The role of parvalbumin interneuron dysfunction across neurodegenerative dementias.

Parvalbumin-positive (PV+) basket neurons are fast-spiking, non-adapting inhibitory interneurons whose oscillatory activity is essential for regulating cortical excitation/inhibition balance. Their dysfunction results in cortical hyperexcitability and gamma rhythm disruption, which have recently gained substantial traction as contributing factors as well as potential therapeutic targets for the treatment of Alzheimer's Disease (AD). Recent evidence indicates that PV+ cells are also impaired in Frontotemporal Dementia (FTD) and Dementia with Lewy bodies (DLB). However, no attempt has been made to integrate these findings into a coherent pathophysiological framework addressing the contribution of PV+ interneuron dysfunction to the generation of cortical hyperexcitability and gamma rhythm disruption in FTD and DLB. To fill this gap, we epitomized the most recent evidence on PV+ interneuron impairment in AD, FTD, and DLB, focusing on its contribution to the generation of cortical hyperexcitability and gamma oscillatory disruption and their interplay with misfolded protein accumulation, neuronal death, and clinical symptoms' onset. Our work deepens the current understanding concerning the role of PV+ interneuron dysfunction across neurodegenerative dementias, highlighting commonalities and differences among AD, FTD, and DLB, thus paving the way for identifying novel biomarkers and potential therapeutic targets for the treatment of these diseases.

Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Subclinical epileptiform discharges in Alzheimer's disease are associated with increased hippocampal blood flow.

BACKGROUND: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer's disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer's disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus. METHODS: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG. RESULTS: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC. CONCLUSIONS: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT04436341).

Levetiracetam Increases Hippocampal Blood Flow in Alzheimer's Disease as Measured by Arterial Spin Labelling MRI.

BACKGROUND: Patients with Alzheimer's disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. OBJECTIVE: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. METHODS: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI. RESULTS: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. CONCLUSION: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.

The multifactorial nature of healthy brain ageing: Brain changes, functional decline and protective factors.

As the global population faces a progressive shift towards a higher median age, understanding the mechanisms underlying healthy brain ageing has become of paramount importance for the preservation of cognitive abilities. The first part of the present review aims to provide a comprehensive look at the anatomical changes the healthy brain endures with advanced age, while also summarizing up to date findings on modifiable risk factors to support a healthy ageing process. Subsequently, we describe the typical cognitive profile displayed by healthy older adults, conceptualizing the well-established age-related decline as an impairment of four main cognitive factors and relating them to their neural substrate previously described; different cognitive trajectories displayed by typical Alzheimer's Disease patients and successful agers with a high cognitive reserve are discussed. Finally, potential effective interventions and protective strategies to promote cognitive reserve and defer cognitive decline are reviewed and proposed.

What Are the Key Diagnostic Cognitive Impairment and Dementia Subtypes and How to Integrate all of the Diagnostic Data to Establish a Diagnosis?

Diagnosis of dementia requires a detailed history, physical examination, imaging, and sometimes neuropsychological testing or ancillary tests. Mild cognitive impairment is defined as an objective impairment in cognitive performance but preserved ability to do activities of daily living. Dementia is diagnosed once impairment in activities of daily living develops. Common types of dementia covered here include mild cognitive impairment, Alzheimer's disease, Lewy body dementia, frontotemporal dementia, the primary progressive aphasias, and vascular dementia.

A study of flex miniaturized coils for focal nerve magnetic stimulation.

BACKGROUND: Peripheral magnetic stimulation (PMS) is emerging as a complement to standard electrical stimulation (ES) of the peripheral nervous system (PNS). PMS may stimulate sensory and motor nerve fibers without the discomfort associated with the ES used for standard nerve conduction studies. The PMS coils are the same ones used in transcranial magnetic stimulation (TMS) and lack focality and selectiveness in the stimulation. PURPOSE: This study presents a novel coil for PMS, developed using Flexible technologies, and characterized by reduced dimensions for a precise and controlled targeting of peripheral nerves. METHODS: We performed hybrid electromagnetic (EM) and electrophysiological simulations to study the EM exposure induced by a novel miniaturized coil (or mcoil) in and around the radial nerve of the neuro-functionalized virtual human body model Yoon-Sun, and to estimate the current threshold to induce magnetic stimulation (MS) of the radial nerve. Eleven healthy subjects were studied with the mcoil, which consisted of two 15 mm diameter coils in a figure-of-eight configuration, each with a hundred turns of a 25 µm copper-clad four-layer foil. Sensory nerve action potentials (SNAPs) were measured in each subject using two electrodes and compared with those obtained from standard ES. The SNAPs conduction velocities were estimated as a performance metric. RESULTS: The induced electric field was estimated numerically to peak at a maximum intensity of 39 V/m underneath the mcoil fed by 70 A currents. In such conditions, the electrophysiological simulations suggested that the mcoil elicits SNAPs originating at 7 mm from the center of the mcoil. Furthermore, the numerically estimated latencies and waveforms agreed with those obtained during the PMS experiments on healthy subjects, confirming the ability of the mcoil to stimulate the radial nerve sensory fibers. CONCLUSION: Hybrid EM-electrophysiological simulations assisted the development of a miniaturized coil with a small diameter and a high number of turns using flexible electronics. The numerical dosimetric analysis predicted the threshold current amplitudes required for a suprathreshold peripheral nerve sensory stimulation, which was experimentally confirmed. The developed and now validated computational pipeline will be used to improve the performances (e.g., focality and minimal currents) of new generations of mcoil designs.

In Older Adults the Antidepressant Effect of Repetitive Transcranial Magnetic Stimulation Is Similar but Occurs Later Than in Younger Adults.

Background: Treatment resistant depression is common in older adults and treatment is often complicated by medical comorbidities and polypharmacy. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for this group due to its favorable profile. However, early influential studies suggested that rTMS is less effective in older adults. This evidence remains controversial. Methods: Here, we evaluated the rTMS treatment outcomes in a large international multicenter naturalistic cohort of >500 patients comparing older vs. younger adults. Results: We show that older adults, while having similar antidepressant response to younger adults, respond more slowly, which may help to explain differences from earlier studies when the duration of a treatment course was shorter. Conclusions: Such evidence helps to resolve a long-standing controversy in treating older depressed patients with rTMS. Moreover, these findings provide an important data point in the call to revise policy decisions from major insurance providers that have unfairly excluded older adults.

Corticomotor plasticity as a predictor of response to high frequency transcranial magnetic stimulation treatment for major depressive disorder.

BACKGROUND: Many patients with treatment-resistant depression (TRD) respond to repetitive transcranial magnetic stimulation (rTMS) treatment. This study aimed to investigate whether modulation of corticomotor excitability by rTMS predicts response to rTMS treatment for TRD in 10 Hz and intermittent theta-burst stimulation (iTBS) protocols. METHODS: Thirteen TRD patients underwent two evaluations of corticomotor plasticity-assessed as the post-rTMS (10 Hz, iTBS) percent change (%∆) in motor evoked potential (MEP) amplitude elicited by single-pulse TMS. Following corticomotor plasticity evaluations, patients subsequently underwent a standard 6-week course of 10 Hz rTMS (4 s train, 26 s inter-train interval, 3000 total pulses, 120% of motor threshold) to the left dorsolateral prefrontal cortex. Treatment efficacy was assessed by the Beck Depression Inventory II (BDI-II) and Hamilton Depression Rating Scale (HAM-D). The change in MEPs was compared between 10 Hz and iTBS conditions and related to the change in BDI-II and HAM-D scores. RESULTS: Analyses of variance revealed that across all time-points, higher post-10 Hz MEP change was a significant predictor of greater improvement on the BDI-II (p < 0.001) and HAM-D (p = 0.022). This relationship was not observed with iTBS (p-values≥0.100). Post-hoc tests revealed the MEP change 20 min post-10 Hz was the strongest predictor of BDI-II improvement. LIMITATIONS: Cortical excitability was measured from the motor cortex, rather than the dorsolateral prefrontal cortex, where treatment is applied. The 10 Hz and iTBS protocols were performed at different intensities consistent with common practice. CONCLUSIONS: Modulation of corticomotor excitability by 10 Hz can predict response to rTMS treatment with 10 Hz rTMS.

Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer's Disease: A Case Series.

BACKGROUND: Alzheimer's disease (AD) is characterized by diffuse amyloid-ß (Aß) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aß and p-Tau deposition presumably via microglia activation in AD mouse models. OBJECTIVE: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). METHODS: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aß, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. RESULTS: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aß as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. CONCLUSION: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection. METHODS: In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments. RESULTS: No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band. CONCLUSIONS: Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients. TRIAL REGISTRATION: Studies were registered separately on ClinicalTrials.gov ( NCT03290326 , registered on September 21, 2017; NCT03412604 , registered on January 26, 2018).

Screening of Parkinson's Disease Using Geometric Features Extracted from Spiral Drawings.

Conventional means of Parkinson's Disease (PD) screening rely on qualitative tests typically administered by trained neurologists. Tablet technologies that enable data collection during handwriting and drawing tasks may provide low-cost, portable, and instantaneous quantitative methods for high-throughput PD screening. However, past efforts to use data from tablet-based drawing processes to distinguish between PD and control populations have demonstrated only moderate classification ability. Focusing on digitized drawings of Archimedean spirals, the present study utilized data from the open-access ParkinsonHW dataset to improve existing PD drawing diagnostic pipelines. Random forest classifiers were constructed using previously documented features and highly-predictive, newly-proposed features that leverage the many unique mathematical characteristics of the Archimedean spiral. This approach yielded an AUC of 0.999 on the particular dataset we tested on, and more importantly identified interpretable features with good promise for generalization across diverse patient cohorts. It demonstrated the potency of mathematical relationships inherent to the drawing shape and the usefulness of sparse feature sets and simple models, which further enhance interpretability, in the face of limited sample size. The results of this study also inform suggestions for future drawing task design and data analytics (feature extraction, shape selection, task diversity, drawing templates, and data sharing).

Higher motor cortical excitability linked to greater cognitive dysfunction in Alzheimer's disease: results from two independent cohorts.

Prior studies have reported increased cortical excitability in people with Alzheimer's disease (AD), but findings have been inconsistent, and how excitability relates to dementia severity remains incompletely understood. The objective of this study was to investigate the association between a transcranial magnetic stimulation (TMS) measure of motor cortical excitability and measures of cognition in AD. A retrospective cross-sectional analysis tested the relationship between resting motor threshold (RMT) and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) across two independent samples of AD participants (a discovery cohort, n=22 and a larger validation cohort, n=129) and a control cohort of cognitively normal adults (n=26). RMT was correlated with ADAS-Cog in the discovery-AD cohort (n=22, ß=-.70, p<0.001) but not in the control cohort (n=26, ß=-0.13, p=0.513). This relationship was confirmed in the validation-AD cohort (n=129, ß=-.35, p<0.001). RMT can be a useful neurophysiological marker of progressive global cognitive dysfunction in AD. Future translational research should focus on the potential of RMT to predict and track individual pathophysiological trajectories of aging.

Day-to-day variability in motor threshold during rTMS treatment for depression: Clinical implications.

BACKGROUND: When repetitive transcranial magnetic stimulation (rTMS) is used to treat medication refractory depression, the treatment pulse intensity is individualized according to motor threshold (MT). This measure is often acquired only on the first day of treatment, as per the protocol currently approved by Food and Drug Administration. OBJECTIVE: Here, we aimed to assess daily MT variability across an rTMS treatment course and simulate the effects of different schedules of MT assessment on treatment intensity. METHODS: We conducted a naturalistic retrospective study with 374 patients from a therapeutic rTMS program for depression that measures MT daily. RESULTS: For each patient, in almost half the TMS sessions, MT varied on average more than 5% as compared to the baseline MT acquired in the first treatment day. Such variability was only minimally impacted by having different TMS technicians acquiring MT in different days. In a smaller cohort of healthy individuals, we confirmed that the motor hotspot localization method, a critical step for accurate MT assessment, was stable in different days, arguing that daily MT variability reflects physiological variability, rather than an artifact of measurement error. Finally, in simulations of the effect of one-time MT measurement, we found that half of sessions would have been 5% or more above or below target intensity, with almost 5% of sessions 25% above target intensity. The simulated effects of weekly MT measurements were significantly improved. CONCLUSIONS: In conclusion, MT varies significantly across days, not fully dependent on methods of MT acquisition. This finding may have important implications for therapeutic rTMS practice regarding safety and suggests that regular MT assessments, daily or at least weekly, would ameliorate the effect.

Seizure risk with repetitive TMS: Survey results from over a half-million treatment sessions.

BACKGROUND: Seizures are rare during repetitive transcranial magnetic stimulation (rTMS) treatment, but estimating risk is difficult because of study heterogeneity and sampling limitations. Moreover, there are few studies comparing rates between device manufacturers. OBJECTIVE: The objective of this study was to calculate rTMS seizure rates across various FDA-cleared devices in naturalistic clinical settings. METHODS: In July and August 2018, approximately 500 members of the Clinical TMS Society (CTMSS) were electronically surveyed about seizures in their practices. Seizures were distinguished from non-seizures by a remote semi-structured interview with a Board-certified neurologist and Co-Chair of the CTMSS Standards Committee. Exact Poisson calculations were used to estimate seizure rates and confidence intervals across the four most widely used manufacturers. RESULTS: The survey was completed by 134 members, with 9 responses excluded because of data inconsistencies. In total, 18 seizures were reported in 586,656 sessions and 25,526 patients across all device manufacturers. The overall seizure rate was 0.31 (95% CI: 0.18, 0.48) per 10,000 sessions, and 0.71 (95% CI: 0.42, 1.11) per 1000 patients. The Brainsway H-coil seizure rate of 5.56 per 1000 patients (95% CI: 2.77,9.95) was significantly higher (p < 0.001) than the three most widely used figure- 8 coil devices' combined seizure rate of 0.14 per 1000 patients (95% CI: 0.01, 0.51). CONCLUSION: The absolute risk of a seizure with rTMS is low, but generic Brainsway H-coil treatment appears to be associated with a higher relative risk than generic figure- 8 coil treatment. Well-designed prospective studies are warranted to further investigate this risk.

Cognitive Impairment in Aging Physicians: Current Challenges and Possible Solutions.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

Gamma-induction in frontotemporal dementia (GIFTeD) randomized placebo-controlled trial: Rationale, noninvasive brain stimulation protocol, and study design.

INTRODUCTION: Frontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non-invasive brain stimulation thought to engage neural activity in a frequency-specific manner and thus suited to restore altered brain oscillatory patterns. METHODS: This is a multi-site, randomized, double-blind, placebo-controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1-hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3- to 6-months follow-up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers. RESULTS: The trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data-collection site. DISCUSSION: This study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism.