15	13 8 8	29 27 27	8 11 11	3 5^* 5	n.a.	5 5 5
	Real	19 22 22	17 29 27	15 18^* 17	8 11^* 11	27 45^* 43	11 8 8	5 9^∧ 9	5 6 6
4	Sham	22 22 22	20 17 17	n.a.	34 30 30	10 10 10	37 37 37	10 13 13	6 6 6	n.a.	5 5 5
	Real	22 22 22	17 18 18	30 32^∧ 32	10 13^* 12	37 46^∧ 45	13 18^* 16	6 6 6	5 6 6
6	Sham	21 20 20	23 18 18	221 221 221	30 23 23	8 7 7	26 29 28	12 13 13	7 5 5	n.a.	5 5 5
	Real	20 24^* 23	18 26 25	221 191 195	23 25^∧ 25	7 6 6	29 35^* 33	13 16^* 15	5 9^∧ 8	5 4 4
8	Sham	21 21 21	49 50 50	83 92 92	35 34 32	16 16 16	32 32 32	12 15^* 14	8 9 9	26 26 26	10 10 10
	Real	21 24^* 24	50 60^∧ 60	92 70^∧ 73	34 30 30	16 16 16	32 32 32	15 16^∧ 16	9 11^∧ 11	26 29^* 29	10 14 ^* 13
10	Sham	22 24^* 24	16 17 17	53 60 60	37 37 37	9 10 10	54 55 55	15 14 14	10 10 10	0 28 26	8 7 7
	Real	24 24 24	17 36 34	60 35^∧ 37	37 40^∧ 40	10 14^* 13	55 55 55	14 15 15	10 13^∧ 12	28 26 26	7 9 9
12	Sham	19 20 20	39 38 38	n.a.	20 22^∧ 22	4 4 4	48 47 46	13 13 13	1 3 3	16 18 18	9 8 8
	Real	20 30^* 28	38 38 38	22 23 23	4 9 7	47 43 43	13 15^* 15	3 6^* 5	18 23 23	8 8 8
14	Sham	16 16 16	12 12 12	n.a.	9 11 10	7 8 7	29 29 29	9 9 9	6 7 7	n.a.	n.a.
	Real	16 17 17	12 14 14	11 10 10	8 7 7	29 35^* 34	9 8 8	7 7 7
16	Sham	20 20 20	58 57 57	188 188 188	54 54 54	17 21^∧ 20	44 48^∧ 47	13 13 13	12 13 13	28 28 28	6 9 9
	Real	20 26^* 25	57 58 57	188 116^* 118	54 70^∧ 68	21 25^∧ 24	48 60^∧ 58	13 16^* 15	13 15^∧ 15	28 33^* 32	9 16^* 15

P, participants; C, conditions; S, sham; R, real stimulation; MMSE, Mini-Mental State Examination; TMT, Trail Making Test (part B-A); FAB, Frontal Assessment Battery; TOL, Tower of London (scores are corrected for age and educational level); BADS, Behavioral Assessment of the Dysexecutive Syndrome; n.a., not administrable; ^*cut-off score has been reached; ^∧further improvement above cut-off score.

Clinical data

Together with the MMSE, all patients were administered two self-report functional scales to evaluate their elementary and instrumental abilities in activities of daily living (ADL, IADL). In such scales, zero score indicates a bedridden invalid who cannot be left alone. In both tests, all patients performed at a normal level.

Ethics statement

The data analyzed in the current study were conformed with the Helsinki Declaration. Our named Institutional Review Board (IRCCS Fondazione Santa Lucia, Rome-Italy) specifically approved this study (Protocol number: CE/PROG.733) with the understanding and written consent of each subject.

Procedure

Neuropsychological and behavioral assessment

Before, after the treatment and at follow-up (1 month after the end of the treatment), all patients underwent a neuropsychological battery which included tests for Attention: Visual Search [62], Trail Making Test (TMT) [63] and Executive functions: the Frontal Assessment Battery (FAB) [64], Phonological Verbal Fluency [65], Semantic Verbal Fluency [66], Clock Test [67], Tower of London (TOL) [68], WEIGL [62], and the Behavioral Assessment of the Dysexecutive Syndrome test (BADS) [69]. The neuropsychological assessment was carried out by a neuropsychologist who was blinded regarding the experimental design. As reported in Table 2, before the treatment, most of the patients resulted below the cut-off score in the MMSE (16 out of 16), in the Clock test (12 out of 16), in the TMT (11 out of 16), which provides information on visual search speed, scanning, and mental flexibility and in most of the tests aimed at specifically investigating executive functions (Semantic Fluency (9 out of 16), FAB (12 out of 16), TOL (15 out of 16)), also in ecological contexts (BADS test 16 out of 16). Five patients were also impaired in the Visual Search test, four in the WEIGL, and three in phonological fluency.

Transcutaneous spinal direct current stimulation

tsDCS was administered using a battery driven Eldith (NeuroConn GmbH, Germany) Programmable Direct Current Stimulator with a pair of surface-soaked sponge electrodes (5×7 cm). Real stimulation consisted of 20 min of 2 mA anodal current with the active electrode on the 10th thoracic vertebra while the reference electrode was placed over the right shoulder on the deltoid muscle [52, 53]. For sham stimulation, the same electrode position was used. In this condition, the current was initially increased in a ramp like fashion over 30 s, eliciting a slight tingling sensation but the stimulator was turned off after 30 s [70]. All patients underwent the two conditions (anodal and sham) in a randomized-counterbalanced double-blind design. As this was a double-blind study, both the examiner and the patient were blinded regarding the stimulation condition and the stimulator was turned on/off by a third person. At the end of each condition, none of the participants was able to notice differences in the intensity of sensation between the two conditions (anodal versus sham), not being aware of what condition they were performing [71]. In both conditions (anodal versus sham), patients underwent concurrent cognitive training (see below). The treatment was performed in ten daily sessions over two weeks (Monday to Friday - week-end off - Monday to Friday). There were four weeks of intersession interval between the anodal and the sham condition. The order of conditions was randomized across subjects (see Fig. 1).

Fig. 1

Overview of study design.

Cognitive treatment

For each patient, the rehabilitative program comprised 10 one-hour sessions over two weeks for each condition (tsDCS anodal versus sham). The cognitive treatment was administered through Cogniplus software (Schuhfried), a cognitive battery aimed at training different cognitive abilities embedded in lifelike scenarios. All participants underwent exercises in three specific domains: executive functions, alertness and selective attention. In the executive functions training, patients were asked to work with a virtual town plan on which nine different buildings were shown together with their names (e.g., post-office, café, insurance office, cultural center). To the right of the town plan, there was a box in which outstanding and completed errands were listed. At the start the patient was given a list of things that need to be done at various locations. The patient had to devise an appropriate strategy and decide in which order carry out the errands and visit the different buildings. Different priorities need to be observed, depending on the training form. Factors such as the formulation of the task, information about journey times, the number of errands/appointments to be attended to and other task characteristics vary in the different training forms and affect the difficulty of the task. The alertness task was included in order to control for possible tsDCS effects simply due to enhanced cognitive arousal. Moreover, although none of the patients but five were impaired in the selective attention task, we decided to further enhance this ability which would prove useful for the executive functions training.

RESULTS

Data analysis

Before, after the treatment and at follow-up (4 weeks after the end of each treatment condition [anodal versus sham]), the patients’ performance was evaluated by comparing the mean score obtained in the executive functions, alertness and selective attention trainings. Data were analyzed using SPSS 17.0 software. Three repeated measures ANOVAs were performed separately for the three trainings. For each analysis, two “within” factors were considered: CONDITION (anodal versus sham) and TIME (baseline (T0) versus end of treatment (T10) versus follow-up (FU). The post-hoc Bonferroni test was conducted on the significant effects observed in the ANOVA. The values of p≤0.05 were considered statistically significant.

Executive functions

The analysis showed a significant effect of CONDITION (anodal versus Sham, F (1,15) = 61.54, p ≤ 0.001) and TIME [Baseline (T0) versus End of treatment (T10) versus Follow-up (F/U), F (2,30) = 112.85, p≤0.001]. The interaction CONDITION x TIME was also significant (F (2,30) = 81.67, p≤0.001). The Bonferroni’s post-hoc test revealed that, while no significant differences emerged in the mean score between the two conditions at T0 (anodal 4 versus sham 4, p = 1), the mean score was significantly greater in the anodal than in the sham condition at T10 (anodal 13 versus sham 9, p≤0.001) and persisted at F/U (anodal 14 versus sham 9, p≤0.001). Significant differences also emerged between T0 and T10 for the sham condition (5, p≤0.001) (see Fig. 2).

Fig. 2

Mean score at baseline (T0), at the end of treatment (T10) and at follow-up (F/U, 1 month after the end of treatment) for the anodal and sham condition, respectively.

We ran further analysis by adding the order of conditions (anodal versus sham) as fixed factor. The analysis revealed that the results were not significantly affected by the order of condition (F (1,14) = 0.005, p = 0.94).

Alertness

The analysis showed no significant effect of CONDITION (anodal versus Sham, F (1,15) = 0.58, p = 0.46), but a significant effect of TIME [Baseline (T0) versus End of treatment (T10) versus Follow-up (F/U), F (2,30) = 128.68, p≤0.001]. The interaction CONDITION×TIME was not significant (F (2,30) = 0.02, p = 0.98).

Selective attention

The analysis showed no significant effect of CONDITION (anodal versus Sham, F (1,15) = 0.57, p = 0.46), but a significant effect of TIME [Baseline (T0) versus End of treatment (T10) versus Follow-up (F/U), F (2,30) = 62.17, p≤0.001]. The interaction CONDITION×TIME was not significant (F (2,30) = 0.96, p = 0.39).

In Table 2, the results collected in the different neuropsychological tests before, after the treatment and at follow-up are reported. For each neuropsychological test, the comparison between the number of patients who reached the cut-off score or further improved above the cut-off score after anodal and sham tsDCS compared to baseline is also reported in Table 3.

Table 3

For each neuropsychological test, the number of patients who reached the cut-off score^* or further improved above the cut-off score^∧ after anodal or sham tsDCS compared to baseline is reported

Neuropsychological Tests	Baseline (number of AD below the cut-off score)	Post-Anodal tsDCS	Baseline (number of AD below the cut-off score)	Post-Sham tsDCS
MMSE	16/16	^*7/16	13/16	^*1/13 +^∧1/16
Clock Test	12/16	^*2/12 +^∧ 2/16
TMT (B-A)	11/16	^*3/11 +^∧4/16	9/16	^∧1/16
Visual Search	5/16	^*4/5 +^∧5/16	4/16	^∧1/16
Phonological Fluency	3/16	^*1/3 +^∧6/16	3/16	^∧3/16
Semantic Fluency	9/16	^*5/9 +^∧3/16	7/16	^∧1/16
FAB	12/16	^*6/12 +^∧1/16	10/16	^*1/10
WEIGL	4/16	^*2/4 +^∧6/16	3/16	^*1/3
TOL	15/16	^*5/15	12/16	^∧1/16
BADS	16/16	^*7/16

TMT, Trail Making Test; FAB, Frontal Assessment Battery; TOL, Tower of London; BADS, Behavioral Assessment of the Dysexecutive Syndrome.

DISCUSSION

The present study investigated whether tsDCS combined with cognitive training improves executive functions in a group of sixteen AD patients. Interestingly, results showed that, although the amount of improvement at the end of training was greater in both tsDCS conditions (anodal versus sham) compared to baseline due to the cognitive treatment, anodal tsDCS exerted greater effects compared to sham. No difference was observed between the two conditions in the alertness training. Thus, these data indicate the specific and non-generalized effects of tsDCS arguing against a result simply due to enhanced cognitive arousal which should have influenced also the alertness task. Anodal tsDCS did not exert any influence also in the selective attention task, probably due to the fact that, in the neuropsychological assessment, most of the patients were already above the cut-off score before the training, thus, there was no substantial need to further exercise these skills. More importantly, the follow-up testing revealed that the improvement found in executive functions lasted over 4 weeks after the intervention and generalized to different neuropsychological tests. In particular, after anodal tsDCS several patients obtained a score above the cut-off in the MMSE and improved in an ecological battery for executive functions. Moreover, in several other tasks, among which selective attention, most patients either reach the cut-off score or further improved their performance levels (see Table 3). Interestingly, as also noted in previous tDCS works [38 , 41], only anodal stimulation produced significant changes compared to sham.

Thus, we believe that these results are very promising as only ten days of tsDCS combined with cognitive training revealed beneficial effects in a cognitive domain, such as executive functions, which heavily interferes with the quality of life in AD individuals [25 –27]. Moreover, these effects lasted well beyond the end of the treatment confirming the effectiveness of the training and the importance of supporting AD patients with cognitive treatment delivered in ecological contexts. Indeed, our tasks were all embedded in realistic environments. The use of ecological contexts for our training is in line with recent proposals which emphasize to encourage cognitive performance in AD populations in real contexts settings [72, 73].

As stated in the Introduction, several studies have already emphasized that a deficit in executive functions strongly impacts on the quality of life of AD patients causing a dramatic reduction in their personal autonomy [25, 74]. Accordingly, it has also been shown that, from the early stage of the disease, a decrease in frontal lobes activity is observed [27 , 76]. Indeed, very recently, using brain morphometry, Garcia-Alvarez and collaborators [77] have found that executive functions impairments in AD were strongly related to frontal cerebral circuitry damage (i.e., superior prefrontal cortex, middle frontal gyrus, dorso-lateral prefrontal cortex). Interestingly, after anodal tDCS, glucose metabolic changes were observed in the prefrontal cortices [42].

Given these data, we might speculate that, in our study, anodal tsDCS has exerted functional neural changes into the cortex and, in particular, into the prefrontal region, leading to an improvement of executive functions. Indeed, previous evidence by our group has shown that tsDCS combined with language training influenced a wide network of sensorimotor structures, among which the premotor cortex and the cerebellum [53]. Indeed, beyond the motor, premotor and somatosensory cortex, the cerebellum has strong functional connections with different areas subserving higher-order cognitive functions, such as the prefrontal and parietal cortices, the cingulate and parahippocampal gyri [78 –83]. Accordingly, cerebellar stimulation modulates cognitive processes in healthy volunteers [49] and affects cholinergic activity, having a direct impact on the cholinergic system in AD [84]. More recently, it has also been found that cerebellar stimulation impairs abnormal cerebellar-cortical inhibitory connections resolving maladaptive cortical excitability [85].

Since simulation based sensorimotor mechanisms have been shown to play a role in executive functions tasks [16 –18], we should expect that influencing activity over the premotor cortex and the cerebellum through tsDCS would have improved these abilities, as it was the case. Since prefrontal activity is at the basis of executive functions, we cannot exclude also that, in our patients, which were all at an early stage of their disease, the improvement relied on their cognitive reserve [86]. Indeed, it has been suggested that cognitive reserve impacts on neurodegenerative process by increasing connectivity in a network involving fronto-parietal nodes [84].

In our work, tsDCS was used, for the first time, in order to investigate its role in promoting executive functions in AD. Since the spinal cord is directly connected, through its spinal ascendant tracts, with different cortical regions, we believe that spinal stimulation might result more efficacious than tDCS since it enhances activity into a network of cortical regions promoting compensatory strategies also in the case of neurodegenerative diseases. Indeed, it has been suggested that intervertebral disks are characterized by an electrical conductivity one order of magnitude larger than spongy bones over the brain [87, 88]. This means that the application of electric current over the spinal cord more easily reaches the nervous fibers with respect to the application of the same amount of current over the cortex. Thus, differently from previous paradigms which have used cortical [89, 90] or cerebellar stimulation [49 , 86], we suggest that tsDCS might result more effective for cognitive recovery, at least for those functions related to sensorimotor processes, because an appropriate positioning of the anode over the spinal cord would induce current density which reaches homogeneously different parts of the brain network. This would remove the need to establish which part of the system should be targeted with stimulation.

In summary, for the first time, we reported evidence for an improvement in executive functions in AD after spinal stimulation which lasted over one month after the end of the treatment. We are aware that one limitation of our study is represented by the small sample of participants included. Thus, in order to confirm our results, further studies on larger samples of participants are needed. It is necessary also to acknowledge that the methodology adopted in the present study did not allow us to exclude the presence of depressive symptoms in our group which commonly coexist with AD. Therefore, we cannot rule out the hypothesis that tsDCS has improved executive functions via depressive symptoms alleviation and not via direct impact on AD-related cognitive impairments.

In conclusion, although future studies should further confirm tsDCS efficacy for cognitive recovery, we believe that these data are extremely relevant for treatment outcomes. Indeed, given that executive functions play a crucial role in in the quality of life of AD, they highlight the therapeutic potential of tsDCS as a viable tool for promoting cognitive recovery and/or postpone cognitive decline in these patients.

Footnotes

ACKNOWLEDGMENTS

We are extremely grateful to SCHUHFRIED GmbH for providing free access to the computerized cognitive training CogniPlus used in this study. The authors declare that the research was conducted in absence of any commercial or financial relationships which would constitute a conflict of interest.

Authors’ disclosures available online ().

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