Alvaro Pascual-Leone, MD, PhD

ObjectiveLimited 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.MethodsA small exploratory study was conducted with adults with a cognitive subtype of FND recruited from a single cognitive neurology center in the United States. Participants were given the expectation of receiving cranial stimulation that could benefit their memory symptoms; however, the intervention was sham transcranial magnetic stimulation (placebo). Outcomes included measures of short-term memory testing, subjective memory rating, and state anxiety before and after stimulation. After the study, the true objective and rationale for investigating placebo effects were explained in a scripted debriefing session. Acceptability of the study design and qualitative feedback were …

BackgroundTranscranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but anatomical targets for anxiety remain unclear. Lesion network mapping can be used to optimize existing targets but has not been shown to identify novel effective targets.MethodsAcross seven datasets (n= 936), we used a normative connectome database (n= 1000) to estimate connectivity of lesions and stimulation sites that modify anxiety independent of depression. Datasets included incidental brain lesions, routine clinical TMS sites which show incidental variability in location, TMS sites in a clinical trial that targeted a specific brain coordinate but measured incidental variability in brain connectivity, and subthalamic DBS sites in Parkinson's disease.ResultsLesions (n= 451) and TMS sites (n= 111) that modify anxiety were connected to a common normative brain circuit (p= 0.01). In …

INTRODUCTION Early detection of Alzheimer's disease and cognitive impairment is critical to improving the healthcare trajectories of aging adults, enabling early intervention and potential prevention of decline. METHODS To evaluate multi‐modal feature sets for assessing memory and cognitive impairment, feature selection and subsequent logistic regressions were used to identify the most salient features in classifying Rey Auditory Verbal Learning Test‐determined memory impairment. RESULTS Multimodal models incorporating graphomotor, memory, and speech and voice features provided the stronger classification performance (area under the curve = 0.83; sensitivity = 0.81, specificity = 0.80). Multimodal models were superior to all other single modality and demographics models. DISCUSSION The current research contributes to the prevailing multimodal profile of those with cognitive impairment …

ObjectivesWe re-analysed data from published meta-analyses testing the effects of Transcranial Magnetic Stimulation (TMS) on Major Depressive Disorder (MDD) in adults. We applied up-to-date meta-analytic techniques for handling heterogeneity including the random-effects Hartung-Knapp-Sidik-Jonkman method and estimated 95% prediction intervals. Heterogeneity practices in published meta-analyses were assessed as a secondary aim.Study design and settingWe performed systematic searches of systematic reviews with meta-analyses that included randomised controlled trials assessing the efficacy, tolerability, and side effects of TMS on MDD. We performed risk of bias assessment using A MeaSurement Tool to Assess Reviews (AMSTAR) 2 and re-analysed meta-analyses involving 10 or more primary studies.ResultsWe included 29 systematic reviews and re-analysed 15 meta-analyses. Authors of all …

Objective To assess the potential protective effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the onset of dementia, including vascular dementia (VaD), Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB), in patients with type 2 diabetes mellitus (T2DM) compared to those treated with dipeptidyl peptidase-4 inhibitors (DPP4i). Background Oral antidiabetic drugs (OADs) including metformin, dipeptidyl peptidase-4 inhibitor (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) for type 2 diabetes mellitus (T2DM) have been explored in clinical trials as potential therapeutic candidates that may be repurposed for dementia. The aim of the present study was to investigate whether the use of SGLT2i may prevent dementia in patients with T2DM. Design/Methods This was a population-based cohort study that enrolled adult patients with T2DM from 92 …

BackgroundAs 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 screening and prompt follow-up assessments of cognitive function, thus overcoming economic and time limitations.ObjectiveIn this work, two versions of a digital solution called Guttmann Cognitest® were tested.MethodsTwo hundred and one middle-aged adults used the first version (Group A), while 132 used the second one, which included improved tutorials and practice screens (Group B). This second version was also validated in an older age group (Group C).ResultsThis digital solution was found to be highly satisfactory in terms of usability and feasibility, with good …

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 provide alternative treatment options and outcomes. Here, we use causal brain mapping and clustering methods to identify two distinct brain networks, based on common patterns of connectivity to lesions that selectively modify behaviors and symptoms. Due to the behavioral items in each cluster, we hypothesize that these networks are related to positive and negative affect, respectively. Across ten different datasets of patients receiving transcranial magnetic stimulation (TMS) or deep brain stimulation (DBS), 1, 5, 6 stimulation site connectivity to each of our two brain networks independently predicted improvement in depressive symptoms. Thus, we defined two networks which are independently and causally involved in depression symptoms.

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 to a common normative brain circuit (r= 0.68, p= 0.01). In an independent dataset (n= 300), individualized TMS site connectivity to this circuit predicted anxiety change (p= 0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n= 74, p= 0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p= 0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.