==== Front Transl Neurodegener Transl Neurodegener Translational Neurodegeneration 2047-9158 BioMed Central London 224 10.1186/s40035-020-00224-z Review Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques Yuan Ti-Fei 12 Li Wei-Guang 3 Zhang Chencheng 4 Wei Hongjiang 5 Sun Suya 6 Xu Nan-Jie 3 Liu Jun jly0520@hotmail.com 6 http://orcid.org/0000-0002-1438-0038Xu Tian-Le xu-happiness@shsmu.edu.cn 2 1 grid.16821.3c0000 0004 0368 8293Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030 China 2 grid.260483.b0000 0000 9530 8833Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001 China 3 grid.16821.3c0000 0004 0368 8293Center for Brain Science, Shanghai Children’s Medical Center, and Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China 4 grid.16821.3c0000 0004 0368 8293Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China 5 grid.16821.3c0000 0004 0368 8293Institute for Medical Imaging Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030 China 6 grid.16821.3c0000 0004 0368 8293Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China 7 12 2020 7 12 2020 2020 9 4421 3 2020 19 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD. Keywords Alzheimer’s diseaseParkinson’s diseaseSynapseNeurotransmitterSynaptic plasticityBrain stimulationDeep brain stimulationTranscranial magnetic stimulationhttp://dx.doi.org/10.13039/501100003399Science and Technology Commission of Shanghai Municipality18JC142030218JC142030318JC1420304Yuan Ti-Fei Liu Jun Xu Tian-Le Shanghai Municipal Science and Technology Major Project2018SHZDZX05Xu Tian-Le SJTU Trans-med Awards Research2019015Zhang Chencheng http://dx.doi.org/10.13039/501100003395Shanghai Municipal Education CommissionInnovative research team of high-level local universities in ShanghaiXu Tian-Le issue-copyright-statement© The Author(s) 2020 ==== Body Background Alzheimer’s disease (AD) and Parkinson’s disease (PD) are common neurodegenerative disorders characterized by a progressive decline in cognitive and motor functions, respectively. Both disorders are associated with neuronal loss in various brain regions, particularly the hippocampus associated with memory impairment in AD [1] and the substantia nigra pars compacta associated with motor dysfunction in PD [2]. Impaired synaptic plasticity in affected brain structures and networks is thought to represent a critical pathological mechanism underlying the progressive cognitive and motor deficits seen in these neurodegenerative disorders [3, 4]. Synaptic plasticity involves a complex series of presynaptic and postsynaptic biochemical events that are triggered by external or internal stimuli and may induce short- or long-standing changes in the strength of synaptic transmission, thereby modifying brain structure and function, and subsequently, behavior [5]. Persistent and activity-dependent strengthening (termed long-term potentiation; LTP) and weakening (long-term depression; LTD) of excitatory synapses in the hippocampus are widely thought to underlie the learning and memory processes in the mammalian brain. Although the precise electrical and chemical events responsible for the modification of synaptic strength remain poorly understood, it seems that both the presynaptic release of glutamate and the activation of N-methyl-D-aspartate receptors are required for the initiation of subsequent biochemical processes that give rise to LTP or LTD in the hippocampal memory-related circuits [5]. Persistent forms of synaptic plasticity like those found in the hippocampus have been identified in other brain areas and networks, including the dopaminergic nigrostriatal pathway, which has been implicated in the pathogenesis of PD and the progressive decline of motor functions in PD patients, including the impaired motor skill learning [2, 3]. The impaired synaptic plasticity thus may be a basic cellular mechanism mediating the progressive cognitive and motor deficits observed in AD and PD patients. If this hypothesis were valid, measures of human brain synaptic plasticity and its impairment could offer vital quantitative biomarkers that could aid in the diagnosis and prognosis of patients with AD or PD [6, 7]. Moreover, therapeutic modulation of the impaired synaptic plasticity in affected patients, e.g., using brain stimulation or neuropharmacological interventions, would be expected to alleviate, delay, or halt the progressive clinical deterioration seen in these disorders [4, 6]. To date, most evidence supporting the hypothesis that the impaired synaptic plasticity contributes to the progressive cognitive and motor deficits in AD and PD has come from cellular and animal models, as well as from post-mortem neuropathological studies in brain tissues of patients. For example, in the context of the amyloid hypothesis of AD, amyloid precursor protein transgenic mice have been found to display impaired in vitro and in vivo LTP in the hippocampus, which correlates with the spatial memory deficits [8]. Similarly, in the 6-hydroxydopamine rat model of PD, striatal LTP and LTD were found to be aberrant, whereas chronic treatment with the dopamine precursor levodopa (L-dopa) restored the deficits in striatal synaptic plasticity [3]. However, the findings from animal research and human postmortem neuropathological studies cannot be readily generalized to the brain and cognitive functions and dysfunctions in living persons. Fortunately, the past two decades have witnessed the development of various noninvasive and invasive brain stimulation techniques that permit the measurement or modulation of synaptic plasticity in the living human brain. These novel brain stimulation techniques, ranging from transcranial magnetic stimulation (TMS) [9] to deep brain stimulation (DBS) [10], allow for the implementation of neural stimulation systems with unprecedented spatial and temporal precision. Here, we first discuss the different brain stimulation techniques currently available and then evaluate the results of clinical studies that applied these techniques to assess or modulate the impaired neuroplasticity at the local and network levels in AD and PD patients. Main text In the past decade, various noninvasive and invasive brain stimulation techniques have been utilized to measure and/or modulate impaired neurotransmission and plasticity in patients with AD or PD. The noninvasive brain stimulation techniques used include TMS, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial ultrasound stimulation. In several studies, these noninvasive brain stimulation techniques have been found to improve the cognitive deficits in AD [11] and the motor symptoms of PD [12, 13]. The invasive brain stimulation techniques employed include intracranial recordings of local field potentials (LFPs) and associated neuronal oscillations in different frequency bands, DBS of the subthalamic nucleus (STN) or globus pallidus internus (GPi) in patients with PD [10, 14] and the recent DBS of the fornix white matter bundle in patients with AD [15]. Among the brain stimulation techniques, DBS is a well-established effective tool in the clinical management of patients with movement disorders, including PD [10, 12, 13, 16]. Here, we mainly focus on TMS and DBS, which are used in many clinical studies published so far, as well as tDCS, which has often been used in studies of patients with PD. TMS TMS involves the delivery of a transient magnetic field through a coil placed on the surface of the skull, thereby producing a brief electrical current that activates a small area of brain beneath the coil [9] (Fig. 1a). TMS can easily be combined with structural brain MRI for TMS targeting, with simultaneous scalp EEG or EMG recordings, and with associated motor-evoked potentials (MEPs), which are focal surface muscle twitches following a brief TMS pulse above the motor cortex. TMS-evoked potentials, which are time- and phase-locked to the onset of the TMS pulse itself, can also be extracted from the scalp EEG. The delivery of a single TMS pulse can transiently activate or inhibit the underlying cortical region, while the delivery of repetitive TMS (rTMS) pulses can induce longer-lasting, plasticity-like changes in brain functions [9]. In past decade, researchers have found that the delivery of 3-pulse 50-Hz bursts at a frequency of 5 Hz, referred to as the theta burst stimulation (TBS), induces levels of cortical plasticity similar to those produced using conventional rTMS protocols [17]. Fig. 1 The effects of DBS and rTMS in the brain. a Basic principles of rTMS and its network effects. The TMS involves the delivery of a transient magnetic field through a coil placed on the surface of the skull, thereby producing a brief electrical current that activates a small area of brain beneath the coil. While the delivery of a single TMS pulse can transiently activate or inhibit the underlying cortical region, that of rTMS pulses can induce longer-lasting, plasticity-like changes in brain functions. It is commonly assumed that the rTMS-induced cortical plasticity and network activation are responsible for its actions on motor and cognitive function and dysfunction. Typically, cortical rTMS can evoke striatal dopamine release (see red arrows), which in turn results in changes of cortical plasticity. Please see the text for more details. b Synaptic modulation effects of rTMS. The rTMS can modulate NMDAR and/or metabotropic glutamate receptor (mGluR)-dependent synaptic plasticity probably by enhancing the release of different neurotransmitters (i.e. glutamate, GABA), modulating glial activity, promoting neurotrophic signaling (i.e., BDNF), and promoting calcium-mediated signaling, thereby influencing synaptic transmission even in distal brain regions. c Basic principles of DBS. The DBS involves the delivery of electric current to an electrode implanted in a brain structure or nucleus of interest. The effects of DBS can be influenced by the brain tissue surrounding the DBS electrode and the spatial configuration of activated or inhibited neuronal populations in the target brain structure. The physiological effects of DBS are complex and can occur at the molecular, cellular, local, and network levels. Of note, the inherent complexity and wide range of effects of DBS can extend beyond the target network and function of interest. Moreover, DBS has lasting effects on neurotransmitter concentration, function, dynamics, and glial activity, thereby altering the microenvironment of the brain and influencing neural plasticity. Red arrows denote presumable signal flows under STN DBS in PD patients. Please see the text for more details. d The local cellular effects of DBS include the inhibition of neuronal-cell bodies and the activation of neighboring axons as well as astrocytes. Abbreviations: DA, dopamine; f, frequency; NMDAR, N-methyl-D-aspartic acid receptor; mGluR, metabotropic receptor; BDNF, brain-derived neurotrophic factor; 5-HT, serotonin; GPe, globus pallidus externus; GPi, globus pallidus internus; STN, subthalamic nucleus; GLU, glutamate; ADE, adenosine The paired-pulse TMS could be used as a measurement tool for cortical functioning. Short intracortical inhibition (SICI) and short intracortical facilitation (SICF) are common measures used in the paired-pulse TMS studies, which are based on the MEP amplitude evoked by a test stimulus presented at a short latency after the delivery of an initial conditioning stimulus. SICI typically occurs at latency intervals less than 5 ms after the onset of the test stimulus, whereas SICF emerges at intervals between 8 and 30 ms. It is thought that SICI reflects GABAergic, especially the GABA-A-mediated interneuron inhibition in the cortex [9]. Another commonly used measure involves the threshold for producing an MEP response, which appears to be affected by drugs targeting voltage-dependent sodium or calcium channels [9]. In paired-associative stimulation (PAS) studies, the TMS measures of interest are usually short-afferent inhibition (SAI) and long-afferent inhibition (LAI), which are elicited at latencies of about 20 ms and 200 ms, respectively, after somatosensory stimulation of the hand or peripheral nerve electric stimulation. SAI is believed to reflect the sensory-motor plasticity in the motor cortex and seems to be mediated mainly by muscarinic acetylcholine receptors [18]. The neurobiological mechanisms through which rTMS impacts brain function in health and disease are not yet fully understood. It is commonly assumed that the rTMS-induced cortical plasticity and network activation are responsible for its action on motor and cognitive function and dysfunction [19] (Fig. 1a). It has been demonstrated that rTMS influences remote brain regions, enhances the release of different neurotransmitters, modulates glial activity, and promotes neurotrophic signaling [20–22] (Fig. 1b). Also, rTMS stimulation seems to evoke glutamate/GABA release [23, 24] and to facilitate calcium-mediated signaling, thereby modulating synaptic plasticity [25] (Fig. 1b). In addition, cortical rTMS can evoke striatal dopamine release and is able to induce changes in cortical plasticity (Fig. 1a). In general, the TMS approach has been found useful in assessing the excitability in specific cortical regions and in mapping different sensory, cognitive, and motor functions [9]. rTMS is also effective to briefly facilitate or inhibit brain and cognitive functions in patients with neurodegenerative diseases, but whether it could facilitate cognitive functions in healthy persons remains controversial [26]. TMS in AD Measurement studies To assess the functional integrity of the primary motor cortex in AD, an early study evaluated the MEP-based SAI in 15 patients with AD and 12 age-matched healthy controls [27]. The results showed that the SAI size was significantly reduced compared with that of the healthy controls. Furthermore, administration of a single dose of the cholinesterase inhibitor rivastigmine increased the SAI in a subgroup of 6 patients. The authors suggested that SAI could serve as a noninvasive test to assess cholinergic transmission and sensory-motor plasticity in the motor cortex of patients with AD. Subsequent rTMS studies have confirmed and extended these results [18, 27–32]. For example, one study demonstrated the early occurrences of impaired SAI and MEP amplitudes in AD [18]. Another study reported that patients with AD displayed reduced motor thresholds and MEP onset latencies, which correlated with the AD symptom severity [29]. Furthermore, the reduced motor thresholds in AD patients do not seem to correlate with the impaired inhibitory effects on cortical neurons, as measured by SAI and SICI [30]. Another study using intermittent TBS has demonstrated that the dopaminergic pathways are also involved in the cortical plasticity in AD by showing that the impaired LTP-like cortical plasticity in affected patients could be restored by administration of the dopamine agonist rotigotine [33]. In addition, the TMS-based measures of LTP-like cortical plasticity seem to have predictive value for cognitive decline, even for the rate of decline, in patients with AD [34]. Although the LTD types of cortical plasticity are typically not impaired in patients with AD [35], the dopaminergic modulation of LTD-like plasticity induced by low-frequency (1 Hz) rTMS stimulation has been reported to be impaired in patients with AD, which could be restored by means of levodopa treatment [36]. Taken together, these findings indicate that the impaired sensory-motor plasticity and hyperexcitability of the motor cortex are independent contributors to, or are the consequences of, the primary pathophysiological processes that give rise to AD. More recently, the TMS-based measurements have also been found useful in differentiating patients with AD from patients with frontotemporal dementia or dementia with Lewy bodies [37–39]. If these findings are confirmed, TMS parameters may be developed into clinically useful biomarkers that can help improve the diagnostic accuracy and differential diagnosis of AD [34, 40]. Treatment studies Most studies on rTMS treatment in AD patients have focused on the dorsolateral prefrontal cortex (DLPFC) due to its involvement in cognitive functions, particularly working memory and executive behavioral control [41]. To assess the DLPFC plasticity in AD patients, one study used a PAS procedure involving trains of low-frequency (0.1 Hz) TMS pulses applied to the DLPFC combined with scalp EEG recordings and median nerve electric stimulation at the wrist [42]. After the PAS procedure, the participants also completed a cognitive task assessing the working memory. The results showed that the PAS-induced potentiation of cortical, TMS-evoked potential recorded over the DLPFC was significantly smaller in patients with AD than in age-matched healthy controls. The patients also performed more poorly in the working memory task than healthy controls. Moreover, the extent of PAS-induced long-term type of potentiation in the DLPFC was associated with the performance in the working memory task. These results have been substantiated and generalized to the population of patients with mild cognitive impairment [11, 43–46]. These findings suggest that the dysfunction of DLPFC and working memory impairment are an early pathophysiological and cognitive feature of AD. A randomized, sham-controlled rTMS study reported that five daily sessions of high-frequency (20 Hz) rTMS over the DLPFC improved cognitive functioning, daily living activities, and mood/depressive symptoms in patients with mild to moderate AD, which were maintained at 1- and 3-month follow-up [47]. By contrast, the low-frequency (1 Hz) rTMS did not yield significant clinical benefits to patients in this study. Furthermore, a sham-controlled tDCS study found that the daily at-home tDCS over the DLPFC for 6 months improved or stabilized cognitive function and the rate of regional cerebral glucose metabolism in 11 patients with AD [48]. These results indicate that the rTMS- or tDCS-based interventions could play an important role in AD treatment, but the findings were preliminary and tentative due to the small sample size and limited experimental control. In addition, it has been reported that the cognitive dysfunction in patients with AD could be predicted from the measures of long-distance functional connectivity (derived from the TMS-EEG-evoked component P30 generated in the parietal cortex) between the DLPFC and the superior parietal cortex [49]. Similarly, several other studies [50–53] have found that rTMS applied to the frontal, temporal, or parietal cortical regions can improve the memory, attention, and language abilities in patients with mild to moderate degrees of AD, but again it remains to be established whether these improvements are robust and can be sustained over the long-term course of AD [54]. Cognitive training interventions have been developed that can improve the cognitive function in mild to moderate stages of AD [55–57], and the combination of these interventions with rTMS may yield larger and synergistic effects on clinical symptoms of patients. To test this, a small study interlaced rTMS with daily cognitive training sessions for 6 weeks, followed by maintenance sessions for an additional 3 months, in patients with probable AD, treated for more than 2 months with cholinesterase inhibitors [58]. The results showed that the combination of rTMS with cognitive training yielded significant improvements in the cognitive functioning and daily living activities of patients at 6-week and 4.5-month follow-ups. A multicenter randomized, double-blind, sham-controlled study (n = 131 at study entry, n = 129 at follow-up) substantiated that the combination of cognitive training with rTMS yielded improvements in cognitive function in 60- to 90-year-old, unmedicated patients with mild AD [59]. These findings suggest that the combination of rTMS with cognitive training could be a valuable approach to AD treatment. As discussed later, the combination of rTMS with physical therapy may be similarly beneficial for patients with PD. TMS in PD The administration of rTMS over the primary motor cortex or DLPFC has been found to improve the motor symptoms and non-motor symptoms (e.g., cognitive deficits, and affective symptoms) in patients with PD [12, 13, 60]. Several rTMS studies have assessed the excitability and plasticity of the motor cortex in patients with PD. A paired-pulse study examined SICI and SICF in 12 PD patients at both ON and OFF medication states and in 12 age-matched healthy controls [61]. The results revealed that SICF was increased in the PD patients in the OFF-medication state and was reduced by the administration of dopaminergic medications. Furthermore, the reduction in SICF from the OFF- to ON-medication state correlated with the improvement in PD motor signs. By contrast, SICI was found to be reduced in the PD OFF-state and could only be partially normalized by dopaminergic medications. The authors suggest that PD patients may be characterized by abnormally increased facilitation of certain cortical motor circuits, as well as by abnormally decreased inhibition of motor cortex activity. In addition, a recent study found reduced thresholds for producing MEPs in patients with PD dementia, which were also detected in AD and vascular dementia [62], indicating that the hyperexcitability of the motor cortex, as indexed by MEP-based motor thresholds, may not be specific to PD or AD. Another study used a PAS protocol to examine the MEP-based cortical plasticity in 16 patients with moderate PD and 9 healthy controls [63]. The results showed that the PAS increased the MEP size in healthy controls but not in patients who were off medication. Moreover, L-dopa restored the deficit in the PAS-induced MEP potentiation in one subgroup of 7 patients defined by the presence of dyskinesias, while it failed to restore the MEP-potentiation deficit in the other subgroup of 9 patients with dyskinesias [63]. Similar supporting evidence for the aberrant motor cortex plasticity in PD has been reported by another study using PAS [64] and a study using intermittent TBS [65]. Interestingly, in PD patients treated with DBS of the STN, the PAS-induced cortical plasticity was only evident when both DBS and medication were ON [66], indicating that DBS combined with medication can reverse the impairment of PAS-induced motor cortex plasticity in PD patients. Several studies have used tDCS to assess cortical plasticity in PD. When tDCS is used, the person under study is required to wear a headgear containing electrodes through which current can be delivered. Like rTMS, prolonged (e.g., several minutes) tDCS administration results in changes in cortical excitability that outlast the period of stimulation [67]. The administration of so-called anodal tDCS makes the brain more active and responsive, whereas cathodal tDCS decreases the activity and has inhibitory effects. It is assumed that the cortical plasticity induced by tDCS is mediated by changes in neurotransmitter function, neurotrophic signaling, and glial activity [68–70]. Clinical studies have reported that anodal tDCS over the DLPFC improves cognitive function in PD patients [48, 71, 72], as well as improving their motor functions when applied to the cortical motor areas [72, 73]. Notably, anodal tDCS combined with rTMS has been found to exert interactive, synergistic facilitating effects on gait function of PD patients [74]. Similarly, anodal tDCS combined with physical therapy seems to produce larger improvements of gait and balance in PD patients than using either tDCS or physical therapy alone [75]. DBS DBS involves the delivery of electric current to an electrode implanted in a brain structure or nucleus of interest, such as the STN in PD (Fig. 1c). The physiological effects of DBS vary by stimulation parameters (e.g., frequency, amplitude, pulse width and duration), DBS target of interest, and the preexisting brain state. In addition, the DBS effects can be affected by the brain tissue surrounding the DBS electrode, as well as by the spatial configuration of neuronal populations activated or inhibited in the targeted brain structure [76]. The physiological effects of DBS are complex and can occur at the molecular, cellular, local, and network levels (Fig. 1c) [10, 77]. Furthermore, it is important to know the inherent complexity and widespread effects of DBS, which can extend beyond the targeted networks and functions of interest (Fig. 1c) [76]. DBS has persisting effects on neurotransmitter concentration, function, and dynamics, as well as on glial activity, thereby changing the microenvironment of brain and affecting the neuroplasticity (Fig. 1d) [78, 79]. It should be added that the neurosurgical implantation of DBS electrodes provides unique opportunities to record LFPs near the contact point. Time-frequency analysis of the LFP data makes it possible to assess the integrity of neuronal oscillations in different frequency bands. The neuronal oscillations observed at the LFP level are not necessarily locally generated but may reflect the temporal summation and ‘integration’ of activity from spatially distinct populations of neurons. This allows investigation of neural synchrony by applying short trains of high-frequency DBS to induce or modulate neuronal oscillations. For example, high-frequency DBS of the STN produces an enduring LFP-based potentiation in the substantia nigra pars reticulata of patients who have received an oral administration of L-dopa, whereas the patients who have not received L-dopa administration do not show an enduring potentiation [80]. These results demonstrate that DBS can be a valuable tool to examine and modulate neuronal oscillations, which are considered to be the basis for higher brain and motor functions. DBS in AD DBS has revolutionized the treatment and care of PD patients over the past three decades [10, 81], but the application of DBS for the management of cognitive impairment in AD has only been in the beginning. Studies of DBS treatment have mainly focused on the functional integrity of the fornix in AD patients. The fornix is the major white matter fiber bundle in the limbic system and forms important input and output pathways of the hippocampus, a brain region known to mediate learning and memory processes. Accordingly, fornix DBS is hypothesized to improve memory function in AD by modulating dysfunctional hippocampal memory circuits and networks. A randomized, sham-controlled, double-blind clinical trial, however, found no significant changes in cognitive function at 1-year follow-up in patients with mild AD who had received fornix DBS [82]. In another randomized clinical trial, fornix DBS did not affect the cognitive outcomes of AD patients (n = 42), although the stimulation occasionally triggered spontaneous memory flashbacks in 48% of the patients during the initial programming of the stimulator [83]. The recollection of these vivid memories of past events reflects the declarative long-term memory, or episodic memory, which is known to be mediated by hippocampal networks and disrupted in AD. It remains to be determined why the fornix DBS treatment failed to affect the memory function in the AD patients in these two studies. A possible explanation is that these studies used open-loop DBS, rather than the closed-loop DBS that can provide timely stimulation in response to the pathological brain activity [15]. Compared to the open-loop DBS, the closed-loop DBS is more sensitive and more powerful, because the programming of DBS parameters is conducted automatically based on the measured biomarker. Indeed, it has been proposed that the disruption of intracranial LFPs or associated fast neuronal oscillations may be a rapid and effective feedback signal in the closed-loop DBS treatment for AD [15]. DBS in PD As mentioned above, DBS of the STN or GPi is a safe and effective treatment for motor symptoms of PD, but the therapeutic mechanisms remain elusive. It is commonly assumed that DBS improves PD symptoms and signs by restoring abnormal dopaminergic neurotransmission and synaptic plasticity in motor structures and networks in affected patients [10, 66, 76]. Yet, the modulation of dysfunctional glutamatergic and GABAergic pathways within the thalamocortical and corticostriatal networks may also contribute to the clinically significant improvements in motor and non-motor symptoms of severely affected, medication-refractory patients receiving DBS of the STN or GPi [10, 76, 84]. Additional clinical evidence for the involvement of neuroplasticity facilitation in the therapeutic effects of DBS in PD has come from the observation that the symptoms of PD respond to DBS treatment on dramatically varied timescales (Table 1). Most commonly, tremor and rigidity are alleviated rapidly (within seconds or minutes) after DBS, possibly through its immediate action on aberrant neurotransmission and network motor function. It takes more time (e.g., hours) for the improvement of bradykinesia by DBS, which may stem from the short-term changes in synaptic transmission and plasticity. Finally, it takes even more time (days or weeks) for axial signs of PD to respond to DBS, indicating the involvement of more enduring changes in the brain, especially the long-term plasticity and ultimately functional reorganization (Table 1). Table 1 aTime course of clinical effects and hypothesized therapeutic mechanisms of DBS in PD [77, 85] Mechanism Time after turning DBS on PD symptom Immediate modulation of synaptic function Seconds Tremor Rigidity Minutes Tremor Rigidity Bradykinesia Short-term synaptic plasticity Hours Bradykinesia Axial symptoms Long-term synaptic plasticity (functional reorganization) Days Axial symptoms Weeks Axial symptoms aBased on refs [77, 85] Future directions Various noninvasive and invasive brain stimulation techniques have emerged as valuable tools for the assessment of brain plasticity and functional modulation of cognitive and motor networks in health and disease. However, apart from DBS that has proven effective for PD, extensive research efforts are still required before these brain stimulation tools can be applied to the clinical management of neurodegenerative diseases such as AD and PD. As indicated above, a promising area of further research is the combination of different brain stimulation tools, or the combination of a single brain stimulation tool with cognitive training in AD or with physical therapy in PD. Further development of closed-loop DBS is expected to offer a powerful clinical tool that is faster and more effective in restoring ongoing pathological brain activities, especially in AD. In addition, the use of PAS typically involves the pairing of motor cortex TMS pulses with peripheral sensory nerve stimulation. A recent study employed a new technical protocol and reported that the pairing of DBS pulses at the STN and TMS pulses at the primary motor cortex at specific time intervals can induce cortical plasticity in PD patients [86]. This combination of rTMS and DBS offers a new tool to assess and modulate cortical plasticity in patients with neurodegenerative diseases. Similarly, further development of ultrasound stimulation [87] may become another brain stimulation tool to examine and modulate the impaired synaptic transmission and plasticity in neurodegenerative diseases. In a similar vein, a recent animal study on addiction used low-frequency DBS of the nucleus accumbens paired with a dopamine receptor D1 antagonist to selectively depotentiate excitatory inputs on D1-expressing medium spiny neurons, and found a reversal of synaptic plasticity and enduring abolishment of behavioral sensitization to cocaine [88]. The strategy of combining DBS with pharmacology is also novel and may enable precise targeting and modulation of neuroplasticity in key brain regions and networks involved in AD and PD. Different brain stimulation tools can be combined for both research and clinical purposes. For example, repeated pairing of DBS-TMS pulses at certain time intervals can induce cortical plasticity in PD patients [86]. Also, prior application of tDCS/tACS can potentiate or suppress the rTMS-induced plasticity [89, 90]. Furthermore, patterned DBS and TMS delivered in a repetitive mode are promising novel therapeutic interventions for neurodegenerative diseases. Conclusions The various brain stimulation techniques discussed herein have been found valuable as a research tool, but are not yet suitable as a clinical tool that assists in diagnosis, treatment, or prognosis of individual patients with AD or PD, except the DBS for PD. Well-controlled, translational, and interdisciplinary preclinical and clinical studies are needed for translating basic scientific knowledge into improved diagnostics and therapeutics. To move forward the field of brain stimulation, it is critical to elucidate the specific mechanisms of brain plasticity produced by different brain stimulation techniques, and to optimize the clinical procedure for individualized treatment based on neuroplasticity measurements. The next-generation neuromodulation systems are expected to be more flexible in terms of stimulation parameters and patterns, allowing increased control of stimulation parameters and rapid response to the patient’s ongoing neural activity in a closed-loop manner. Taken together, these research developments and technological innovations hold tremendous promise for improving the safety, clinical efficacy, and diagnostic accuracy of brain stimulation tools for AD and PD patients. Abbreviations ADAlzheimer’s disease DBSdeep brain stimulation DLPFCdorsolateral prefrontal cortex EEGelectroencephalogram GABA-AA type γ-aminobutyric acid receptor GPiglobus pallidus internus HFShigh-frequency stimulation LFPlocal field potential LTDlong-term depression LTPlong-term potentiation MEPmotor evoked potential NMDARN-methyl-D-aspartic acid receptor PASpaired associative-stimulation PDParkinson’s disease SAIshort latency afferent inhibition SICFshort intracortical facilitation SICIshort intracortical inhibition STNsubthalamic nucleus tACStranscranial alternating current stimulation TBSTheta burst stimulation tDCStranscranial direct current stimulation TEPTMS evoked potential TMStranscranial magnetic stimulation Ti-Fei Yuan, Wei-Guang Li and Chencheng Zhang contributed equally to this work. Acknowledgements We thank Jie Liu for the illustration. Authors’ contributions TFY, WGL, CZ, JL, and TLX designed the review; all authors wrote the paper together, and have read and approved the final version of the manuscript. Funding This review was supported by grants from the Science and Technology Commission of Shanghai Municipality (18JC1420302, 18JC1420303, 18JC1420304), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX05), SJTU Trans-med Awards Research (2019015), and Innovative Research Team of High-Level Local Universities in Shanghai. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. ==== Refs References 1. Barnes J Bartlett JW van de Pol LA Loy CT Scahill RI Frost C A meta-analysis of hippocampal atrophy rates in Alzheimer's disease Neurobiol Aging 2009 30 11 1711 1723 10.1016/j.neurobiolaging.2008.01.010 18346820 2. Sako W Murakami N Izumi Y Kaji R MRI can detect nigral volume loss in patients with Parkinson's disease: evidence from a meta-analysis J Parkinsons Dis 2014 4 3 405 411 10.3233/JPD-130332 24577503 3. Pisani A Centonze D Bernardi G Calabresi P Striatal synaptic plasticity: implications for motor learning and Parkinson's disease Mov Disord 2005 20 4 395 402 10.1002/mds.20394 15719415 4. Cramer SC Sur M Dobkin BH O'Brien C Sanger TD Trojanowski JQ Harnessing neuroplasticity for clinical applications Brain. 2011 134 Pt 6 1591 1609 10.1093/brain/awr039 21482550 5. Citri A Malenka RC Synaptic plasticity: multiple forms, functions, and mechanisms Neuropsychopharmacology. 2008 33 1 18 41 10.1038/sj.npp.1301559 17728696 6. Olsson B Zetterberg H Hampel H Blennow K Biomarker-based dissection of neurodegenerative diseases Prog Neurobiol 2011 95 4 520 534 10.1016/j.pneurobio.2011.04.006 21524681 7. Colom-Cadena M Spires-Jones T Zetterberg H Blennow K Caggiano A DeKosky ST The clinical promise of biomarkers of synapse damage or loss in Alzheimer's disease Alzheimers Res Ther 2020 12 1 21 10.1186/s13195-020-00588-4 32122400 8. Chapman PF White GL Jones MW Cooper-Blacketer D Marshall VJ Irizarry M Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice Nat Neurosci 1999 2 3 271 276 10.1038/6374 10195221 9. Hallett M Transcranial magnetic stimulation: a primer Neuron. 2007 55 2 187 199 10.1016/j.neuron.2007.06.026 17640522 10. Miocinovic S Somayajula S Chitnis S Vitek JL History, applications, and mechanisms of deep brain stimulation JAMA Neurol 2013 70 2 163 171 10.1001/2013.jamaneurol.45 23407652 11. Freitas C Mondragon-Llorca H Pascual-Leone A Noninvasive brain stimulation in Alzheimer's disease: systematic review and perspectives for the future Exp Gerontol 2011 46 8 611 627 21511025 12. Cantello R Tarletti R Civardi C Transcranial magnetic stimulation and Parkinson's disease Brain Res Brain Res Rev 2002 38 3 309 327 10.1016/S0165-0173(01)00158-8 11890979 13. Fregni F Simon DK Wu A Pascual-Leone A Non-invasive brain stimulation for Parkinson's disease: a systematic review and meta-analysis of the literature J Neurol Neurosurg Psychiatry 2005 76 12 1614 1623 10.1136/jnnp.2005.069849 16291882 14. Zhang C, Wang L, Hu W, Wang T, Zhao Y, Pan Y, et al. Combined unilateral subthalamic nucleus and contralateral Globus Pallidus Interna deep brain stimulation for treatment of Parkinson disease: a pilot study of symptom-tailored stimulation. Neurosurgery. 2020;87(6):1139–47. 15. Senova S Chaillet A Lozano AM Fornical closed-loop stimulation for Alzheimer's disease Trends Neurosci 2018 41 7 418 428 10.1016/j.tins.2018.03.015 29735372 16. Anderson WS Lenz FA Surgery insight: deep brain stimulation for movement disorders Nat Clin Pract Neurol 2006 2 6 310 320 10.1038/ncpneuro0193 16932575 17. Huang YZ Edwards MJ Rounis E Bhatia KP Rothwell JC Theta burst stimulation of the human motor cortex Neuron. 2005 45 2 201 206 10.1016/j.neuron.2004.12.033 15664172 18. Terranova C SantAngelo A Morgante F Rizzo V Allegra R Arena MG Impairment of sensory-motor plasticity in mild Alzheimer's disease Brain Stimul. 2013 6 1 62 66 10.1016/j.brs.2012.01.010 22476006 19. Denslow S Lomarev M George MS Bohning DE Cortical and subcortical brain effects of transcranial magnetic stimulation (TMS)-induced movement: an interleaved TMS/functional magnetic resonance imaging study Biol Psychiatry 2005 57 7 752 760 10.1016/j.biopsych.2004.12.017 15820232 20. Muller MB Toschi N Kresse AE Post A Keck ME Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain Neuropsychopharmacology. 2000 23 2 205 215 10.1016/S0893-133X(00)00099-3 10882847 21. Pell GS Roth Y Zangen A Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms Prog Neurobiol 2011 93 1 59 98 10.1016/j.pneurobio.2010.10.003 21056619 22. Gersner R Kravetz E Feil J Pell G Zangen A Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals J Neurosci 2011 31 20 7521 7526 10.1523/JNEUROSCI.6751-10.2011 21593336 23. Li Y, Huo X, Song T. The effects of chronic repetitive transcranial magnetic stimulation on glutamate and gamma-aminobutyric acid in rat brain. Brain Res. 2009;1260:94–9. 24. Moretti J Poh EZ Rodger J rTMS-induced changes in Glutamatergic and dopaminergic systems: relevance to cocaine and methamphetamine use disorders Front Neurosci 2020 14 137 10.3389/fnins.2020.00137 32210744 25. Lenz M Platschek S Priesemann V Becker D Willems LM Ziemann U Repetitive magnetic stimulation induces plasticity of excitatory postsynapses on proximal dendrites of cultured mouse CA1 pyramidal neurons Brain Struct Funct 2015 220 6 3323 3337 10.1007/s00429-014-0859-9 25108309 26. Patel R Silla F Pierce S Theule J Girard TA Cognitive functioning before and after repetitive transcranial magnetic stimulation (rTMS): a quantitative meta-analysis in healthy adults Neuropsychologia. 2020 141 107395 10.1016/j.neuropsychologia.2020.107395 32142730 27. Di Lazzaro V Oliviero A Tonali PA Marra C Daniele A Profice P Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation Neurology. 2002 59 3 392 397 10.1212/WNL.59.3.392 12177373 28. Lu B Nagappan G Guan X Nathan PJ Wren P BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases Nat Rev Neurosci 2013 14 6 401 416 10.1038/nrn3505 23674053 29. Khedr EM Ahmed MA Darwish ES Ali AM The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study Neurophysiol Clin 2011 41 3 107 113 10.1016/j.neucli.2011.03.002 21784322 30. Di Lazzaro V Oliviero A Pilato F Saturno E Dileone M Marra C Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease J Neurol Neurosurg Psychiatry 2004 75 4 555 559 10.1136/jnnp.2003.018127 15026495 31. Inghilleri M Conte A Frasca V Scaldaferri N Gilio F Santini M Altered response to rTMS in patients with Alzheimer's disease Clin Neurophysiol 2006 117 1 103 109 10.1016/j.clinph.2005.09.016 16364684 32. Di Lorenzo F Ponzo V Bonni S Motta C Negrao Serra PC Bozzali M Long-term potentiation-like cortical plasticity is disrupted in Alzheimer's disease patients independently from age of onset Ann Neurol 2016 80 2 202 210 10.1002/ana.24695 27255833 33. Koch G Di Lorenzo F Bonni S Giacobbe V Bozzali M Caltagirone C Dopaminergic modulation of cortical plasticity in Alzheimer's disease patients Neuropsychopharmacology. 2014 39 11 2654 2661 10.1038/npp.2014.119 24859851 34. Motta C Di Lorenzo F Ponzo V Pellicciari MC Bonni S Picazio S Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease J Neurol Neurosurg Psychiatry 2018 89 12 1237 1242 10.1136/jnnp-2017-317879 30464028 35. Koch G Di Lorenzo F Bonni S Ponzo V Caltagirone C Martorana A Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients J Alzheimers Dis 2012 31 3 593 599 10.3233/JAD-2012-120532 22647254 36. Koch G Esposito Z Codeca C Mori F Kusayanagi H Monteleone F Altered dopamine modulation of LTD-like plasticity in Alzheimer's disease patients Clin Neurophysiol 2011 122 4 703 707 10.1016/j.clinph.2010.10.033 21075682 37. Benussi A Di Lorenzo F Dell'Era V Cosseddu M Alberici A Caratozzolo S Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia Neurology. 2017 89 7 665 672 10.1212/WNL.0000000000004232 28747446 38. Benussi A Alberici A Ferrari C Cantoni V Dell'Era V Turrone R The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease Alzheimers Res Ther 2018 10 1 94 10.1186/s13195-018-0423-6 30227895 39. Benussi A Grassi M Palluzzi F Koch G Di Lazzaro V Nardone R Classification accuracy of Transcranial magnetic stimulation for the diagnosis of neurodegenerative dementias Ann Neurol 2020 87 3 394 404 10.1002/ana.25677 31925823 40. Maclin JMA Wang T Xiao S Biomarkers for the diagnosis of Alzheimer's disease, dementia Lewy body, frontotemporal dementia and vascular dementia Gen Psychiatr 2019 32 1 e100054 10.1136/gpsych-2019-100054 31179427 41. Fuster JM. The Prefrontal Cortex (5th edition). San Diego: Academic Press; 2015. 42. Kumar S Zomorrodi R Ghazala Z Goodman MS Blumberger DM Cheam A Extent of dorsolateral prefrontal cortex plasticity and its association with working memory in patients with Alzheimer disease JAMA Psychiatry 2017 74 12 1266 1274 10.1001/jamapsychiatry.2017.3292 29071355 43. Cotelli M Manenti R Cappa SF Geroldi C Zanetti O Rossini PM Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease Arch Neurol 2006 63 11 1602 1604 10.1001/archneur.63.11.1602 17101829 44. Miniussi C Cappa SF Cohen LG Floel A Fregni F Nitsche MA Efficacy of repetitive transcranial magnetic stimulation/transcranial direct current stimulation in cognitive neurorehabilitation Brain Stimul. 2008 1 4 326 336 10.1016/j.brs.2008.07.002 20633391 45. Rossini PM Rossi S Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential Neurology. 2007 68 7 484 488 10.1212/01.wnl.0000250268.13789.b2 17296913 46. Chou YH Ton That V Sundman M A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer's disease Neurobiol Aging 2020 86 1 10 10.1016/j.neurobiolaging.2019.08.020 31783330 47. Ahmed MA Darwish ES Khedr EM El Serogy YM Ali AM Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia J Neurol 2012 259 1 83 92 10.1007/s00415-011-6128-4 21671144 48. Im JJ Jeong H Bikson M Woods AJ Unal G Oh JK Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer's disease Brain Stimul 2019 12 5 1222 1228 10.1016/j.brs.2019.06.003 31196835 49. Bagattini C Mutanen TP Fracassi C Manenti R Cotelli M Ilmoniemi RJ Predicting Alzheimer's disease severity by means of TMS-EEG coregistration Neurobiol Aging 2019 80 38 45 10.1016/j.neurobiolaging.2019.04.008 31077959 50. Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, Cappa SF, et al. Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry. 2011;82(7):794–7. 51. Eliasova I Anderkova L Marecek R Rektorova I Non-invasive brain stimulation of the right inferior frontal gyrus may improve attention in early Alzheimer's disease: a pilot study J Neurol Sci 2014 346 1–2 318 322 10.1016/j.jns.2014.08.036 25216556 52. Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, et al. Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease. Neuroimage. 2018;169:302–11. 53. Lin Y, Jiang WJ, Shan PY, Lu M, Wang T, Li RH, et al. The role of repetitive transcranial magnetic stimulation (rTMS) in the treatment of cognitive impairment in patients with Alzheimer's disease: a systematic review and meta-analysis. J Neurol Sci. 2019;398:184–91. 54. Weiler M, Stieger KC, Long JM, Rapp PR. Transcranial Magnetic Stimulation in Alzheimer's Disease: Are We Ready? eNeuro. 2020;7(1):ENEURO.0235–19.2019. 55. Spector A Thorgrimsen L Woods B Royan L Davies S Butterworth M Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial Br J Psychiatry 2003 183 248 254 10.1192/bjp.183.3.248 12948999 56. Gates NJ Sachdev P Is cognitive training an effective treatment for preclinical and early Alzheimer's disease? J Alzheimers Dis 2014 42 Suppl 4 S551 S559 10.3233/JAD-141302 25171716 57. Hill NT Mowszowski L Naismith SL Chadwick VL Valenzuela M Lampit A Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis Am J Psychiatry 2017 174 4 329 340 10.1176/appi.ajp.2016.16030360 27838936 58. Bentwich J Dobronevsky E Aichenbaum S Shorer R Peretz R Khaigrekht M Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study J Neural Transm (Vienna) 2011 118 3 463 471 10.1007/s00702-010-0578-1 21246222 59. Sabbagh M, Sadowsky C, Tousi B, Agronin ME, Alva G, Armon C, et al. Effects of a combined transcranial magnetic stimulation (TMS) and cognitive training intervention in patients with Alzheimer's disease. Alzheimers Dement. 2020;16(4):641–50. 60. Boggio PS Fregni F Bermpohl F Mansur CG Rosa M Rumi DO Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson's disease and concurrent depression Mov Disord 2005 20 9 1178 1184 10.1002/mds.20508 15895421 61. Ni Z Bahl N Gunraj CA Mazzella F Chen R Increased motor cortical facilitation and decreased inhibition in Parkinson disease Neurology. 2013 80 19 1746 1753 10.1212/WNL.0b013e3182919029 23576626 62. Khedr EM Ahmed OG Sayed HM Abo-Elfetoh N Ali AM Gomaa AM Electrophysiological differences in cortical excitability in different forms of dementia: a transcranial magnetic stimulation and laboratory biomarkers study Neurophysiol Clin 2020 50 3 185 193 10.1016/j.neucli.2020.05.001 32591186 63. Morgante F Espay AJ Gunraj C Lang AE Chen R Motor cortex plasticity in Parkinson's disease and levodopa-induced dyskinesias Brain. 2006 129 Pt 4 1059 1069 10.1093/brain/awl031 16476674 64. Bagnato S Agostino R Modugno N Quartarone A Berardelli A Plasticity of the motor cortex in Parkinson's disease patients on and off therapy Mov Disord 2006 21 5 639 645 10.1002/mds.20778 16353175 65. Suppa A Marsili L Belvisi D Conte A Iezzi E Modugno N Lack of LTP-like plasticity in primary motor cortex in Parkinson's disease Exp Neurol 2011 227 2 296 301 10.1016/j.expneurol.2010.11.020 21145888 66. Kim SJ Udupa K Ni Z Moro E Gunraj C Mazzella F Effects of subthalamic nucleus stimulation on motor cortex plasticity in Parkinson disease Neurology. 2015 85 5 425 432 10.1212/WNL.0000000000001806 26156511 67. Ziemann U Paulus W Nitsche MA Pascual-Leone A Byblow WD Berardelli A Consensus: motor cortex plasticity protocols Brain Stimul. 2008 1 3 164 182 10.1016/j.brs.2008.06.006 20633383 68. Monte-Silva K Liebetanz D Grundey J Paulus W Nitsche MA Dosage-dependent non-linear effect of L-dopa on human motor cortex plasticity J Physiol 2010 588 Pt 18 3415 3424 10.1113/jphysiol.2010.190181 20660568 69. Stagg CJ Nitsche MA Physiological basis of transcranial direct current stimulation Neuroscientist. 2011 17 1 37 53 10.1177/1073858410386614 21343407 70. Medeiros LF de Souza IC Vidor LP de Souza A Deitos A Volz MS Neurobiological effects of transcranial direct current stimulation: a review Front Psychiatry 2012 3 110 10.3389/fpsyt.2012.00110 23293607 71. Doruk D Gray Z Bravo GL Pascual-Leone A Fregni F Effects of tDCS on executive function in Parkinson's disease Neurosci Lett 2014 582 27 31 10.1016/j.neulet.2014.08.043 25179996 72. Benninger DH Lomarev M Lopez G Wassermann EM Li X Considine E Transcranial direct current stimulation for the treatment of Parkinson's disease J Neurol Neurosurg Psychiatry 2010 81 10 1105 1111 10.1136/jnnp.2009.202556 20870863 73. Fregni F Boggio PS Santos MC Lima M Vieira AL Rigonatti SP Noninvasive cortical stimulation with transcranial direct current stimulation in Parkinson's disease Mov Disord 2006 21 10 1693 1702 10.1002/mds.21012 16817194 74. von Papen M Fisse M Sarfeld AS Fink GR Nowak DA The effects of 1 Hz rTMS preconditioned by tDCS on gait kinematics in Parkinson's disease J Neural Transm (Vienna) 2014 121 7 743 754 10.1007/s00702-014-1178-2 24562404 75. Kaski D Dominguez RO Allum JH Islam AF Bronstein AM Combining physical training with transcranial direct current stimulation to improve gait in Parkinson's disease: a pilot randomized controlled study Clin Rehabil 2014 28 11 1115 1124 10.1177/0269215514534277 24849794 76. Kringelbach ML Green AL Owen SL Schweder PM Aziz TZ Sing the mind electric - principles of deep brain stimulation Eur J Neurosci 2010 32 7 1070 1079 10.1111/j.1460-9568.2010.07419.x 21039946 77. Herrington TM Cheng JJ Eskandar EN Mechanisms of deep brain stimulation J Neurophysiol 2016 115 1 19 38 10.1152/jn.00281.2015 26510756 78. McIntyre CC Anderson RW Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation J Neurochem 2016 139 Suppl 1 338 345 10.1111/jnc.13649 27273305 79. Vedam-Mai V, van Battum EY, Kamphuis W, Feenstra MG, Denys D, Reynolds BA, et al. Deep brain stimulation and the role of astrocytes. Mol Psychiatry. 2012;17(2):124–31. 80. Prescott IA Dostrovsky JO Moro E Hodaie M Lozano AM Hutchison WD Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients Brain. 2009 132 Pt 2 309 318 10.1093/brain/awn322 19050033 81. Armstrong MJ Okun MS Diagnosis and treatment of Parkinson disease: a review JAMA. 2020 323 6 548 560 10.1001/jama.2019.22360 32044947 82. Lozano AM Fosdick L Chakravarty MM Leoutsakos JM Munro C Oh E A phase II study of fornix deep brain stimulation in mild Alzheimer's disease J Alzheimers Dis 2016 54 2 777 787 10.3233/JAD-160017 27567810 83. Deeb W Salvato B Almeida L Foote KD Amaral R Germann J Fornix-region deep brain stimulation-induced memory flashbacks in Alzheimer's disease N Engl J Med 2019 381 8 783 785 10.1056/NEJMc1905240 31433930 84. Li D Zhang C Gault J Wang W Liu J Shao M Remotely programmed deep brain stimulation of the bilateral subthalamic nucleus for the treatment of primary Parkinson disease: a randomized controlled trial investigating the safety and efficacy of a novel deep brain stimulation system Stereotact Funct Neurosurg 2017 95 3 174 182 10.1159/000475765 28571034 85. Temperli P Ghika J Villemure JG Burkhard PR Bogousslavsky J Vingerhoets FJ How do parkinsonian signs return after discontinuation of subthalamic DBS? Neurology. 2003 60 1 78 81 10.1212/WNL.60.1.78 12525722 86. Udupa K Bahl N Ni Z Gunraj C Mazzella F Moro E Cortical plasticity induction by pairing subthalamic nucleus deep-brain stimulation and primary motor cortical Transcranial magnetic stimulation in Parkinson's disease J Neurosci 2016 36 2 396 404 10.1523/JNEUROSCI.2499-15.2016 26758832 87. Zhou H, Niu L, Meng L, Lin Z, Zou J, Xia X, et al. Noninvasive ultrasound deep brain stimulation for the treatment of Parkinson's disease model mouse. Research (Wash D C). 2019;2019:1748489. 88. Creed M Pascoli VJ Luscher C Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology Science. 2015 347 6222 659 664 10.1126/science.1260776 25657248 89. Guerra A Suppa A Bologna M D'Onofrio V Bianchini E Brown P Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation Brain Stimul. 2018 11 4 734 742 10.1016/j.brs.2018.03.015 29615367 90. Cosentino G Fierro B Paladino P Talamanca S Vigneri S Palermo A Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex Eur J Neurosci 2012 35 1 119 124 10.1111/j.1460-9568.2011.07939.x 22211744