Alvaro Pascual-Leone

Harvard Medical School, Boston, MA, United States · Neurology

By 2050, 1 in 4 people worldwide will be living with hearing impairment. We propose a digital Speech Hearing Screener (dSHS) using short nonsense word recognition to measure speech-hearing ability. The importance of hearing screening is increasing due to the anticipated increase in individuals with hearing impairment globally. We compare dSHS outco...

Introduction Alzheimer’s disease and related dementias (ADRD) represent a substantial global public health challenge with multifaceted impacts on individuals, families, and healthcare systems. Brief cognitive screening tools such as the Mini-Cog© can help improve recognition of ADRD in clinical practice, but widespread adoption continues to lag. We...

Background Dual task paradigms are thought to offer a quantitative means to assess cognitive reserve and the brain’s capacity to allocate resources in the face of competing cognitive demands. The most common dual task paradigms examine the interplay between gait or balance control and cognitive function. However, gait and balance tasks can be physi...

Postoperative Delirium (POD) is the most common complication following surgery among older adults, and has been consistently associated with increased mortality and morbidity, cognitive decline, and loss of independence, as well as markedly increased health-care costs. The development of new tools to identify individuals at high risk for POD could...

Introduction Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The prima...

Introduction Individuals with subjective cognitive decline (SCD) express concern about self-perceived cognitive decline despite no objective impairment and are at higher risk of developing Alzheimer’s disease. Despite documented links between SCD and repetitive negative thinking (RNT), the specific impact of RNT on brain integrity and cognition in...

Purpose The objective of this prospective, single-centre case series was to investigate feasibility, clinical outcomes, and neural correlates of non-invasive Neuromodulation-Induced Cortical Prehabilitation (NICP) before brain tumor surgery. Previous studies have shown that gross total resection is paramount to increase life expectancy but is count...

Introduction A rapid and reliable neuropsychological protocol is essential for the efficient assessment of neurocognitive constructs related to emergent neurodegenerative diseases. We developed an AI-assisted, digitally administered/scored neuropsychological protocol that can be remotely administered in ~10 min. This protocol assesses the requisite...

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal...

Introduction Understanding the impact of different lifestyle trajectories on health preservation and disease risk is crucial for effective interventions. Methods This study analyzed lifestyle engagement over five years in 3,013 healthy adults aged 40-70 from the Barcelona Brain Health Initiative using K-means clustering. Nine modifiable risk facto...

Primary brain neoplasms are associated with elevated mortality and morbidity rates. Brain tumour surgery aims to achieve maximal tumour resection while minimizing damage to healthy brain tissue. Research on Neuromodulation Induced Cortical Prehabilitation (NICP) has highlighted the potential, before neurosurgery, of establishing new brain connectio...

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped...

Background Digital neuropsychological tests reliably capture real-time, process-based behavior that traditional paper/pencil tests cannot detect, enabling earlier detection of neurodegenerative illness. We assessed relations between informant-based subtle and mild functional decline and process-based features extracted from the digital Trail Making...

Background By 2050, 1 in 4 people worldwide will be living with hearing impairment by 2050. We propose a digital Speech Hearing Screener (dSHS) using short nonsense word recognition to measure speech-hearing ability. We compare dSHS outcomes with standardized pure-tone averages (PTA) and speech-recognition thresholds (SRT). 50 participants (aged 55...

This Viewpoint discusses lecanemab use and the risk of cerebral macrohemorrhage for patients with mild cognitive impairment or early dementia.

Purpose Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (L-DLPFC) may improve the clinical symptoms of depression. This multicenter study (N=35) tested remotely supervised and repeated daily multichannel tDCS delivered at home designed to target the L-DLPFC in...

Objective: Limited research has directly investigated whether and how placebo effects can be harnessed for the treatment of functional neurological disorder (FND), despite a long-standing and controversial history of interest in this area. Methods: A small exploratory study was conducted with adults with a cognitive subtype of FND recruited from...

Objective We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer’s disease (AD), AD-related dementias, and nondementia conditions with comorbid cognitive impairment. Design Systematic review, Meta-Analysis Setting We searched MEDLINE, Embase, Cochrane database, APA PsycINFO, Web of Science, and...

Background: Interventions to recover upper extremity (UE) function after moderate-to-severe stroke are limited. Transcranial random noise stimulation (tRNS) is an emerging non-invasive technique to improve neuronal plasticity and may potentially augment functional outcomes when combined with existing interventions, such as functional electrical st...

INTRODUCTION: Early detection of Alzheimer’s disease and cognitive impairment is critical to improving the healthcare trajectories of aging adults, enabling early intervention and potentially prevention of decline. METHODS: To evaluate multi-modal feature sets for assessing memory and cognitive impairment, feature selection and subsequent logistic...

The prevalence of Alzheimer's disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptat...

Background Disease-modifying treatments for Alzheimer’s disease highlight the need for early detection of cognitive decline. However, at present, most primary care providers do not perform routine cognitive testing, in part due to a lack of access to practical cognitive assessments, as well as time and resources to administer and interpret the test...

Background As the world population continues to age, the prevalence of neurological diseases, such as dementia, poses a significant challenge to society. Detecting cognitive impairment at an early stage is vital in preserving and enhancing cognitive function. Digital tools, particularly mHealth, offer a practical solution for large-scale population...

Background It is essential both drug and lifestyle‐based interventions aimed to delay the onset of advanced cognitive decline deliver a meaningful outcome for the patient. In the early stages of Alzheimer’s disease and related dementias (ADRDs), patient‐reported outcome (PRO) measures should be used in parallel with biological investigations of ADR...

Background Digital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assess...

Background Nearly 6.7 million people aged 65 and older in the US are living with Alzheimer’s disease (AD). Early detection of dementia presents a difficult challenge, as the earliest signs of cognitive decline often go undetected. Thus, more sensitive and clinically meaningful cognitive screening tools are needed. Evaluating the patient’s dependenc...

Background Over 55 million people worldwide are currently diagnosed with Alzheimer’s disease (AD) and live with debilitating episodic memory deficits (World Health Organization, 2022). Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normali...

Background Early detection of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease and Related Dementias (ADRD) is key to optimal management. Digital tests allow for the reliable capture of meaningful, process‐based neuropsychological test parameters that traditional paper/pencil measures fail to detect, thus enabling earlier detection. We asses...

Background Alzheimer’s disease (AD) is associated with increased cortical excitability, including an elevated risk of seizures. Transcranial magnetic stimulation with electromyography (TMS‐EMG‐EEG) can be used to index intracortical excitability. Prior work has shown that TMS‐based excitability measures are altered in AD and are related to disease...

Background DCTclock™ is an AI‐enabled digital cognitive assessment (DCA) that strongly discriminates between cognitively impaired and unimpaired individuals (receiver operating area under‐the‐curve AUC = 0.89). Among cognitively unimpaired individuals, DCTclock predicts greater PET Aβ burden and shows stronger discrimination (Cohen’s d = 0.76) betw...

Background Markers sensitive to brain changes at the transition from mild cognitive impairment (MCI) to dementia due to Alzheimer’s disease (AD) are needed for aiding prognosis and the selection of potential responders to novel interventional therapies. EEG markers may be advantageous due to their accessibility. Prior research suggests that AD is a...

Background Digital cognitive assessments (DCA) enable quick, sensitive, and reliable assessment of neurocognitive operations that underlie dementia and mild cognitive impairment (MCI). We examined how well the DCTclockTM DCA, Mini‐Mental State Examination (MMSE), and Philadelphia (repeatable) Veral Learning Test (PrVLT) can classify memory clinic p...

Background Repetitive Negative Thinking (RNT) includes negative thoughts about the future (worry) and past (ruminative brooding). RNT has been associated with Alzheimer’s disease (AD) pathology (Marchant et al. Alzheimers Dement . 2020;16(7)) and different patterns of functional connectivity of the triple network of attention, namely, the default m...

Background Digital cognitive assessments (DCA) enable quick, sensitive, and reliable assessment of neurocognitive operations that underlie dementia and mild cognitive impairment (MCI). We examined how well the DCTclock TM DCA, Mini‐Mental State Examination (MMSE), and Philadelphia (repeatable) Veral Learning Test (PrVLT) can classify memory clinic...

Background Positive and negative psychological factors represent pertinent moderators of relative risk and protection for cognitive decline and dementia. For example, repetitive negative thinking has been associated with accelerated cognitive decline and AD pathology ¹ , whereas self‐reflection and purpose in life have been related to better cognit...

Background Alzheimer’s disease is characterized by cortical hyperexcitability in the early stages, which may be attributed to the intricate interplay between tau and amyloid β pathologies. To combat the propagation of tau pathology and cognitive decline, it may be beneficial to maintain a high degree of functional brain network segregation. Additio...

Background Digital assessment technology provides rapid and reliable assessment of neurocognitive abilities associated with Alzheimer’s Disease and Related Dementia (ADRD) and Mild Cognitive Impairment (MCI). Dysexecutive and amnestic impairment typify many ADRD and MCI disorders. Here, we evaluate a 10‐minute digitally administered protocol assess...

Background Distinguishing mild cognitive impairment (MCI) and Alzheimer’s disease‐related dementia (ADRD) requires assessing the clinical impact of cognitive deficits on a patient’s activities of daily living. To accurately monitor cognitive decline, it is thus critical to combine early screening of cognitive deficits with the assessment of functio...

Background Alzheimer’s disease (AD) has a relatively well‐characterized pathology of amyloid‐β and tau accumulation. Yet, disease progression from preclinical to clinical stage remains largely unpredictable at the individual level. Growing evidence shows disrupted synaptic signaling in functionally connected brain networks early in the preclinical...

The World Health Organization (WHO) has designated this the decade of Healthy Ageing--focused on developing and maintaining functional ability that enables well-being in older age. We developed the Healthy Aging Initiative (HAI), a prospective cohort study of adults 55+ measuring functional ability, going beyond a disease-focused model of populatio...

In older adults, performing an attention-demanding cognitive task while standing comes with a ‘cost’ (i.e., decrement) to postural control. Transcranial direct current stimulation (tDCS) designed to facilitate the excitability of the left dorsal-lateral prefrontal cortex (L-DLPFC) and motor cortex (M1) mitigates this dual-task cost (DTC). The effec...

Therapeutic brain stimulation targets are typically designed to treat specific psychiatric or neurological symptoms. 1–4 This approach presents a dilemma when treating patients with comorbidities, atypical symptom profiles, or overlapping symptoms. Identifying targets that modulate groups of behavioral or cognitive symptoms across diagnoses may pro...

Introduction Screening for neurocognitive impairment and psychological distress in ambulatory primary and specialty care medical settings is an increasing necessity. The Core Cognitive Evaluation™ (CCE) is administered/scored using an iPad, requires approximately 8 min, assesses 3- word free recall and clock drawing to command and copy, asks questi...

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the left primary motor cortex, on...

Presentation on the Healthy Aging Initiative research study at the Gerontological Society of America annual conference.

Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders. However, its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a...

Background The Successful Aging after Elective Surgery (SAGES) II Study was designed to examine the relationship between delirium and Alzheimer's disease and related dementias (AD/ADRD), by capturing novel fluid biomarkers, neuroimaging markers, and neurophysiological measurements. The goal of this paper is to provide the first complete description...

Introduction Neurosurgery for brain tumors needs to find a complex balance between the effective removal of targeted tissue and the preservation of surrounding brain areas. Neuromodulation-induced cortical prehabilitation (NICP) is a promising strategy that combines temporary inhibition of critical areas (virtual lesion) with intensive behavioral t...

With human life expectancy and proportion of older adults increasing, global use of evidence-supported preventative methods to minimize risk of brain-related disabilities such as Alzheimer's disease and other dementias—as well as interventions to slow rate of disease progression—is important. Sustained engagement in cognitive and physical exercise...

Objectives: Cognitive dispersion, representing intraindividual fluctuations in cognitive performance, is associated with cognitive decline in advanced age. We sought to elucidate sociodemographic, neuropsychological, and brain connectivity correlates of cognitive dispersion in middle age, and further consider potential influences of the severity o...

Objectives: There has been recent interest in the administration of transcranial electrical stimulation (tES) by a caregiver, family member, or patient themselves while in their own homes (HB-tES). The need to properly train individuals in the administration of HB-tES is essential, and the lack of a uniform training approach across studies has com...

Background and objectives Choroid plexus (ChP) is emerging as a key brain structure in the pathophysiology of neurodegenerative disorders. In this observational study we investigated ChP volume in a large cohort of frontotemporal lobar degeneration (FTLD) spectrum patients to explore a possible link between ChP volume and other disease-specific bio...

Objective To investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer’s disease (AD). Methods Data were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50–...

Background Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via cha...

Background Repetitive Negative Thinking (RNT) includes negative thoughts about the future (worry) and past (rumination), and has been associated with AD physiopathology (Marchant et al. Alzh&Dement 2020;16:1054). Prefrontal and anterior cingulate cortices play a major role in RNT (Demnitz‐King et al., Psychiatry Res Neuroimaging. 2021;316:111353)....

Background Identifying factors that confer resilience to developing delirium is critical given the negative impact of delirium on clinical care and risk for mortality. Here, we investigated a cohort of cognitively normal older adults undergoing elective surgery and examined the role of pre‐operative memory function and cortical thickness in the inc...

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in high...

BACKGROUND Dual task paradigms are thought to offer a quantitative means to assess cognitive reserve and the brain’s capacity to allocate resources in the face of competing cognitive demands. The most common dual task paradigms examine the interplay between gait or balance control and cognitive function. However, gait and balance tasks can be physi...

Background Over 55 million people worldwide are currently diagnosed with Alzheimer’s disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activ...

Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of...

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the primary motor cortex, on modul...