Improved language performance in Alzheimer disease following brain stimulation
... Noninvasive neuromodulation via external brain stimulation can enhance neuroplasticity with the potential for mitigating disease progression by strengthening synaptic activity and activating neuronal populations associated with memory and learning pathways (Antal et al., 2022;Weiler et al., 2020). Several studies have shown high frequency repetitive transcranial magnetic stimulation (rTMS) to be an effective treatment for individuals with mild cognitive impairment (MCI) and AD when applied to the left and/or right dorsolateral prefrontal cortex (DLPFC) with clear improvements found on standardized assessments of cognitive function (Devi et al., 2014;Zhao et al., 2016;Cotelli et al., 2011). Here, we present a case report of a 44-year-old patient with clinical and laboratory characteristics of definite early-onset AD who showed marked cognitive improvements following rTMS treatment. ...
... Patient underwent daily MRI-navigated rTMS sessions. The stimulation parameters were chosen based, in part, on current trial evidence for early-onset dementia (Ahmed et al., 2012, Devi et al., 2014, Cotelli et al., 2011. All stimulations were performed using a figure-of-eight coil using the CloudTMS Machine (Neurosoft Ltd, Russia). ...
... To our knowledge, this is the first known case report of applying TMS stimulation on a clinically and laboratory-confirmed patient with early-onset AD. Stimulation of the DLPFC at 20 Hz was selected based on current randomized clinical trials (RCT) of applying TMS for late-onset AD (Alcalá-Lozano et al., 2018;Weiler et al., 2020;Ahmed et al., 2012;Devi et al., 2014;Zhao et al., 2016;Cotelli et al.,2011), showing significant improvements in cognition maintained for 3 or more months (Ahmed et al.,2012). Other studies have shown long-lasting improvements in memory (Zhao et al., 2016) and verbal functioning, specifically in sentence comprehension, noun/verb identification (Cotelli et al., 2011), and nonverbal and verbal agility in patients with late-onset AD (Zhao et al., 2016). ...
Background:
Early-onset Alzheimer's Disease (AD) is a rare form of AD defined as exhibiting signs and symptoms before age 65. Several studies have shown high frequency repetitive transcranial magnetic stimulation (rTMS) to be an effective treatment for individuals with mild cognitive impairment (MCI) and AD when applied to the left and/or right dorsolateral prefrontal cortex (DLPFC) with clear improvements found on standardized assessments of cognitive function.
Case report:
Here, we present a case report of a 44-year-old patient with clinical and laboratory characteristics of definite early-onset AD.
Findings:
rTMS led to marked cognitive improvements. We hope to inspire more clinical interest in exploring rTMS for treatment of dementia.
... rTMS involves the application of coils to the scalp to modulate underlying brain activity by generating a magnetic eld that surrounds cortical neurons, using a strong but brief electromagnetic pulse [7]. Previous studies on neuromodulation have con rmed the ability of rTMS acting on the dorsolateral prefrontal cortex (DLPFC) to enhance overall cognitive function and improve clinical performance [8,9]. Several recent studies have underscored the potential of rTMS targeted at the precuneus (PCUN) to enhance memory and attenuate cognitive decline in preclinical AD [10,11]. ...
... Recent research on the impact of rTMS on brain networks has mostly focused on the changes in FC within these networks [9,21]. However, FC is based on the correlation between the time series of brain regions, thus lacking the ability to provide the directionality of inter-regional brain interactions; hence, it does not represent real "connectivity" [22]. ...
Objectives
Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered as the spectrum of preclinical Alzheimer’s disease (AD), with abnormal brain network connectivity as the main neuroimaging feature. Repetitive transcranial magnetic stimulation (rTMS) has been proven to be an effective non-invasive technique for addressing neuropsychiatric disorders. This study aims to explore the potential of targeted rTMS to regulate effective connectivity within the default mode network (DMN) and the executive control network (CEN), thereby improving cognitive function.
Methods
A cross-sectional analysis using the spectral dynamic causal model was conducted to examine effective connectivity patterns in the DMN and CEN among the three groups. Subsequently, longitudinal analysis assessed the changes in effective connectivity patterns and cognitive function before and after rTMS in patients with SCD and aMCI, exploring the correlation between them.
Results
Cross-sectional analysis showed different effective connectivity patterns in the DMN and CEN among the three groups. Longitudinal analysis showed that the effective connectivity pattern of the SCD had changed, accompanied by improvements in episodic memory. Correlation analysis indicated a negative relationship between effective connectivity from the left angular gyrus (ANG) to the anterior cingulate gyrus and the ANG.R to the right middle frontal gyrus, with visuospatial and executive function, respectively. In patients with aMCI, episodic memory and executive function improved, while the effective connectivity pattern remained unchanged.
Conclusions
This study demonstrates that PCUN-targeted rTMS in SCD regulates the abnormal effective connectivity patterns in DMN and CEN, thereby improving cognition function. Conversely, in aMCI, the mechanism of improvement may differ. Our findings further suggest that rTMS is more effective in preventing or delaying disease progression in the earlier stages of the AD spectrum.
... However, these studies only evaluated the immediate cognitive effects of a single rTMS session, and the long-term effects remain unknown. In a third trial of ten patients with AD divided into two groups, one group received high-frequency (20 Hz) rTMS over the left DLPFC for four weeks while the other received placebo rTMS for two weeks, followed by real rTMS for two weeks [20]. The authors observed that the real rTMS group had significantly higher rates of correct responses after 2 weeks of therapy, and both groups still had improved performance 8 weeks after the end of treatment. ...
The current literature review aimed to evaluate the effectiveness of rTMS on the precuneus as a potential treatment for Alzheimer’s disease (AD). Although the number of studies specifically targeting the precuneus is limited, the results from this review suggest the potential benefits of this approach. Future studies should focus on exploring the long-term effects of rTMS on the precuneus in Alzheimer’s disease patients, as well as determining the optimal stimulation parameters and protocols for this population. Additionally, investigating the effects of rTMS on the precuneus in combination with other brain regions implicated in AD may provide valuable insights into the development of effective treatment for this debilitating neurodegenerative disorder.
... Since 1998 the number of clinical trials that use TMS to address neuropsychiatric conditions has grown exponentially with a doubling time of approximately 2.5 years 5 . Based on data from these clinical trials, the FDA has approved TMS for treatment resistant depression, and most insurance companies reimburse for multi-session in clinic therapy if patients fail traditional antidepressant therapy 6 .There is also promising data that TMS can be used to treat obsessive compulsive disorder 7 , PTSD 8 , and Alzheimer's disease 9 . While TMS is a clinically proven therapy there are two major limitations to this therapy. ...
Refractory neurological and psychiatric disorders are increasingly treated with brain stimulation therapies using implanted neuromodulation devices. Current commercially available stimulation systems, however, are limited by the need for implantable pulse generators and wired power; the complexity of this architecture creates multiple failure points including lead fractures, migration, and infection. Enabling less invasive approaches could increase access to these therapies. Here we demonstrate the first millimeter-sized leadless brain stimulator in large animal and human subjects. This Digitally programmable Over-brain Therapeutic (or DOT) is approximately 1 cm in width yet can produce sufficient energy to stimulate cortical activity on-demand through the dura. This extreme miniaturization is possible using recently developed magnetoelectric wireless power transfer that allows us to reach power levels required to stimulate the surface of the brain without direct contact to the cortical surface. This externally powered cortical stimulation (XCS) opens the possibility of simple minimally invasive surgical procedures to enable precise, long-lasting, and at-home neuromodulation with tiny implants that never contact the surface of the brain.
... /fncir. . been proven to be a beneficial stimulation target for AD (Cotelli et al., 2008(Cotelli et al., , 2011Ahmed et al., 2012). The IPL related to bottomup attention and episodic memory is an important node of the ECN (Xiao et al., 2022). ...
Purpose
To investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG).
Method
We selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, n = 11) or sham (sham rTMS+COG, n = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with “time” as the within-subjects factor (three levels: T0, T4, and T8) and “group” as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA).
Results
At the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function.
Conclusion
Multisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.
... is associated with better performance in neuropsychiatric testing (as others have demonstrated with transcranial magnetic stimulation and transcranial direct current stimulation [79,80]), and second being that potential hyperexcitation due to APOE-E4 both precedes and may even influence increased spread of amyloid plaques before cognitive impairment is identified [81]. It is also possible that the APOE-E4 genotype may be protective against a subtle deficit associated with β-amyloid pathology, and consistent with the antagonistic pleiotropy hypothesis; whereby a gene controls both beneficial and detrimental traitsand provides novel evidence that these effects persist into older age, even among individuals who cognitively unimpaired (but may have additional AD risk factors) [82][83][84]. ...
Background: Sex differences impact Alzheimer's disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology.
Objective: Examine how AD risk factors (age, APOE-ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures.
Methods: Individuals from the OASIS-3 cohort (age 42-95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231).
Results: In absence of AD risk factors (APOE-ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β = -0.007). Regression modeling including APOE-ɛ4 allele carriers (Aβ-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β = 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the trail-making test (p < 0.05).
Conclusion: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE-ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.
Deep transcranial magnetic stimulation (DTMS) is a new non-invasive neuromodulation technique based on repetitive transcranial magnetic stimulation technology. The new H-coil has significant advantages in the treatment and mechanism research of psychiatric and neurological disorders. This is due to its deep stimulation site and wide range of action. This paper reviews the clinical progress of DTMS in psychiatric and neurological disorders such as Parkinson’s disease, Alzheimer’s disease, post-stroke motor dysfunction, aphasia, and other neurological disorders, as well as anxiety, depression, and schizophrenia.
Background: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. Objective: Examine how AD risk factors (age, APOE ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. Methods: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). Results: In absence of AD risk factors (APOE ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β= –0.007). Regression modeling including APOE ɛ4 allele carriers (Aβ–) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β= 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β= 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the Trail Making Test (p < 0.05). Conclusions: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population.
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, and the morbidity increases with the aging population aggravation. The clinical symptoms of AD mainly include cognitive impairment...
Introduction
Transcranial magnetic stimulation (TMS) is a non-invasive intervention that holds promise for improving cognitive function in individuals with Alzheimer's disease (AD). However, the effectiveness of this therapy and the optimal TMS parameters has not reached a consensus. The purpose of the meta-analysis was to systematically discern the effectiveness of different components of TMS protocols on cognitive improvement in patients with mild cognitive impairment (MCI) and AD.
Methods
The meta-analysis was preregistered on Prospero (registration number: CRD42022345482). PubMed, Web of Science, Science Direct, and Cochrane Library databases were used to search, screen and identify eligible studies with the following keywords: Transcranial Magnetic Stimulation OR TMS OR theta burst stimulation AND Alzheimer OR Alzheimers OR Alzheimer's OR mild cognitive impairment OR MCI. Randomized controlled trials (RCTs) of participants with accepted standardized diagnostic criteria were searched by two authors independently. The risk of bias was assessed using an adapted Cochrane Risk of Bias tool. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effects models. Subgroup analyses were performed to investigate the influential factors.
Results
A total of 21 studies and 25 trials were included in this meta-analysis. The findings revealed a significant overall cognition improvement of real stimulation compared with sham stimulation (short-term effects: SMD, 0.91; 95% CI 0.44–1.38; P < 0.01; long-lasting effects: SMD, 0.91; 95% CI 0.27–1.55; P < 0.01). Subgroup analysis demonstrated that stimulation of the left dorsolateral prefrontal cortex and bilateral cerebellums, as well as moderate frequency stimulation (5 Hz and 10 Hz) on mild and moderate cognitive impairment patients, were more effective than other TMS protocols. However, the additional application of cognitive training showed no significant improvement.
Conclusion
Cognitive improvement effect of TMS was demonstrated in MCI and AD patients in both short-term assessment and long-lasting outcomes, and the efficiency of TMS is affected by the stimulation frequency, stimulation site, and participant characteristics. Further RCTs are needed to validate the findings of our subgroup analysis.
Systematic review registration
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345482 , identifier: CRD42022345482.
Language functions comprise a distributed neural system, largely lateralised to the left cerebral hemisphere. Late recovery from aphasia after a focal lesion, other than by behavioural strategies, has been attributed to one of two changes at a systems level: a laterality shift, with mirror region cortex in the contralateral cortex assuming the function(s) of the damaged region; or a partial lesion effect, with recovery of perilesional tissue to support impaired language functions. Functional neuroimaging with PET allows direct observations of brain functions at systems level. This study used PET to compare regional brain activations in response to a word retrieval task in normal subjects and in aphasic patients who had shown at least some recovery and were able to attempt the task. Emphasis has been placed on single subject analysis of the results as there is no reason to assume that the mechanisms of recovery are necessarily uniform among aphasic patients.
Six right handed aphasic patients, each with a left cerebral hemispheric lesion (five strokes and one glioma), were studied. Criteria for inclusion were symptomatic or formal test evidence of at least some recovery and an ability to attempt word retrieval in response to heard word cues. Each patient underwent 12 PET scans using oxygen-15 labelled water (H2(15)O) as tracer to index regional cerebral blood flow (rCBF). The task, repeated six times, required the patient to think of verbs appropriate to different lists of heard noun cues. The six scans obtained during word retrieval were contrasted with six made while the subject was "at rest". The patients' individual results were compared with those of nine right handed normal volunteers undergoing the same activation study. The data were analysed using statistical parametric mapping (SPM96, Wellcome Department of Cognitive Neurology, London, UK).
Perception of the noun cues would be expected to result in bilateral dorsolateral temporal cortical activations, but as the rate of presentation was only four per minute the auditory perceptual activations were not evident in all people. Anterior cingulate, medial premotor (supplementary speech area) and dorsolateral frontal activations were evident in all normal subjects and patients. There were limited right dorsolateral frontal activations in three of the six patients, but a similar pattern was also found in four of the nine normal subjects. In the left inferolateral temporal cortex, activation was found for the normal subjects and five of the six patients, including two of the three subjects with lesions involving the left temporal lobe. The only patient who showed subthreshold activation in the left inferolateral temporal activation had a very high error rate when performing the verb retrieval task.
The normal subjects showed a left lateralised inferolateral temporal activation, reflecting retrieval of words appropriate in meaning to the cue from the semantic system. Lateralisation of frontal activations to the left was only relative, with right prefrontal involvement in half of the normal subjects. Frontal activations are associated with parallel psychological processes involved in word retrieval, including task initiation, short term (working) memory for the cue and responses, and prearticulatory processes (even though no overt articulation was required). There was little evidence of a laterality shift of word retrieval functions to the right temporal lobe after a left hemispheric lesion. In particular, left inferolateral temporal activation was seen in all patients except one, and he proved to be very inefficient at the task. The results provide indirect evidence that even limited salvage of peri-infarct tissue with acute stroke treatments will have an important impact on the rehabilitation of cognitive functions.
The application of cognitive rehabilitation in early stage of dementia is based on theoretical evidence regarding the neuropsychology of memory impairments in Alzheimer's disease (AD). While short-term forgetting is impaired, long-term forgetting appears to be relatively spared. The memory problems in AD does not appears to be of impaired of storage but the deficits to lie in encoding and acquisition of new memories. Indeed the anatomical areas most affected in the early stage of AD are the medial temporal lobe structures; these areas are critical in the consolidation of new memories. The aim of the cognitive rehabilitation is to promote maximal adaptive cognitive functioning in patient with neurologically induced cognitive deficits.
In this chapter, methodological aspects of neuropsychological assessment will be discussed. First, a brief theoretical neuropsychological
framework is presented related to the study of brain–behavior interactions. We will focus on the use of global screening tests,
specific neuropsychological tests, computerized assessment, and the development of a test battery that is optimized for use
in young and older diabetes patients. The important cognitive domains will be introduced in relation to their assessment:
intelligence, executive function, learning and memory, attention and working memory, perception, language, and information-processing
speed. The chapter will address psychometric aspects, such as validity and reliability, as well as sensitivity, which are
important for the interpretation of test results. Other psychological constructs that are potential confounders for cognitive
performance in diabetes patients are discussed, such as coping, personality, motivation, and mood. Finally, the chapter will
discuss the clinical significance of statistically significant differences between cases and controls, both with respect to
clinical decision-making in individual patients and on group level.
Key wordsNeuropsychology–Assessment–Psychological Test–Cognition–Dementia–Aging–Personality
There is renewed interest in the functional role of oscillatory brain activity in specific frequency bands, investigated in humans through electroencephalography (EEG) and magnetoencephalography (MEG) recordings. In parallel, there is a growing body of research on non-invasive direct stimulation of the human brain via repetitive (rhythmic) transcranial magnetic stimulation (TMS), and on those frequencies that have the strongest behavioural impact. There is, therefore, great potential in combining these two lines of research to foster knowledge on brain rhythms, in addition to potential therapeutic applications of rhythmic brain stimulation. Here, we review findings from this rapidly evolving field linking intrinsic brain oscillations to distinct sensory, motor and cognitive operations. The findings emphasize that brain rhythms are causally implicated in cognitive functions.
Word-finding difficulty (anomia) is commonly observed in Alzheimer's dementia (AD). The aim of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) applied to the dorso-lateral prefrontal cortex (dlPFC) on picture naming in 24 probable AD patients with different degrees of cognitive decline.
High-frequency rTMS was applied to the left and right dlPFC during object and action naming in AD patients. A sham stimulation was used as a control condition.
Whilst, as previously reported, stimulation to both the left and the right dlPFC improved action, but not object naming in the mild AD group; an improved naming accuracy for both classes of stimuli was found in the moderate to severe group.
Repetitive transcranial magnetic stimulation applied to the dlPFC improves naming performance also in the advanced stages of AD. Moreover, in the severe group the effect is not specific for action naming, as in the case of the mild AD group. These findings suggest that rTMS can affect the intrinsic ability of the brain to restore or compensate for damaged function and may represent an useful new tool for cognitive rehabilitation.
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.