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Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: A systematic review and meta-analysis
Abstract
Background
Pharmacological and conventional non‐pharmacological treatments for behavioural and psychological symptoms of dementia (BPSD) have only modest efficacy. Furthermore, pharmacotherapy carries the risk of important side‐effects. Non‐invasive brain stimulation (repetitive transcranial magnetic stimulation; TMS or transcranial direct current stimulation; tDCS) are valuable and safe for cognitive function in Alzheimer Disease (AD). However, there have been few studies, and there is no consensus, regarding the use of these techniques to treat BPSD.
Methods
We performed a systematic review of the literature and meta‐analysis of studies reporting the effect of rTMS or tDCS on BPSD.
Results
Seven articles were included. Five randomized, controlled clinical trials and 2 open‐label clinical trials. Five studies investigated the effects of rTMS and two the effects of tDCS. Both studies using tDCS reported no evidence of efficacy on BPSD, while 2 of the 3 RCT's using rTMS found statistically significant benefits. In an exploratory meta‐analysis with 4 of the RCT studies we did not find evidence of efficacy of non‐invasive brain stimulation techniques, with an overall effect of – 0.02 (95% CI= ‐0.90, 0.94; I²=85%). However, when we used only the data from the studies that applied rTMS we found a positive effect on BPSD, with an overall effect of ‐0.58(95% CI=‐1.02, ‐0.14; I²=0%). With regards to the adverse effects reported, these were mild and not clinically relevant.
Conclusions
Our results establish a tendency for efficacy of rTMS protocols on BPSD, while corroborating their safety and tolerability, suggesting the need for further research.
... Apathy, broadly described as diminished motivation for goaldirected activities across various domains including behavior, cognition, emotion, and social interaction (Dujardin, 2013;Marin, 1991), is one of the most pervasive and frequent NPS associated with AD, and has an overall prevalence of approximately around 50% (Grossman et al., 2021;Zhao et al., 2016). Further, apathy accelerates the progression from MCI to dementia and are linked to greater functional and cognitive deficits (Palmer et al., 2010;van Dalen et al., 2018). The primary drivers and precise mechanism of apathy in AD is little understood, and it is also uncertain if it arises as secondary psychological responses brought on by cognitive deficiencies or whether they are a direct consequence of AD pathology. ...
... A recent meta-analysis sheds light on the non-pharmacological interventions, including emotional and stimulation-based approaches and their effectiveness in alleviating apathetic symptoms in MCI and dementia (Vacas et al., 2019). The use of such interventions (e.g., art and music therapy, exercise etc.), however, appears quite inconsistent and difficult from a methodological perspective, and lacks conceptual precision (Ferrero-Arias et al., 2011;Goris et al., 2016;Manera et al., 2020). ...
... Neuromodulation approaches, such as repetitive transcranial magnetic stimulation (rTMS), electric convulsive therapy, and transcranial direct current stimulation (tDCS), have also been recently suggested for the treatment of negative symptoms in Alzheimer's (Nagata et al., 2022). Although their effectiveness in treating apathy is still unclear, preliminary research suggests that approaches like rTMS maybe useful in reducing behavioral disturbances (Vacas et al., 2019). While repeated anodal tDCS across left dlPFC had no effects on apathy in individuals with mild AD (Suemoto et al., 2014), rTMS over the same region was associated with improved AES-C scores in MCI patients (Padala et al., 2018). ...
In addition to memory deficits and other cognitive disturbances, patients with Alzheimer's disease (AD) experience neuropsychiatric symptoms, notably apathy, which is a state of impaired motivation observed by deficits in goal directed behavior. Apathy is a multifaceted neuropsychiatric condition and appears to be a prognostic indicator, correlating with the progression of AD. Strikingly, recent studies point out that the neurodegenerative pathology of AD may drive apathy independent of cognitive decline. These studies also highlight that neuropsychiatric symptoms, in particular apathy, might manifest early in AD. Here, we review the current understanding of the neurobiological underpinnings of apathy as a neuropsychiatric symptom of AD. Specifically, we highlight the neural circuits and brain regions recognized to be correlated with the apathetic symptomatology. We also discuss the current evidence that supports the notion that apathy and cognitive deficits may develop as independent but concurrent phenomena driven by AD pathology, suggesting its efficacy as an additional outcome measure in Alzheimer's disease clinical trials. The current and prospective therapeutic interventions for apathy in AD from a neurocircuitry based perspective are also reviewed.
... The risk of bias frequently affected the domains of the randomization process and selection of the reported data while missing outcome was rare. Unclear reporting was present involving INTRODUCTION Non-invasive brain stimulation (NIBS) has been tested to modify the cognition of healthy participants, as well as to mitigate cognitive symptoms in neurodegenerative disorders (Guse et al., 2010;Vacas et al., 2019). The two most common forms of NIBS, namely transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have both been characterized by a great variability of application and diverse stimulation parameters. ...
... Although accumulating evidence supports the efficacy of TMS in modulating cognition, not only the determination of the effectiveness, but also the estimation of the effect size is crucial which likewise needs to be based on reliable data. Reviews indicating positive cognitive effects of NIBS in neurodegenerative disorders have reported serious limitations of the analyzed studies (Freitas et al., 2011;Elder and Taylor, 2014;Hsu et al., 2015;Vacas et al., 2019). The limitations included high heterogeneity among the applied measurements and stimulation parameters, increased variability due to specific characteristics among demented samples, and low statistical power resulting from small sample sizes. ...
... We included data from 36 clinical trials. Several reviews and meta-analyses have lately concluded the positive effect of NIBS in neurodegenerative disorders (Freitas et al., 2011;Elder and Taylor, 2014;Hsu et al., 2015;Vacas et al., 2019); however, important limitations have been overlooked involving the methodology and the stimulation parameters. Our goal was to examine the extent to which these methodological issues are present in the field, and to provide objective recommendations on how to improve future research. ...
Background: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been proposed as a new therapeutic way to enhance the cognition of patients with dementia. However, serious methodological limitations appear to affect the estimates of their efficacy. We reviewed the stimulation parameters and methods of studies that used TMS or tDCS to alleviate the cognitive symptoms of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Moreover, we evaluated the risk of bias in these studies. Our aim was to highlight the current vulnerabilities of the field and to formulate recommendations on how to manage these issues when designing studies. Methods: Electronic databases and citation searching were used to identify studies administering TMS or tDCS on patients with AD or MCI to enhance cognitive function. Data were extracted by one review author into summary tables with the supervision of the authors. The risk of bias analysis of randomized-controlled trials was conducted by two independent assessors with version 2 of the Cochrane risk-of-bias tool for randomized trials. Results: Overall, 36 trials were identified of which 23 randomized-controlled trials underwent a risk of bias assessment. More than 75% of randomized-controlled trials involved some levels of bias in at least one domain. Stimulation parameters were highly variable with some ranges of effectiveness emerging. Studies with low risk of bias indicated TMS to be potentially effective for patients with AD or MCI while questioned the efficacy of tDCS. Conclusions: The presence and extent of methodical issues affecting TMS and tDCS research involving patients with AD and MCI were examined for the first time. The risk of bias frequently affected the domains of the randomization process and selection of the reported data while missing outcome was rare. Unclear reporting was present involving randomization, allocation concealment, and blinding. Methodological awareness can potentially reduce the high variability of the estimates regarding the effectiveness of TMS and tDCS. Studies with low risk of bias delineate a range within TMS parameters seem to be effective but question the efficacy of tDCS.
... In one meta-analysis, repetitive transcranial magnetic stimulation (rTMS) was found to be beneficial for the management of BPSD (overall effect, −0.58; p=0.01). 17 The only adverse effect noted from the rTMS was tiredness, and it was noted as being mild. One systematic review noted that approximately 88% of individuals with BPSD receiving electroconvulsive therapy (ECT) showed improvements on yelling, screaming, agitation, aggression, and food intake. ...
... These medication classes and treatments have multiple trials to assess their efficacy and adverse effects among individuals with BPSD. [12][13][14][15][16][17][18] However, evidence for the use of propranolol for the management of BPSD is similar to the evidence available for using prazosin Contributions: RRT conceptualized the article and wrote the introduction, results, discussions, and conclusion sections of the article. RRT and DJT completed the literature search for this review. ...
Propranolol is a β-adrenergic antagonist used in the management of hypertension, cardiac arrhythmia, and angina pectoris. There is some evidence that propranolol may benefit individuals with behavioural and psychological symptoms of dementia (BPSD). A total of three case series, one randomized controlled trial and one case report were identified (from a literature search of three major databases: PubMed, Ovid, and Cochrane collaboration) that assessed the use of propranolol for the management of BPSD. From these studies, it appears that propranolol improves BPSD, including agitation and aggression. Propranolol is also well tolerated with no significant bradycardia or hypotension noted in these studies. Current data on the use of propranolol for the management of BPSD are limited in comparison to other pharmacological agents (atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, and cannabinoids) and treatment modalities (repetitive transcranial magnetic stimulation and electroconvulsive therapy). The efficacy and safety of these treatments among individuals with BPSD has been evaluated in multiple controlled studies. In clinical practice, the routine use of propranolol among people with BPSD cannot be recommended at this time given the limited data. However, propranolol can be trialled among individuals with BPSD when symptoms have not responded adequately to other medications. Propranolol may also be used prior to embarking on trials of repetitive transcranial magnetic stimulation and electroconvulsive therapy among people with BPSD given the greater acceptance of this medication in the general population.
... Presently, successful neuroprotective or curative treatments for AD are lacking [1]. However, one promising alternative therapy is repetitive Transcranial Magnetic Stimulation (rTMS) [2]. Most studies have chosen the dorsolateral prefrontal cortex (DLPFC) as the stimulus target because of its neuroplasticity and important role in cognitive functions (such as association memory) [3]. ...
... Robust synaptic plasticity is critical for cognitive processes, such as learning and memory [7]. Liao and Sara et al. demonstrated the efficacy of rTMS on cognitive function and behavioral psychiatric symptoms of AD [2,8]. In addition, the correlation analysis in our study demonstrated improvement in cognition assessment in addition to the improvement in depression symptoms (p > 0.05; see supplemental material). ...
... Repetitive transcranial magnetic stimulation (rTMS) is noninvasive stimulation applied to the brain transcranially and produces favorable outcomes for patients with various neurological and psychiatric disorders (Lefaucheur et al. 2014). Previous studies have demonstrated that rTMS could help improve individuals' cognitive function (Hsu et al. 2015) and alleviate behavioral and psychological symptoms (BPSD) in AD (Vacas et al. 2018). However, among these clinical studies, the protocols (e.g., stimulated areas, parameters) are inconsistent and in-depth research on the underlying mechanisms has been rare. ...
... In the present study, rTMS-CT helped to improve BPSD, which may be attributable to the following reasons. First, the left DLPFC is involved in regulating and controlling emotion and behavior (Vacas et al. 2018). As described in previous studies (Kumfor et al. 2018;Rosenberg et al. 2015), a higher score for cognitive apathy in the NPI assessment and for agitation in patients with AD was associated with an impairment in the frontal cortex-especially in the dorsomedial prefrontal cortex and the frontal pole. ...
Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer’s disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [¹H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using ¹H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer’s Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.
... Transcranial The lack of consistent efficacy for improving apathy and depression across investigations of noninvasive brain stimulation may be attributed to study methodologies, including the stimulation parameters utilized, diagnostic criteria for the NCD or the behavioral syndrome, or a study's sample size. 143 Considering the promising evidence from some trials, future research with noninvasive brain stimulation for treating apathy and depression is warranted. Trials demonstrating efficacy in improving apathy and depression may provide further evidence to support the distinct neuroanatomical substrates of apathy and depression in this patient population. ...
Objectives:
This narrative review describes the clinical features of apathy and depression in individuals with neurocognitive disorders (NCDs), with the goal of differentiating the two syndromes on the basis of clinical presentation, diagnostic criteria, neuropathological features, and contrasting responses to treatments.
Methods:
Literature was identified using PubMed, with search terms to capture medical conditions of interest; additional references were also included based on our collective experience and knowledge of the literature.
Results:
Evidence from current literature supports the distinction between the two disorders; apathy and depression occur with varying prevalence in individuals with NCDs, pose different risks of progression to dementia, and have distinct, if overlapping, neurobiological underpinnings. Although apathy is a distinct neuropsychiatric syndrome, distinguishing apathy from depression can be challenging, as both conditions may occur concurrently and share several overlapping features. Apathy is associated with unfavorable outcomes, especially those with neurodegenerative etiologies (e.g., Alzheimer's disease) and is associated with an increased burden for both patients and caregivers. Diagnosing apathy is important not only to serve as the basis for appropriate treatment, but also for the development of novel targeted interventions for this condition. Although there are currently no approved pharmacologic treatments for apathy, the research described in this review supports apathy as a distinct neuropsychiatric condition that warrants specific treatments aimed at alleviating patient disability.
Conclusions:
Despite differences between these disorders, both apathy and depression pose significant challenges to patients, their families, and caregivers; better diagnostics are needed to develop more tailored treatment and support.
... 4,14 These effects are spread-out via structural and/or connectivity to other areas involved in the network corresponding to the stimulated area, with the aim of establishing optimal neural activity between their nodes. 15 In recent decades, NIBS techniques have been used therapeutically to normalize aberrant patterns of cortical activity and ameliorate abnormal brain function for management of several neurological disorders including chronic pain 16,17 , motor function, cognitive and communication impairments caused by stroke [18][19][20][21][22] , or neurodegenerative diseases [23][24][25] , or psychiatric disorders such as depression 26,27 , anxiety disorders 28,29 , obsessive-compulsive disorder 30,31 , schizophrenia 32,33 , and craving/addiction. 34,35 In addition, some studies using NIBS have shown promise effects in improving motor performance in non-athletes 9,36 and athletes. ...
Background: With the increasing meta-analysis studies of noninvasive brain stimulation (NIBS) a major review has become a logical step to provide evidence to support decision-makers.
Objective: Umbrella reviews of the Working-Group of NAPeN Network (a Brazilian scientific network for NIBS development) will summarize the results of existing evidence in meta-analysis with focus on NIBS techniques applied forclinical settings, exercise and sports science.
Methods and materials: Firstly, a screening was performed to identify meta-analysis in which NIBS were applied to neurological and psychiatric disorders and healthy subjects. A second literature search was conducted in the Pubmed using a PICO-question for each population and NIBS techniques found in the first search. Methodological quality and certainty of evidence will be evaluated using the AMSTAR 2 and GRADE framework, respectively.
Partial results: After the first search, we found meta-analyses including repetitive transcranial magnetic stimulation and transcranial direct current stimulation, applied in populations with neurological (cerebral palsy, chronic pain, dementia, epilepsy, essential tremor, multiple sclerosis, Parkinson’s disease, tinnitus, tourette syndrome, and stroke) and psychiatric disorders (anxiety, attention-deficit hyperactivity, autism spectrum, obsessive-compulsive and post-traumatic stress disorders, schizophrenia, craving/addiction and depression), and in healthy subjects. A total of 118 meta-analyses will be included in the qualitative review. The results of evidence were identified in the outcomes of seven umbrella reviews.
Conclusion: Evidence of therapeutic and nontherapeutic use of NIBS techniques will support experts to produce consensus statements and assist professionals in making decisions of incorporating or not NIBS into clinical practice.
... 4,14 These effects are spread-out via structural and/or connectivity to other areas involved in the network corresponding to the stimulated area, with the aim of establishing optimal neural activity between their nodes. 15 In recent decades, NIBS techniques have been used therapeutically to normalize aberrant patterns of cortical activity and ameliorate abnormal brain function for management of several neurological disorders including chronic pain 16,17 , motor function, cognitive and communication impairments caused by stroke [18][19][20][21][22] , or neurodegenerative diseases [23][24][25] , or psychiatric disorders such as depression 26,27 , anxiety disorders 28,29 , obsessive-compulsive disorder 30,31 , schizophrenia 32,33 , and craving/addiction. 34,35 In addition, some studies using NIBS have shown promise effects in improving motor performance in non-athletes 9,36 and athletes. ...
BACKGROUND: With the increasing meta-analysis studies of noninvasive brain stimulation (NIBS) a major review has become a logical step to provide evidence to support decision-makers. OBJECTIVE: Umbrella reviews of the Working-Group of NAPeN Network (a Brazilian scientific network for NIBS development) will summarize the results of existing evidence in meta-analysis with focus on NIBS techniques applied for clinical settings, exercise and sports science. METHODS AND MATERIALS: Firstly, a screening was performed to identify meta-analysis in which NIBS were applied to neurological and psychiatric disorders and healthy subjects. A second literature search was conducted in the Pubmed using a PICO-question for each population and NIBS techniques found in the first search. Methodological quality and certainty of evidence will be evaluated using the AMSTAR 2 and GRADE framework, respectively. PARTIAL RESULTS: After the first search, we found meta-analyses including repetitive transcranial magnetic stimulation and transcranial direct current stimulation, applied in populations with neurological (cerebral palsy, chronic pain, dementia, epilepsy, essential tremor, multiple sclerosis, Parkinson's disease, tinnitus, tourette syndrome, and stroke) and psychiatric disorders (anxiety, attention-deficit hyperactivity, autism spectrum, obsessive-compulsive and post-traumatic stress disorders, schizophrenia, craving/ addiction and depression), and in healthy subjects. A total of 118 meta-analyses will be included in the qualitative review. The results of evidence were identified in the outcomes of six umbrella reviews. CONCLUSION: Evidence of therapeutic and nontherapeutic use of NIBS techniques will support experts to produce consensus statements and assist professionals in making decisions of incorporating or not NIBS into clinical practice.
... Alzheimer's disease [67][68][69][70] and in patients with cognitive deficits and dementia. [71][72][73] The beneficial effect of rTMS treatment has also been shown in improving episodic memory in cognitively deficient individuals 74 14 and extends to other brain areas through decrease/ increase in axonal release of monoamine neurotransmitters, such as dopamine. 81 tDCS has widely been used to treat several mental, neuropsychiatric, and cognitive disorders (see a summary in Table 2). ...
Treatment for brain diseases has been disappointing because available medications have failed to produce clinical response across all the patients. Many patients either do not respond or show partial and inconsistent effect, and even in patients who respond to the medications have high relapse rates. Brain stimulation has been seen as an alternative and effective remedy. As a result, brain stimulation has become one of the most valuable therapeutic tools for combating against brain diseases. In last decade, studies with the application of brain stimulation techniques not only have grown exponentially but also have expanded to wide range of brain disorders. Brain stimulation involves passing electric currents into the cortical and subcortical area brain cells with the use of noninvasive as well as invasive methods to amend brain functions. Over time, technological advancements have evolved into the development of precise devices; however, at present, most used noninvasive techniques are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), whereas the most common invasive technique is deep brain stimulation (DBS). In the current review, we will provide an overview of the potential of noninvasive (rTMS and tDCS) and invasive (DBS) brain stimulation techniques focusing on the treatment of mental, psychiatric, and cognitive disorders.
... A meta-analysis by Vacas et al. that included data from two studies of rTMS amongst individuals with NPS found benefits for rTMS amongst individuals with BPSD (overall effect −0.58; p=0.01). 29 The investigators found that minor tiredness was the only adverse effect identified from rTMS. ...
Prazosin, a centrally acting α1 adrenoceptor antagonist, has been included in two published algorithms amongst the list of medications that may be used in the management of behavioural and psychological symptoms of dementia (BPSD). However, a review of PubMed, Ovid and Cochrane Collaboration found that there was only one small published randomized controlled trial (RCT) that evaluated the use of prazosin amongst individuals with BPSD. Evidence from this good quality RCT indicates that prazosin appears to benefit individuals with agitation and aggression amongst individuals with BPSD and this medication is well tolerated. When compared to other treatments for BPSD, including atypical antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, repetitive transcranial magnetic stimulation and electroconvulsive therapy, where there are multiple studies for each of these treatment modalities, the data for the use of prazosin for BPSD are limited to just one good quality RCT. Given the limitations in available data, the routine use of prazosin for the treatment of BPSD cannot be recommended at this time. However, prazosin may be used for the management of agitation and aggression amongst individuals with dementia when other medication classes, like acetylcholinesterase inhibitors, memantine, antidepressants and/or atypical antipsychotics, have been ineffective or not tolerated.
... In recent decades, NIBS techniques have been used therapeutically to normalize aberrant patterns of cortical activity and ameliorate abnormal brain function for management of several neurological disorders including chronic pain [16,17], motor function, cognitive and communication impairments caused by stroke [18][19][20][21][22], or neurodegenerative diseases [23][24][25], or psychiatric disorders such as depression [26,27], anxiety disorders [28,29], obsessive-compulsive disorder [30,31], schizophrenia [32,33], and craving/addiction [34,35]. In addition, some studies using NIBS have shown promise effects in improving motor performance in non-athletes [9,36] and athletes [37,38]. ...
... Recently published reviews and meta-analyses made inconsistent conclusions on the effects of NIBS on global cognition and specific cognitive domains in MCI and AD. [32][33][34][35][36] According to Chu et al's 37 meta-analysis investigating the effects of NIBS on both AD and MCI, no significant effects of NIBS were found in patients with MCI subgroups. Even in the main outcomes, NIBS did not show any clinical meaningful benefits on global cognition in MCI and AD. ...
The therapeutic approaches currently applied in Alzheimer's disease (AD) and similar neurodegenerative diseases are essentially based on pharmacological strategies. However, despite intensive research, the effectiveness of these treatments is limited to transient symptomatic effects, and they are still far from exhibiting a true therapeutic effect capable of altering prognosis. The lack of success of such pharmacotherapy-based protocols may be derived from the cases in the majority of trials being too advanced to benefit significantly in therapeutic terms at the clinical level. For neurodegenerative diseases, mild cognitive impairment (MCI) may be an early stage of the disease continuum, including Alzheimer's. Noninvasive brain stimulation (NIBS) techniques have been developed to modulate plasticity in the human cortex in the last few decades. NIBS techniques have made it possible to obtain unique findings concerning brain functions, and design novel approaches to treat various neurological and psychiatric conditions. In addition, its synaptic and cellular neurobiological effects, NIBS is an attractive treatment option in the early phases of neurodegenerative diseases, such as MCI, with its beneficial modifying effects on cellular neuroplasticity. However, there is still insufficient evidence about the potential positive clinical effects of NIBS on MCI. Furthermore, the huge variability of the clinical effects of NIBS limits its use. In this article, we reviewed the combinatory approach of NIBS with various neuroimaging and electrophysiological methods. Such methodologies may provide a new horizon to the path for personalized treatment, including a more individualized pathophysiology approach which might even define new specific targets for specific symptoms of neurodegenerations.
... Alzheimer's disease [67][68][69][70] and in patients with cognitive deficits and dementia. [71][72][73] The beneficial effect of rTMS treatment has also been shown in improving episodic memory in cognitively deficient individuals 74 14 and extends to other brain areas through decrease/ increase in axonal release of monoamine neurotransmitters, such as dopamine. 81 tDCS has widely been used to treat several mental, neuropsychiatric, and cognitive disorders (see a summary in Table 2). ...
... When neuropsychiatric symptoms have been examined, they are usually assessed as a secondary outcome and without specifying the symptom. There is preliminary evidence to suggest that rTMS might be effective for attenuating their severity [94]. A very recent preliminary study of apathy in AD found that stimulation to the left dorsolateral prefrontal cortex was associated with greater improvement in AES-C relative to sham treatment [95]. ...
Apathy is a neurobehavioral syndrome characterized by impaired motivation for goal-directed behaviors and cognitive activity, alongside blunted affect. Apathy is a common neuropsychiatric syndrome in Alzheimer's disease (AD), with a 5-year prevalence over 70%. Apathy also serves as a prognostic indicator, correlating with the progression of AD. Despite advances in its conceptualization and understanding of its neural basis, there is very limited empirical evidence to support the available strategies for the treatment of apathy in AD. Given its complex pathophysiology, including distinct substrates for different apathy dimensions (affective, cognitive, and behavioral), it is unlikely that a single pharmacological or nonpharmacological strategy will be effective for all cases of apathy in AD. High-quality evidence research is needed to better understand the role of specific strategies aiming at a personalized approach.
... The DLPFC, which anatomically corresponds to Brodmann areas 9 and 46, is one of the most popular rTMS targets for treating cognitive impairment. Although high-frequency rTMS of the left DLPFC has been found to be effective in alleviating cognitive symptoms in patients with MCI (Drumond Marra et al., 2015;Cheng et al., 2018) and AD (Luber and Lisanby, 2014;Vacas et al., 2019), the neuroimaging mechanisms are poorly understood. Uncovering the mechanisms of action of TMS is critical to improving treatment efficacy and developing new therapeutic stimulation parameters. ...
Individuals with amnestic mild cognitive impairment (aMCI) have a high risk of developing Alzheimer's disease. Although repetitive transcranial magnetic stimulation (rTMS) is considered a potentially effective treatment for cognitive impairment in patients with aMCI, the neuroimaging mechanisms are poorly understood. Therefore, we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University, China. Twenty-four patients with aMCI were randomly assigned to receive true rTMS (treatment group, n = 12, 6 men and 6 women; age 65.08 ± 4.89 years) or sham stimulation (sham group, n = 12, 5 men and 7 women; age 64.67 ± 4.77 years). rTMS parameters included a stimulation frequency of 10 Hz, stimulation duration of 2 seconds, stimulation interval of 8 seconds, 20 repetitions at 80% of the motor threshold, and 400 pulses per session. rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks. Our results showed that compared with baseline, Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation (ALFF) was significantly increased at the end of treatment and 1 month after treatment. Compared with the sham group, the ALFF values in the right inferior frontal gyrus, triangular part of the inferior frontal gyrus, right precuneus, left angular gyrus, and right supramarginal gyrus were significantly increased, and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group. These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas. This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University, China (approval No. BYL20190901) on September 3, 2019, and registered in the Chinese Clinical Trials Registry (registration No. ChiCTR1900028180) on December 14, 2019.
... 5 Non-invasive neuromodulation therapies (for example transcranial magnetic stimulation; transcranial direct current stimulation) are currently being investigated for the treatment of neuropsychological symptoms, such as aggressive behaviour and agitation. 9 These techniques can alter cortical excitability, resulting in widespread connectivity modifications and restoration of normal connectivity patterns. 10,11 More recently, low-intensity focused ultrasound has emerged as a neuromodulatory alternative to target deep cortical areas and subcortical structures. ...
Aggressive behaviour is a highly prevalent and devastating condition in autism spectrum disorder resulting in impoverished quality of life. Gold-standard therapies are ineffective in about 30% of patients leading to greater suffering. We investigated cortical thickness in individuals with autism spectrum disorder with pharmacological-treatment-refractory aggressive behaviour compared with those with non-refractory aggressive behaviour and observed a brain-wide pattern of local increased thickness in key areas related to emotional control and overall decreased cortical thickness in those with refractory aggressive behaviour, suggesting refractoriness could be related to specific morphological patterns. Elucidating the neurobiology of refractory aggressive behaviour is crucial to provide insights and potential avenues for new interventions.
... Noninvasive brain stimulation methods such as repetitive transcranial magnetic stimulation, (rTMS) and transcranial direct current stimulation (tDCS) have been tested in depression, schizophrenia, autism, and cognitive deficits in AD and MCI (Wei et al., 2017;Barahona-Correâ et al., 2018;Cruz Gonzalez et al., 2018;Osoegawa et al., 2018). A meta-analysis of randomized controlled trials found rTMS protocols to demonstrate efficacy but not tDCS (Vacas et al., 2018); however, both were found to demonstrate safety and tolerability in the studied population. ...
The core symptoms of different dementia subtypes are the behavioral and psychological symptoms of dementia (BPSD) and its neuropsychiatric symptoms (NPS). BPSD symptoms may occur at any stage in the case of dementia due to Alzheimer’s disease (AD), whereas they tend to occur early on in the case of its behavioral variant frontotemporal dementia or dementia with Lewy bodies and are essential for diagnosis. BPSD treatment consists of non-pharmacological as well as pharmacological interventions, with non-pharmacological interactions being suggested as first-line treatment. Agitation, psychotic features, apathy, depression, and anxiety may not respond to acetylcholinesterase inhibitors or memantine in AD cases; therefore, antipsychotics, antidepressants, sedative drugs or anxiolytics, and antiepileptic drugs are typically prescribed. However, such management of BPSD can be complicated by hypersensitivity to antipsychotic drugs, as observed in DLB, and a lack of effective pro-cognitive treatment in the case of frontotemporal dementia. The present paper reviews current knowledge of the management of BPSD and its limitations and discusses on-going clinical trials and future therapeutic options.
... Although the application of these methods has reportedly contributed to the positive outcomes in clinical states (e.g., see Lefaucheur et al., 2020), the effects induced in the brain are not fully understood. According to the growing number of meta-analyses, the efficacy of brain stimulation methods is inconsistent across different conditions, e.g., depression (Razza et al., 2020;Sonmez et al., 2019;Moffa et al., 2020), mild cognitive impairments and dementia (Vacas et al., 2019;Chou et al., 2020;Wang et al., 2020), anxiety and post-traumatic stress (Cirillo et al., 2019), autism spectrum disorders (Barahona-Corrêa et al., 2018), ADHD (Salehinejad et al., 2019), positive and negative symptoms of schizophrenia (Aleman et al., 2018;Kim et al., 2019;Yang et al., 2019). Further research could benefit from the combination of NIBS with different neurophysiological measures like ASSR. ...
Neural oscillations represent a fundamental mechanism that enables coordinated action during normal brain functioning. Auditory steady-state responses (ASSRs) are used to test the ability to generate gamma-range activity. Different non-invasive brain stimulation (NIBS) techniques have the potential to modulate neural activation patterns that are aberrant in a variety of neuropsychiatric disorders. Here, we summarize the current state of knowledge on how different methods of NIBS (transcranial altering current stimulation—tACS, transcranial direct current stimulation—tDCS, transcranial random noise stimulation—tRNS, paired associative stimulation—PAS, repetitive transcranial magnetic stimulation—rTMS) affect the gamma-range ASSRs in both healthy and clinical populations. We show that the current research has been far from systematic and methodologically heterogeneous. Nevertheless, some brain stimulation techniques, especially tACS and rTMS show strong potential for further exploration. We outline the main findings and provide directions for further research into neuromodulation of ASSRs as a promising biomarker of different psychopathological conditions such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), autism.
... Compared with meta-analysis studies that aim for a summary of findings in a relatively established research topic, some reviews focus on exploring potential questions and mechanisms in a new direction of research with a limited set of available studies (Hirsch et al., 2018;Vacas et al., 2018;Lan et al., 2017;Bala et al., 2013). The goal of this study is consistent with the latter group and aims to explore the relative new direction of tDCS in treatment for AVH and its potential underlying mechanisms. ...
Auditory hallucinations are the most common psychiatric symptoms of schizophrenia with high recurrence and refractoriness. Transcranial direct current stimulation (tDCS), a novel, non-invasion and affordable brain stimulation technique, has been recently applying on the schizophrenia patients to treat the auditory hallucinations. To analyze the efficacy of tDCS treatment on such symptoms and to reveal its potential working mechanisms, we carried out a structured literature search in PubMed, Embase and Cochrane Library database up to May 12, 2018. Five studies that met inclusion criteria with a total of 137 patients were included in this meta-analysis. After pooling all the data, we found that there was no significant effect between active group and sham group of tDCS (p = 0.18). When we removed one study that did not collaboratively stimulate the frontal-temporal sites, the active tDCS group marks a significant improvement of therapeutic effect compared with sham group (p = 0.007). Our findings suggested that tDCS could be a promising tool to alleviate auditory hallucinations, provided that the simulation sites and protocols are targeting at the sensorimotor frontal-parietal network.
... (11) Limit the vicious circle of autodestructive events due to the increased Ca2+ influx resulting from excessive membrane depolarization or intra-axonal Na+ overload in the context of ischemia or energetic resource failure. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Evidences of tDCS for cognitive aging rehabilitation tDCS is safe to use and has shown potential for enhancing cognition in several studies as the followings; In 2008, Ferrucci et al studied the cognitive effect of tDCS over the temporoparietal areas in 10 patients with AD with anodal tDCS, cathodal tDCS and sham tDCS in 3 sessions for 30 minutes. This study revealed that anodal tDCS over the temporoparietal areas can specifically affect the recognition memory performance in AD. 23 In 2012, Boggio et al. 24 studied cognitive functions in 15 AD patients. ...
Objective
Behavioral and psychological symptoms of dementia (BPSD) are a group of noncognitive symptoms that occur commonly among individuals with dementia. These symptoms worsen the morbidity and mortality among individuals with dementia and significantly increase the cost of caring for these individuals. Transcranial magnetic stimulation (TMS) has been shown to have some benefits in the treatment of BPSD. This review provides an updated summary of the effect of TMS on BPSD.
Methods
We conducted a systematic review of PubMed, Cochrane, and Ovid databases on the use of TMS to treat BPSD.
Results
We found 11 randomized controlled studies that evaluated the use of TMS among individuals with BPSD. Three of these studies examined the effect of TMS on apathy, two of which showed significant benefit. Seven studies showed that TMS significantly improves BPSD: six using repetitive transcranial magnetic stimulation (rTMS) and one using transcranial direct current stimulation (tDCS). Four studies, two evaluating tDCS, one evaluating rTMS, and one evaluating intermittent theta-burst stimulation (iTBS) showed a nonsignificant impact of TMS on BPSD. Adverse events were predominantly mild and transitory in all studies.
Conclusion
Available data from this review indicate that rTMS is beneficial for individuals with BPSD, especially among individuals with apathy, and is well tolerated. However, more data are needed to prove the efficacy of tDCS and iTBS. Additionally, more randomized controlled trials with longer treatment follow-up and standardized use of BPSD assessments are needed to determine the best dose, duration, and modality for effective treatment of BPSD.
Background
Dementia [i.e., Alzheimer disease (AD)], the most common neurodegenerative disease, causes profound negative impacts on executive function and quality of life. Available pharmacological treatments often fail to achieve satisfactory outcomes. Noninvasive brain stimulation (NIBS) techniques, which focally modify cortical function and enhance synaptic long-term potentiation, are potentially beneficial for the cognition in patients with AD. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and safety of different NIBS interventions in patients with AD through NMA.
Methods
Only randomized controlled trials (RCTs) examining NIBS interventions in patients with AD had been included. All NMA procedures were performed under the frequentist model. The primary and secondary outcomes were changes in cognitive function and quality of life, respectively.
Results
Nineteen RCTs (639 participants) were included. The mean treatment and follow-up durations were 5.7 and 10.5 weeks, respectively. The combination of cathodal tDCS of the left dorsolateral prefrontal cortex and anodal tDCS over the right supraorbital region (c-tDCS-F3 + a-tDCS-Fp2) was associated with a significant beneficial effect on cognition compared with sham controls (standardized mean difference=2.43, 95% confidence interval=0.61–4.26, n =12 and 11). It was also associated with the greatest beneficial effect on cognition among all the investigated NIBS approaches. All the methods were well tolerated with regard to the safety profile, as reflected in the rates of adverse events or local discomfort, as well as acceptability, as indicated by dropout rate.
Conclusions
The present findings provide evidence of the benefits of NIBS, especially tDCS, for beneficial effect on cognition in patients with AD. However, because of few studies included, this effect was not replicated yet in the other studies. Therefore, future larger-scale and longer follow-up duration RCTs should be warranted.
Trial registration
PROSPERO CRD42020209516. The current study had been approved by the Institutional Review Board of the Tri-Service General Hospital, National Defense Medical Center (TSGHIRB No. B-109-29).
Background and purpose:
Hypoperfusion of the posterior cingulate cortex (PCC) and precuneus has consistently been reported in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG) is effective in alleviating the symptoms of patients with mild AD. This study investigated the effects of rTMS-COG therapy on cerebral blood flow (CBF), with a special interest in the PCC/precuneus, and whether observed CBF changes are associated with changes in neuropsychological assessments in AD.
Materials and methods:
Twenty-one patients with mild or moderate AD were randomly divided into real rTMS (n = 11) and sham treatment (n = 10) groups, both combined with COG. Neuro-navigated 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks in the real rTMS group. All patients with AD underwent neuropsychological assessment, pseudo-continuous arterial spin labeling, and structural 3D T1-weighted MRI before treatment (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). CBF in the precuneus, PCC, and stimulation targets at the region-of-interest (ROI) level, as well as whole-brain CBF changes at the voxel level, were compared between the two groups at three timepoints.
Results:
rTMS-COG therapy revealed significant group × time interactions for the Mini-Mental State Examination (F = 5.339, p = 0.023, η2 = 0.433) and activities of daily living (F = 5.409, p = 0.039, η2 = 0.436) scores. The regional CBF in the precuneus showed a significant group × time interaction (F = 5.833, p = 0.027, η2 = 0.593). For voxel-level analysis, a significant group main effect was found in the left limbic lobe cluster, with the maximal peak in the left parahippocampus (p < 0.001, uncorrected, peak at [-16 -8 -24]). Simple effects analysis indicated that rTMS-COG therapy induced a decrease in CBF in the precuneus at T1 (p = 0.007) and an increase in the left parahippocampus at T2 (p=0.008). CBF decrease in the precuneus was correlated with better cognitive function immediately after treatment (T1) (r =-0.732, p=0.025).
Conclusion:
Neuropsychological assessments showed immediate and long-term effects on cognitive function and activities of daily living after rTMS-COG therapy. CBF changes induced by high-frequency rTMS-COG therapy are region-dependent, showing immediate effects in the precuneus and long-term effects in the left parahippocampus. These results provide imaging evidence to understand the underlying neurobiological mechanism for the application of rTMS-COG in AD.
Background
Treating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context.
Objective
To investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS–tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS.
Methods
Eighty-four AD patients were randomized to receive rTMS–tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA.
Results
rTMS–tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS–tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS–tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS–tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly.
Conclusions
rTMS–tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety.
Neuropsychiatric symptoms of dementia (NPS) are a group of noncognitive symptoms that occur in over 90% of individuals with dementia. NPS seem to result from a complex interaction among various biological, psychosocial, and environmental factors, and they are associated with greater morbidity and mortality, higher caregiver burden and burnout, high risk of nursing home placement, and increased cost of care for patients with dementia. Use of standardized assessment tools like the Neuropsychiatric Inventory can assist with qualifying and quantifying NPS. In this review, the authors evaluate the evidence for efficacy and safety of nonpharmacological and pharmacological interventions for treating NPS, mostly based on published meta-analyses. Commonly prescribed medications include atypical antipsychotics, acetylcholinesterase inhibitors, memantine, antidepressants, and mood stabilizers. There are also limited data on cannabinoids, repetitive transcranial magnetic stimulation, and ECT in individuals with NPS. Available evidence indicates that several nonpharmacological interventions are beneficial in the management of NPS and are recommended as first-line treatments. Pharmacotherapy should be reserved for the treatment of more severe or refractory NPS or where nonpharmacological management is not feasible. Atypical antipsychotics have shown mostly modest benefit in reducing NPS, and their use is limited by their adverse effect profiles. Recent investigations suggest potential strategies for preventing or at least reducing the risk of dementia and NPS. The authors conclude with brief guidelines for clinical practice as well as future research.
Purpose of Review
To provide a comprehensive overview on the evaluation and management of behavioral and psychological symptoms of dementia (BPSD) using evidence from literature.
Recent Findings
Evidence indicates efficacy for some non-pharmacological techniques including education of caregivers and cognitive stimulation therapy and pharmacological agents like antidepressant and antipsychotics for the management of BPSD. The use of antipsychotics has generated controversy due to the recognition of their serious adverse effect profile including the risk of cerebrovascular adverse events and death.
Summary
BPSD is associated with worsening of cognition and function among individuals with dementia, greater caregiver burden, more frequent institutionalization, overall poorer quality of life, and greater cost of caring for these individuals. Future management strategies for BPSD should include the use of technology for the provision of non-pharmacological interventions and the judicious use of cannabinoids and interventional procedures like ECT for the management of refractory symptoms.
Objectives
Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to modulate brain plasticity, but the neural basis has been little addressed. The purpose was to investigate the effects of rTMS on resting-state brain activity in patients with Alzheimer’s disease (AD).
Methods
Seventeen patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS combined with cognitive training (real group, n = 9); (2) sham rTMS with cognitive training (sham group, n = 8). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex and then the left lateral temporal lobe for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment and resting-state functional magnetic resonance imaging (rsfMRI) before and after treatment. The fractional amplitude of low frequency fluctuation (fALFF) of rsfMRI data in real group were: (1) compared to sham; (2) correlated with rTMS-induced cognitive alterations.
Results
Significantly increased fALFF in right cerebellum/declive, left lingual/cuneus and left cingulate gyrus, as well as decreased fALFF in left middle frontal gyrus were found after 10 Hz rTMS, but not after sham stimulation. Using these suprathreshold regions, we found that rTMS increased functional connectivity between the right cerebellum/declive and left precentral/postcentral gyrus. The fALFF increase in left lingual/cuneus and right cerebellum/declive was associated with significant improvement in cognitive function.
Conclusions
rTMS combined with cognitive training induced increased low frequency fluctuation neural oscillations and functional connectivity in brain regions subserving cognition, suggesting a possible neuronal mechanism of the beneficial effects of rTMS.
Background
Deficits in associative memory (AM) are the earliest and most prominent feature of Alzheimer's disease (AD) and demonstrate a clear cause of distress for patients and their families.
Objective
The present study aimed to determine AM enhancements following accelerated intermittent theta-burst stimulation (iTBS) in patients with AD.
Methods
In a randomized, double-blind, sham-controlled design, iTBS was administered to the left dorsolateral prefrontal cortex (DLPFC) of patients with AD for 14 days. Measurements included AM (primary outcome) and a comprehensive neuropsychological battery. Patients were evaluated at baseline, following the intervention (week 2), and 8 weeks after treatment cessation (week 10).
Results
Sixty patients with AD were initially enrolled; 47 completed the trial. The active group displayed greater AM improvements compared with the sham group at week 2 (P = 0.003), which was sustained at week 10. Furthermore, higher Mini-Mental State Examination (MMSE) scores at baseline were associated with greater AM improvements at weeks 2 and 10. For the independent iTBS group, this correlation predicted improvements in AM (P < 0.001) and identified treatment responders with 92% accuracy. Most of the neuropsychological tests were markedly improved in the active group. In particular, the Montreal Cognitive Assessment and MMSE in the active group increased by 2.8 and 2.3 points, respectively, at week 2, while there was no marked change in the sham group.
Conclusion
In the present study, accelerated iTBS of the DLPFC demonstrated an effective and well-tolerated complementary treatment for patients with AD, especially for individuals with relatively high MMSE scores.
HD-tDCS (High-definition transcranial direct current stimulation) is a novel non-invasive brain stimulation (NIBS) technique based on the principle that when weak intensity electric currents are targeted on specific areas of the scalp, they cause underlying cortical stimulation. HD-tDCS shares its technical methodology with conventional tDCS (montage comprising of one anode and one cathode) except for a few modifications that are believed to have focal and longer-lasting neuromodulation effects. Although HD-tDCS is a recently available NIBS technique, impactful studies, case reports, and few controlled trials have been conducted in this context, facilitating an understanding of its neurobiological effects and the clinical translation of the same in health care set-up. The current article narratively reviews the mechanism of action of HD-tDCS, and it systematically examines the cognitive, clinical, and neurobiological effects of HD-tDCS in healthy volunteers as well as patients with neuropsychiatric conditions. Thus, this review attempts to explore the role of HD-tDCS in present-day practice and the future in the context of various neurological and psychiatric disorders.
Late-life depression (LLD) is often accompanied by mild cognitive impairment (MCI), and at least a subgroup of LLD is a prodromal or clinical high-risk state for Alzheimer's disease (AD). LLD, MCI, and AD may represent a clinical continuum associated with amyloid-β (Aβ) pathology, which indicates that a subgroup of LLD requires preventive intervention against development of dementia. Neuromodulatory interventions using noninvasive brain stimulation techniques such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation have the potential to treat not only LLD but also MCI and AD. Indeed, a growing body of evidence obtained from clinical and experimental studies suggests that these noninvasive brain stimulation techniques may be safe and effective against deteriorative changes associated with Aβ dysmetabolism. Further studies are needed to confirm whether neuromodulatory interventions can be established as tools to delay the progression of the pathological cascade from LLD to dementia.
Developing disease-modifying treatments for Alzheimer dementia requires innovative approaches to identify novel biological targets during the course of the disease. Treatment development for the neuropsychiatric symptoms of Alzheimer may benefit from a mechanistic approach to treatment. There has been progress in identifying mild forms of behavioral impairment along the Alzheimer spectrum that may lead to additional insights into progression to dementia as well as the fundamental mechanisms of the symptoms. Developing therapies for complex neurobehavioral syndromes may require the translation of mechanistic insights into therapy, which may both improve the symptoms and delay progression to dementia in certain patients.
Objective
This meta-analysis aimed at evaluating and comparing the efficacy of noninvasive brain stimulation (NIBS) techniques on the behavioral and psychological symptoms of dementia (BPSD).
Methods
An exhaustive literature retrieval was performed on PubMed, Embase, Cochrane Library, and Web of Science until October 2019. The primary outcome was the relative changes in BPSD severity scores immediately after NIBS and at the last follow-up visit. Subgroup analyses were conducted to compare the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Changes in the severity scores after NIBS were also analyzed with restriction to patients with Alzheimer’s disease (AD).
Results
Ten studies with 324 patients were included, out of which 7 studies involved patients with AD. The analysis results indicated that NIBS significantly improved the BPSD outcome immediately after stimulation (SMD, 0.31; 95% CI, 0.10–0.52; P = 0.005), but not at the last follow-up visit (0.15; − 0.11–0.41; 0.25). Our subgroup analyses suggested that the favorable effects of rTMS remained significant at the last follow-up visit (0.57; 0.18–0.96; 0.004). This discrepancy maybe caused by the continuously insignificant outcomes of tDCS on the whole data. The results for AD patients immediately after stimulation (0.37; 0.12–0.61; 0.003) and at the last follow-up visit (0.29; − 0.19–0.76; 0.24) were both largely similar to those in the whole patient group with dementia.
Conclusions
rTMS, rather than tDCS, was capable of persistently improving the BPSD at an early stage after treatment. More trials are warranted to confirm our results before the establishment of final conclusions.
Behavioural and psychological symptoms of dementia (BPSD) occur in most patients with dementia. They cause great suffering in patients and caregivers, sometimes more so than the cognitive and functional decline inherent to dementia. The clinical features of BPSD include a wide variety of affective, psychotic and behavioural symptoms and signs. The causes and risk factors for BPSD are multiple and include biological, psychological and environmental variables. Frequently, their combination, rather than any specific factor, explains the occurrence of BPSD in an individual patient. Thus, a sound etiopathogenetic investigation including the patient and the family or care team is essential. The aim is to develop an individualized treatment plan using a therapeutic decision tree modified by the individual and environmental risk profile. Still, treatment may be difficult and challenging. Clinical empiricism often steps in where evidence from controlled studies is lacking. Psychosocial treatment approaches are pivotal for successful treatment of BPSD. Often a combination of different non-pharmacological approaches precedes drug treatment (most of which is off-label). Regular assessments of the treatment plan and any prescriptions must be carried out to detect signs of relapse and to stop any medicines that may have become inappropriate. Even with optimal management, BPSD will not disappear completely in some cases and will remain challenging for all involved parties. This article is a narrative review based closely on the interprofessional Swiss recommendations for the treatment of BPSD. To establish the recommendations, a thorough research of the literature has been carried out. Evidence-based data were provided through searches of Medline, Embase, ISI and Cochrane-Database research. Evidence categories of the World Federation of Biological Societies were used. Additionally, the clinical experience of Swiss medical experts was considered.
Background:
Behavioral and psychological symptoms of dementia (BPSD) occur in 70-90% of patients at different stages of Alzheimer's Disease (AD), but the available methods for managing these problems are of limited effectiveness.
Aim:
Assess the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS), applied over the left dorsolateral prefrontal cortex (DLPFC), on BPSD and cognitive function in persons with AD.
Methods:
Fifty-four patients with AD and accompanying BPSD were randomly divided into an intervention group (n=27) and a control group (n=27). In addition to standard antipsychotic treatment, the intervention group was treated with 20Hz rTMS five days a week for four weeks, while the control group was treated with sham rTMS.The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), and the Treatment Emergent Symptom Scale (TESS) were administered by raters who were blind to the group assignment of patients before and after four weeks of treatment.
Results:
Twenty-six subjects from each group completed the study. After four weeks of antipsychotic treatment with adjunctive real or sham rTMS treatment, the mean (sd) total BEHAVE-AD scores and mean total ADAS-Cog scores of both groups significantly decreased from baseline. After adjusting for baseline values, the intervention group had significantly lower scores (i.e., greater improvement) than the control group on the BEHAVE-AD total score, on five of the seven BEHAVE-AD factor scores (activity disturbances, diurnal rhythm, aggressiveness, affective disturbances, anxieties and phobias), on the ADAS-Cog total score, and on all four ADAS-Cog factor scores (memory, language, constructional praxis, and attention). The proportion of individuals whose behavioral symptoms met a predetermined level of improvement (i.e., a drop in BEHAVE-AD total score of > 30% from baseline) in the intervention group was greater than that in the control group (73.1% vs.42.3%, X (2)=5.04, p=0.025).
Conclusion:
Compared to treatment of AD with low-dose antipsychotic medications alone, the combination of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD.
A review of 23 studies investigating the prevalence of Behavioural and psychological symptoms of dementia (BPSD) in the general and learning disability population and measures used to assess BPSD was carried out. BPSD are non-cognitive symptoms, which constitute as a major component of dementia regardless of its subtype Research has indicated that there is a high prevalence of BPSD in the general dementia population. There are limited studies, which investigate the prevalence of BPSD within individuals who have learning disabilities and dementia. Findings suggest BPSDs are present within individuals with learning disabilities and dementia. Future research should use updated tools for investigating the prevalence of BPSD within individuals with learning disabilities and dementia.
Transcranial direct cranial stimulation (tDCS) is a promising non-pharmacological intervention for treating major depressive disorder (MDD). However, results from randomized controlled trials (RCTs) and meta-analyses are mixed. Our aim was to assess the efficacy of tDCS as a treatment for MDD. We performed a systematic review in Medline and other databases from the first RCT available until January 2014. The main outcome was the Hedges' g for continuous scores; secondary outcomes were the odds ratio (ORs) to achieve response and remission. We used a random-effects model. Seven RCTs (n = 259) were included, most with small sample sizes that assessed tDCS as either a monotherapy or as an add-on therapy. Active vs. sham tDCS was significantly superior for all outcomes (g = 0.37; 95% CI 0.04-0.7; ORs for response and remission were, respectively, 1.63; 95% CI = 1.26-2.12 and 2.50; 95% CI = 1.26-2.49). Risk of publication bias was low. No predictors of response were identified, possibly owing to low statistical power. In summary, active tDCS was statistically superior to sham tDCS for the acute depression treatment, although its role as a clinical intervention is still unclear owing to the mixed findings and heterogeneity of the reviewed studies. Further RCTs with larger sample sizes and assessing tDCS efficacy beyond the acute depressive episode are warranted.
Auditory verbal hallucinations (AVHs) are known as a core symptom of schizophrenia, but also occur in a number of other conditions, not least in neurodegenerative disorders such as dementia. In the last decades, Transcranial Magnetic Stimulation (TMS) emerged as a valuable therapeutic approach towards several neurological and psychiatric diseases, including AVHs. Herein we report a case of a seventy-six-years-old woman with vascular-degenerative brain disease, complaining of threatening AVHs. The patient was treated with a high-frequency temporoparietal (T3P3) rTMS protocol for fifteen days. A considerable reduction of AVHs in frequency and content (no more threatening) was observed. Although further research is needed, this seems an encouraging result.
The aim of the study was to compare the long-term efficacy of high versus low frequency repetitive transcranial magnetic stimulation (rTMS), applied bilaterally over the dorsolateral prefrontal cortex (DLPFC), on cognitive function and cortical excitability of patients with Alzheimer's disease (AD). Forty-five AD patients were randomly classified into three groups. The first two groups received real rTMS over the DLPFC (20 and 1 Hz, respectively) while the third group received sham stimulation. All patients received one session daily for five consecutive days. In each session, rTMS was applied first over the right DLPFC, immediately followed by rTMS over the left DLPFC. Mini Mental State Examination (MMSE), Instrumental Daily Living Activity (IADL) scale and the Geriatric Depression Scale (GDS) were assessed before, after the last (fifth) session, and then followed up at 1 and 3 months. Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), and the duration of transcallosal inhibition (TI) before and after the end of the treatment sessions. At base line assessment there were no significant differences between groups in any of the rating scales. The high frequency rTMS group improved significantly more than the low frequency and sham groups in all rating scales (MMSE, IADL, and GDS) and at all time points after treatment. Measures of cortical excitability immediately after the last treatment session showed that treatment with 20 Hz rTMS reduced TI duration. These results confirm that five daily sessions of high frequency rTMS over the left and then the right DLPFC improves cognitive function in patients with mild to moderate degree of AD. This improvement was maintained for 3 months. High frequency rTMS may be a useful addition to therapy for the treatment of AD.
Since the rediscovery of transcranial direct current stimulation (tDCS) about 10 years ago, interest in tDCS has grown exponentially. A noninvasive stimulation technique that induces robust excitability changes within the stimulated cortex, tDCS is increasingly being used in proof-of-principle and stage IIa clinical trials in a wide range of neurological and psychiatric disorders. Alongside these clinical studies, detailed work has been performed to elucidate the mechanisms underlying the observed effects. In this review, the authors bring together the results from these pharmacological, neurophysiological, and imaging studies to describe their current knowledge of the physiological effects of tDCS. In addition, the theoretical framework for how tDCS affects motor learning is proposed.
Behavioral and psychological symptoms of dementia (BPSD), i.e. verbal and physical aggression, agitation, psychotic symptoms (hallucinations and delusions), sleep disturbances, oppositional behavior, and wandering, are a common and potentially severe problem complicating dementia. Their prevalence is very high and it is estimated that up to 90% of patients with Alzheimer's disease (AD) may present at least one BPSD. Beside the obvious impact on the quality of life of people with dementia, BPSD are responsible for increased risk of patient institutionalization and increased costs. Furthermore, they are associated with caregivers' stress and depression. Drugs used include antipsychotics, antidepressants, anticonvulsivants, anxiolytics, cholinesterase inhibitors and N-methyl-D-aspartate receptor modulators. Among these, the most commonly used are anti-psychotics. These drugs have been used for many decades, but in the last years new compounds have been marketed with the promise of comparable efficacy but less frequent adverse effects (especially extra-pyramidal side effects). Their safety, however, has been challenged by data showing a potential increase in adverse cerebrovascular side effects and mortality. This review will summarize the pathophysiology and neuropharmacology of BPSD, it will describe the characteristics of the anti-psychotics most commonly used focusing on their efficacy and safety in BPSD.
The aim of this project was to study the underlying reasons for emergency hospital admission of patients with dementia of the Alzheimer type (DAT) and their characteristics. This prospective 4-month study identified 118 patients with DAT, most of whom were referred to the two emergency departments of the Toulouse University Hospital. The two main reasons for admission were behavioral problems (26.3%) and falls (18.6%). Patients were generally at an advanced stage of the disease process and had substantial evidence of poor nutritional status and loss of activities of daily living ability. About one third of patients had already been admitted to the hospital for the same reasons in the preceding months. Psychotropic drugs predominated (71%) among the current medications taken by the patients and were mainly anxiolytics and neuroleptics. Finally, the discharge report indicated that medications were a contributing factor in the disorders of 25% of patients. We believe that improved information for caregivers and early management and treatment are essential to respond adequately to the problems raised by this population.
The authors systematically reviewed the literature on psychological approaches to treating the neuropsychiatric symptoms of dementia.
Reports of studies that examined effects of any therapy derived from a psychological approach that satisfied prespecified criteria were reviewed. Data were extracted, the quality of each study was rated, and an overall rating was given to each study by using the Oxford Centre for Evidence-Based Medicine criteria.
A total of 1,632 studies were identified, and 162 satisfied the inclusion criteria for the review. Specific types of psychoeducation for caregivers about managing neuropsychiatric symptoms were effective treatments whose benefits lasted for months, but other caregiver interventions were not. Behavioral management techniques that are centered on individual patients' behavior or on caregiver behavior had similar benefits, as did cognitive stimulation. Music therapy and Snoezelen, and possibly sensory stimulation, were useful during the treatment session but had no longer-term effects; interventions that changed the visual environment looked promising, but more research is needed.
Only behavior management therapies, specific types of caregiver and residential care staff education, and possibly cognitive stimulation appear to have lasting effectiveness for the management of dementia-associated neuropsychiatric symptoms. Lack of evidence regarding other therapies is not evidence of lack of efficacy. Conclusions are limited because of the paucity of high-quality research (only nine level-1 studies were identified). More high-quality investigation is needed.
Noninvasive brain stimulation with transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) is valuable in research and has potential therapeutic applications in cognitive neuroscience, neurophysiology, psychiatry, and neurology. TMS allows neurostimulation and neuromodulation, while tDCS is a purely neuromodulatory application. TMS and tDCS allow diagnostic and interventional neurophysiology applications, and focal neuropharmacology delivery. However, the physics and basic mechanisms of action remain incompletely explored. Following an overview of the history and current applications of noninvasive brain stimulation, we review stimulation device design principles, the electromagnetic and physical foundations of the techniques, and the current knowledge about the electrophysiologic basis of the effects. Finally, we discuss potential biomedical and electrical engineering developments that could lead to more effective stimulation devices, better suited for the specific applications.
Objective:
To assess the efficacy of a combination of cognitive training (COG) and repetitive transcranial magnetic stimulation (rTMS), on cognitive performance, locomotor activity, apathy, caregiver burden and dependence of patients with Alzheimer's disease (AD).
Methods:
A combination of COG and rTMS was performed in 10 patients with AD (NeuroAD procedure) for a period of 5weeks (one session per day, 5days a week), without maintenance sessions. Patients were evaluated at the end of the treatment (D45) and 6months later (M6) by the Mini Mental State Examination (MMSE), the Alzheimer disease assessment scale - cognitive subscale (ADAS-Cog), various neuropsychological tests and clinical scores specific for locomotor activity, apathy, caregiver burden, and dependence, recorded before the study (baseline).
Results:
The primary endpoint was the improvement of the ADAS-Cog score at D45, which was reached. Six months after the end of the treatment, the ADAS-Cog score returned to baseline value, except for the best responders who remained significantly improved. The other main result was the improvement of apathy and dependence scores at both D45 and M6 for the entire series of patients. No serious adverse events occurred and all patients completed the study.
Conclusions:
The results of this open-label study confirm the feasibility of the rTMS-COG procedure in AD patients, and suggest that these patients can benefit from the procedure, in terms of cognitive performances, apathy and dependence, even in the long term. These promising results remain to be confirmed in controlled studies based on a larger population size, which could also help identify the prognostic factors associated with good outcome, in order to optimize patient selection.
Non-invasive brain stimulation (NIBS) techniques can significantly modulate cognitive functions in healthy subjects and patients with neuropsychiatric disorders. Recently, they have been applied in patients with mild cognitive impairment (MCI) and subjective cognitive impairment (SCI) to prevent or delay the development of Alzheimer’s disease. Here we review this emerging empirical corpus and discuss therapeutic effects of NIBS on several target functions (e.g., memory for face-name associations and non-verbal recognition, attention, psychomotor speed, everyday memory). Available studies have yielded mixed results, possibly due to differences among their tasks, designs, and samples, let alone the latter’s small sizes. Thus, the impact of NIBS on cognitive performance in MCI and SCI remains to be determined. To foster progress in this direction, we outline methodological approaches that could improve the efficacy and specificity of NIBS in both conditions. Furthermore, we discuss the need for multicenter studies, accurate diagnosis, and longitudinal approaches combining NIBS with specific training regimes. These tenets could cement biomedical developments supporting new treatments for MCI and preventive therapies for Alzheimer’s disease.
Background:
Behavioral and psychological symptoms in dementia (BPSD) are important predictors of institutionalization as well as caregiver burden and depression. Previous reviews have tended to group BPSD as one category with little focus on the role of the individual symptoms. This review investigates the role of the individual symptoms of BPSD in relation to the impact on different measures of family caregiver well-being.
Methods:
Systematic review and meta-analysis of papers published in English between 1980 and December 2015 reporting which BPSD affect caregiver well-being. Paper quality was appraised using the Downs and Black Checklist (1998).
Results:
Forty medium and high quality quantitative papers met the inclusion criteria, 16 were suitable to be included in a meta-analysis of mean distress scores. Depressive behaviors were the most distressing for caregivers followed by agitation/aggression and apathy. Euphoria was the least distressing. Correlation coefficients between mean total behavior scores and mean distress scores were pooled for four studies. Irritability, aberrant motor behavior and delusions were the most strongly correlated to distress, disinhibition was the least correlated.
Conclusions:
The evidence is not conclusive as to whether some BPSD impact caregiver well-being more than others. Studies which validly examined BPSD individually were limited, and the included studies used numerous measures of BPSD and numerous measures of caregiver well-being. Future research may benefit from a consistent measure of BPSD, examining BPSD individually, and by examining the causal mechanisms by which BPSD impact well-being by including caregiver variables so that interventions can be designed to target BPSD more effectively.
Neuropsychiatric symptoms (NPS) are now known to occur almost universally over the course of dementia, Alzheimer?s in particular (1, 2). They also occur with higher-than-expected frequency in the dementia prodrome of mild cognitive impairment (3). Further, NPS in the form of ?mild behavioral impairment,? in the absence of cognitive impairment, may constitute a dementia prodrome (4). NPS are associated with a number of adverse outcomes including accelerated transition from prodrome to dementia (4), and faster progression from early dementia to severe dementia or death [Peters et al, Am J Psychiatry, in press], as well as serious adverse effects for patients and caregivers such as greater disability, worse quality of life, earlier institutionalization, increased burden, and higher health care costs (2). Given their central importance, NPS are increasingly a focus of study with an eye to the development of effective treatments.
Objectives
Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer’s disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD.
Design
Longitudinal cohort study followed annually (median 1.58 years)
Setting
National Alzheimer’s Coordinating Center (NACC) database combining clinical data from 29 Alzheimer’s Disease Centers (ADCs).
Participants
1821 participants with MCI
Measurements
1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes (CDR-Sum) 5) Mini-Mental State Exam (MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, CDR-Sum, and MMSE.
Results
527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS>0 was associated with increased risk of incident dementia (HR 1.47, 95% CI 1.17, 1.84) and AD (HR 1.45, 95% CI 1.14, 1.83). Baseline NPI>0 was associated with increased risk of incident dementia (HR 1.37. 95% CI 1.12, 1.66) and AD (HR 1.35,95% CI 1.09, 1.66).
Conclusions
Neuropsychiatric symptoms in MCI are associated with significantly increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.
IntroductionIndividual studiesThe summary effectHeterogeneity of effect sizesSummary points
Noncognitive neuropsychiatric symptoms (NPS) of dementia (aggression, agitation, depression, anxiety, delusions, hallucinations, apathy, disinhibition) affect individuals with dementia nearly universally across dementia stages and etiologies. NPS are associated with poor outcomes for individuals with dementia and caregivers, including excess morbidity and mortality, greater healthcare use, and earlier nursing home placement, as well as caregiver stress, depression, and difficulty with employment. Although the Food and Drug Administration has not approved pharmacotherapy for NPS, psychotropic medications are frequently used to manage these symptoms, but in the few cases of proven pharmacological efficacy, significant risk of adverse effects may offset benefits. There is evidence of efficacy and limited potential for adverse effects of nonpharmacological treatments, typically considered first line, but their uptake as preferred treatments remains inadequate in real-world clinical settings. Thus, the field currently finds itself in a predicament in terms of management of these difficult symptoms. It was in this context that the University of Michigan Program for Positive Aging, working in collaboration with the Johns Hopkins Alzheimer's Disease Research Center and Center for Innovative Care in Aging sponsored and convened a multidisciplinary expert panel in Detroit, Michigan, in fall 2011 with three objectives: to define critical elements of care for NPS in dementia; to construct an approach describing the sequential and iterative steps of managing NPS in real-world clinical settings that can be used as a basis for integrating nonpharmacological and pharmacological approaches; and to discuss how the approach generated could be implemented in research and clinical care.
Background:
Primary progressive aphasia (PPA) is an untreatable neurodegenerative disorder that disrupts language functions. Previous studies have demonstrated transcranial direct current stimulation (tDCS) may improve language symptoms in patients with post stroke aphasia or neurodegenerative diseases.
Objective:
The present study investigated whether the application of anodal tDCS (AtDCS) to the scalp overlying the left dorsolateral prefrontal cortex (DLPFC), which may increase cortical excitability, in combination with individualized speech therapy would improve naming accuracy in the agrammatic variant of PPA (avPPA).
Methods:
Sixteen avPPA patients were randomly allocated into two subgroups: AtDCS (n = 8) or placebo tDCS (PtDCS). tDCS was applied over the left DLPFC (BA 8/9) 25 minutes per day for two weeks (10 days). Each patient underwent 25 minutes of individualized speech therapy with either AtDCS or PtDCS during each treatment session. Neuropsychological assessment, experimental naming, and linguistic abilities in daily living were assessed at baseline (T0), after two weeks of intervention (T1) and at a 12-week follow-up (T2).
Results:
Significant improvement in experimental naming was observed in both groups at T1 and T2, but this effect was significantly greater in AtDCS than PtDCS patients. Naming correctness, as assessed using the Aachener Aphasie Test, increased selectively in the AtDCS group from T0 to T1, and this effect remained significant at T2. The analysis of daily living language abilities improved selectively in AtDCS group.
Conclusion:
Our results support the beneficial effect of targeted language training in combination with brain stimulation in avPPA patients. tDCS should be considered a useful tool for the improvement of language functions in patients with neurodegenerative diseases in future trials.
Behavioral and psychological symptoms of dementia (BPSD) represent common manifestations among patients affected by Alzheimer's disease (AD). Some reports have recently classified BPSD into specific clusters/subsyndromes exploring the internal structure of the Neuropsychiatric Inventory (NPI). We evaluated whether specific behavioral subsyndromes are associated with worsening cognitive function. Mild to moderate AD patients were recruited from the cohort of the Impact of Cholinergic Treatment USe (ICTUS) study. Neuropsychiatric symptoms were classified in three subsyndromes, identified at baseline, grouping different combinations of NPI items: (1) "psychotic" ("delusions" and/or "hallucinations"); (2) "affective" ("agitation" and/or "depression" and/or "anxiety" and/or "irritability"); and (3) "behavioral" ("euphoria" and/or "apathy" and/or "disinhibition" and/or "aberrant motor behavior"). Mixed model analyses were performed to measure six-monthly changes in the ADAS-Cog score over a follow-up of 2 years, according to these subsyndromes. All analyses were stratified according to AD severity as defined by the Clinical Dementia Rating (CDR). A total of 1,375 AD subjects were recruited. No NPI cluster was found to significantly (p < 0.05) affect the rate of cognitive decline across the 3 CDR classes. Our results suggest that the cognitive course of AD is not substantially influenced by the presence of specific neuropsychiatric phenotypes. Further studies are needed to extend the present findings and identify possible biological and clinical bases for behavioral subsyndromes.
Cortical excitability can be modulated using repetitive transcranial magnetic stimulation (rTMS). Previously, we showed that rTMS combined with cognitive training (rTMS-COG) has positive results in Alzheimer's disease (AD). The goal of this randomized double-blind, controlled study was to examine the safety and efficacy of rTMS-COG in AD. Fifteen AD patients received 1-h daily rTMS-COG or sham treatment (seven treated, eight placebo), five sessions/week for 6 weeks, followed by biweekly sessions for 3 months. The primary outcome was improvement of the cognitive score. The secondary outcome included improvement in the Clinical Global Impression of Change (CGIC) and Neuropsychiatric Inventory (NPI). There was an improvement in the average ADAS-cog score of 3.76 points after 6 weeks in the treatment group compared to 0.47 in the placebo group and 3.52 points after 4.5 months of treatment, compared to worsening of 0.38 in the placebo (P = 0.04 and P = 0.05, respectively). There was also an improvement in the average CGIC score of 3.57 (after 6 weeks) and 3.67 points (after 4.5 months), compared to 4.25 and 4.29 in the placebo group (mild worsening) (P = 0.05 and P = 0.05, respectively). NPI improved non-significantly. In summary, the NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD.
OBJECTIVES:: Individuals with mild cognitive impairment (MCI) are at high risk of developing dementia and/or Alzheimer disease (AD). Among persons with MCI, depression and anxiety have been associated with an increased risk of incident dementia. We examined whether neuropsychiatric symptoms in MCI increased the risk of incident dementia (all-cause) and incident AD. DESIGN:: Longitudinal cohort study followed annually (median: 1.58 years). SETTING:: National Alzheimer's Coordinating Center database combining clinical data from 29 Alzheimer's Disease Centers. PARTICIPANTS:: A total of 1,821 participants with MCI. MEASUREMENTS:: 1) Progression to dementia (all-cause) or AD, 2) Neuropsychiatric Inventory Questionnaire (NPI-Q), 3) Geriatric Depression Scale (GDS), 4) Clinical Dementia Rating Global Score and Sum of Boxes, and 5) Mini-Mental State Examination(MMSE). The association of covariates with risk of incident dementia or AD was evaluated with hazard ratios (HR) determined by Cox proportional-hazards models adjusted for age, ethnicity, Clinical Dementia Rating Global Score and Sum of Boxes, and MMSE. RESULTS:: A total of 527 participants (28.9%) progressed to dementia and 454 (24.9%) to AD. Baseline GDS > 0 was associated with an increased risk of incident dementia (HR: 1.47, 95% CI: 1.17-1.84) and AD (HR: 1.45, 95% CI: 1.14-1.83). Baseline NPI > 0 was associated with an increased risk of incident dementia (HR: 1.37, 95% CI: 1.12-1.66) and AD (HR: 1.35, 95% CI: 1.09-1.66). CONCLUSIONS:: Neuropsychiatric symptoms in MCI are associated with significantly an increased risk of incident dementia and AD. Neuropsychiatric symptoms may be among the earliest symptoms of preclinical stages of AD and targeting them therapeutically might delay transition to dementia.
The aim of this study was (a) to estimate the cost of dementia in Switzerland, (b) to compare the average annual cost for people with dementia who live at home and those living in an institution and (c) to analyse how the average cost per person with dementia who lives at home increases with the severity of dementia.
This prevalence-based cost-of-illness study from a societal perspective combined top-down and bottom-up approaches and included both direct and indirect costs of dementia. Cost estimations were based on Swiss national statistics and surveys, as well as international reviews and expert interviews.
The total annual cost of dementia amounted up to CHF 6.3 billion for the year 2007. Together, institutional and informal care accounted for over 90% of the cost. The average annual cost was estimated at CHF 55'300 per person with dementia who lives at home and at CHF 68'900 per person who lives in an institution. The cost per person living at home with severe dementia was nearly five times the cost per person with mild dementia.
The present study indicates that dementia imposes a considerable economic burden on Swiss society. The cost of dementia is dominated by the costs of care. Diagnosis and treatment related costs are minor. These findings are consistent with contemporary international studies on the subject. The contribution of informal caregivers is substantial since they account for 44% of the total cost of dementia (based on market cost valuation). Given demographic developments in Switzerland, healthcare decision making should have an interest in securing this potential for the future.
Background:
Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them.
Methods:
We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research.
Main findings/discussion:
We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.
The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.
Intracortical inhibition (SICI) and facilitation (ICF) in the human motor cortex can be measured using a paired pulse transcranial magnetic stimulation (ppTMS) protocol. Recently, a technical device has been introduced, which allows recording electroencephalographic (EEG) responses to TMS of a given scalp site. The latency, amplitude and scalp topography of such responses are considered a reflection of cortico-cortical connectivity and functional state. The aim of the present study is to better characterize the neuronal circuits underlying motor cortex connectivity as well as the mechanisms regulating its balance between inhibition and facilitation by means of EEG navigated-ppTMS coregistration.
Sub-threshold and supra-threshold single and ppTMS of the left primary motor cortex were carried out during a multi-channel EEG recording on 8 healthy volunteers; the between-pulse intervals used in the paired pulse trials were 3 (for SICI) and 11 ms (for ICF). Motor evoked potentials (MEPs) from the opposite hand were simultaneously recorded.
Single and ppTMS induced EEG responses characterized by a sequence of negative deflections peaking at approximately 7, 18, 44, 100 and 280 ms alternated with positive peaks at approximately 13, 30, 60 and 190 ms post-TMS. Moreover, ppTMS modulated both EEG evoked activity and MEPs. Amplitude variability of EEG responses was correlated with - and therefore might partially explain - amplitude variability of MEPs.
EEG-ppTMS is a promising tool to better characterize the neuronal circuits underlying cortical effective connectivity as well as the mechanisms regulating the balance between inhibition and facilitation within the human cortices and the corticospinal pathway.
During the last two decades, transcranial magnetic stimulation (TMS) has rapidly become a valuable method to investigate noninvasively the human brain. In addition, repetitive TMS (rTMS) is able to induce changes in brain activity that last after stimulation. Therefore, rTMS has therapeutic potential in patients with neurologic and psychiatric disorders. It is, however, unclear by which mechanism rTMS induces these lasting effects on the brain. The effects of rTMS are often described as LTD- or LTP-like, because the duration of these alterations seems to implicate changes in synaptic plasticity. In this review we therefore discuss, based on rTMS experiments and knowledge about synaptic plasticity, whether the physiologic basis of rTMS-effects relates to changes in synaptic plasticity. We present seven lines of evidence that strongly suggest a link between the aftereffects induced by rTMS and the induction of synaptic plasticity. It is, nevertheless, important to realize that at present it is impossible to demonstrate a direct link between rTMS on the one hand and synaptic plasticity on the other. Therefore, we provide suggestions for future, innovating research, aiming to investigate both the local effects of rTMS on the synapse and the effects of rTMS on other, more global levels of brain organization. Only in that way can the aftereffects of rTMS on the brain be completely understood.
Transcranial magnetic stimulation (TMS) has become a mainstay of cognitive neuroscience, thus facing new challenges due to its widespread application on behaviorally silent areas. In this review we will summarize the main technical and methodological considerations that are necessary when using TMS in cognitive neuroscience, based on a corpus of studies and technical improvements that has become available in most recent years. Although TMS has been applied only relatively recently on a large scale to the study of higher functions, a range of protocols that elucidate how this technique can be used to investigate a variety of issues is already available, such as single pulse, paired pulse, dual-site, repetitive and theta burst TMS. Finally, we will touch on recent promising approaches that provide powerful new insights about causal interactions among brain regions (i.e., TMS with other neuroimaging techniques) and will enable researchers to enhance the functional resolution of TMS (i.e., state-dependent TMS). We will end by briefly summarizing and discussing the implications of the newest safety guidelines.
The purpose of this study was to update the previous estimate of the worldwide cost of dementia in 2005 to 2009.
The cost model is based on prevalence estimates, country and region-specific data on Gross Domestic Product per person and average wage, with results from previously published cost-of-illness studies in different countries. Prevalence figures are updated to 2009 and costs were adjusted to 2009 constant US dollars ($).
The total worldwide societal cost of dementia, based on a dementia population of 34.4 million demented persons, was estimated to $422 billion in 2009, including $142 billion for informal care (34%).
The worldwide cost of dementia has increased by 34% (18% in fixed prices) between 2005 and 2009.
Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer's disease (AD) patients. They are a source of distress for the caregivers and one of the main reasons for nursing home placement, which is the major component of the cost of Alzheimer's disease. The aim of the present study was to assess the direct and indirect cost related to the care of BPSD within a prospective study examining the overall cost of AD in Israel.
Seventy-one community dwelling AD patients were interviewed. Interviews covered information about the number of caregivers' hours invested in caring for the patient and amount of expenditure such as in-house paid help and payments for day care. Effort devoted to BPSD was defined as the number of hours spent by primary and secondary caregivers in a typical week dealing with BPSD (managing aggression, pacing, attempts to leave the house under inappropriate circumstances, or comforting a hallucinating, depressed or anxious patient).
The annual indirect cost for management of BPSD in an AD patient was approximately 2665 dollars -over 25% of the total annual indirect cost of care ($10 520). The annual direct cost of BPSD of an AD patient was approximately 1450 dollars -over 35% of the total annual direct cost of care (3900 dollars).
Approximately 30% (4115 dollars) of the total annual cost of AD (14420 dollars) is invested in the direct management of BPSD. Given the importance of BPSD as one of the main components of the cost of AD, future cost studies should be designed to measure the cost of specific components of BPSD and verify which are the most costly aspects of the disease. Despite the considerable methodological difficulties in disentangling the costs of the specific symptoms of AD, cost effectiveness studies of different interventions should be conducted in order to determine the optimal intervention with relation to cost.
Neuropsychiatric symptoms of dementia are common and associated with poor outcomes for patients and caregivers. Although nonpharmacological interventions should be the first line of treatment, a wide variety of pharmacological agents are used in the management of neuropsychiatric symptoms; therefore, concise, current, evidence-based recommendations are needed.
To evaluate the efficacy of pharmacological agents used in the treatment of neuropsychiatric symptoms of dementia.
A systematic review of English-language articles published from 1966 to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and a manual search of bibliographies was conducted. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs) or meta-analyses of any drug therapy for patients with dementia that included neuropsychiatric outcomes. Trials reporting only depression outcomes were excluded. Data on the inclusion criteria, patients, methods, results, and quality of each study were independently abstracted. Twenty-nine articles met inclusion criteria.
For typical antipsychotics, 2 meta-analyses and 2 RCTs were included. Generally, no difference among specific agents was found, efficacy was small at best, and adverse effects were common. Six RCTs with atypical antipsychotics were included; results showed modest, statistically significant efficacy of olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical antipsychotics are associated with an increased risk of stroke. There have been no RCTs designed to directly compare the efficacy of typical and atypical antipsychotics. Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs investigating valproate showed no efficacy. Two small RCTs of carbamazepine had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors generally showed small, although statistically significant, efficacy. Two RCTs of memantine also had conflicting results for treatment of neuropsychiatric symptoms.
Pharmacological therapies are not particularly effective for management of neuropsychiatric symptoms of dementia. Of the agents reviewed, the atypical antipsychotics risperidone and olanzapine currently have the best evidence for efficacy. However, the effects are modest and further complicated by an increased risk of stroke. Additional trials of cholinesterase inhibitors enrolling patients with high levels of neuropsychiatric symptoms may be warranted.
Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The technique can be used to map brain function and explore the excitability of different regions. Brief interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has some clinical utility, and, because it can influence brain function if delivered repetitively, it is being developed for various therapeutic purposes.
Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research
- Rossi
Noninvasive brain stimulation in Alzheimer's disease: systematic review and perspectives for the future
- Freitas