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.

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.

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.

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.

LTP-like plasticity is impaired in amyloid-positive amnestic MCI but independent of PET-amyloid burden.

Transcranial magnetic stimulation (TMS) reveals decreased efficacy of long-term potentiation-like (LTP-like) neuroplastic mechanisms in Alzheimer's disease (AD). However, it is not yet known whether LTP-like plasticity is also impaired in prodromal AD, or how abnormal TMS measures are related to established AD biomarkers. Here, we investigated the LTP-like response to intermittent theta-burst stimulation in 17 amyloid-positive participants with amnestic mild cognitive impairment (MCI) and 10 cognitively unimpaired controls. Our results showed a lack of LTP-like neuromodulation in MCI compared with controls that was unrelated to quantitative amyloid-beta burden on positron emission tomography. Surprisingly, greater LTP-like response was related to worse memory function in the MCI group, highlighting the complex role of neuroplasticity in the prodromal stages of AD. Overall, our results demonstrate abnormal LTP-like plasticity using intermittent theta-burst stimulation assessment in amyloid-positive participants with MCI. These findings support the potential for development of TMS measures as prognostic markers or therapeutic targets in early-stage symptomatic AD.

Non-invasive measurement of choroid plexus apparent blood flow with arterial spin labeling.

BACKGROUND: The choroid plexus is a major contributor to the generation of cerebrospinal fluid (CSF) and the maintenance of its electrolyte and metabolite balance. Here, we sought to characterize the blood flow dynamics of the choroid plexus using arterial spin labeling (ASL) MRI to establish ASL as a non-invasive tool for choroid plexus function and disease studies. METHODS: Seven healthy volunteers were imaged on a 3T MR scanner. ASL images were acquired with 12 labeling durations and post labeling delays. Regions of the choroid plexus were manually segmented on high-resolution T1 weighted images. Choroid plexus perfusion was characterized with a dynamic ASL perfusion model. Cerebral gray matter perfusion was also quantified for comparison. RESULTS: Kinetics of the ASL signal were clearly different in the choroid plexus than in gray matter. The choroid plexus has a significantly longer T1 than the gray matter (2.33 ± 0.30 s vs. 1.85 ± 0.10 s, p < 0.02). The arterial transit time was 1.24 ± 0.20 s at the choroid plexus. The apparent blood flow to the choroid plexus was measured to be 39.5 ± 10.1 ml/100 g/min and 0.80 ± 0.31 ml/min integrated over the posterior lateral ventricles in both hemispheres. Correction with the choroid plexus weight yielded a blood flow of 80 ml/100 g/min. CONCLUSIONS: Our findings suggest that ASL can provide a clinically feasible option to quantify the dynamic characteristics of choroid plexus blood flow. It also provides useful reference values of the choroid plexus perfusion. The long T1 of the choroid plexus may suggest the transport of water from arterial blood to the CSF, potentially providing a method to quantify CSF generation.

Can Adults with Mild Cognitive Impairment Build Cognitive Reserve and Learn Mindfulness Meditation? Qualitative Theme Analyses from a Small Pilot Study.

BACKGROUND/OBJECTIVE: High levels of chronic stress negatively impact the hippocampus and are associated with increased incidence of mild cognitive impairment (MCI) and Alzheimer's disease. While mindfulness meditation may mitigate the effects of chronic stress, it is uncertain if adults with MCI have the capacity to learn mindfulness meditation. METHODS: 14 adults with MCI were randomized 2:1 to Mindfulness Based Stress Reduction (MBSR) or a wait-list control group. We conducted qualitative interviews with those who completed MBSR. Transcribed interviews were: a) coded using an emergent themes inductive approach informed by grounded theory; b) rated 0-10, with higher scores reflecting greater perceived benefit from, and understanding of, mindfulness meditation. Ratings were correlated with daily home practice times and baseline level of cognitive function. RESULTS: Seven themes emerged from the interviews: positive perceptions of class; development of mindfulness skills, including meta-cognition; importance of the group experience; enhanced well-being; shift in MCI perspective; decreased stress reactivity and increased relaxation; improvement in interpersonal skills. Ratings of perceived benefit and understanding ranged from 2-10 (mean = 7) and of 0-9.5 (mean = 6), respectively. Many participants experienced substantial benefit/understanding, some had moderate, and a few had minimal benefit/understanding. Understanding the key concepts of mindfulness was highly positively correlated with ≥20 minutes/day of home practice (r = 0.90) but not with baseline cognitive function (r = 0.13). CONCLUSIONS: Most adults with MCI were able to learn mindfulness meditation and had improved MCI acceptance, self-efficacy, and social engagement. Cognitive reserve may be enhanced through a mindfulness meditation program even in patients with MCI.

Ultra-focal Magnetic Stimulation Using a µTMS coil: a Computational Study.

A new miniaturized figure-of-eight coil (µCoil) for TMS applications has been developed taking advantage of the Flex circuit technology. First experiments on volunteers demonstrated the ability of the µCoil to elicit sensorial action potentials of the peripheral nervous system. The necessity of reducing the size of standard TMS stimulator arises from the poor spatial resolution of the latter. This study aims to model the µCoil and study the electromagnetic fields induced inside the arm during peripheral nerve stimulation. Results confirmed that the µCoil is capable of inducing a focalized electric field inside the tissues with amplitudes up to 70V/m consistent with the observed peripheral nerve stimulation in healthy volunteers.

Feasibility of Computerized Cognitive-Behavioral Therapy Combined With Bifrontal Transcranial Direct Current Stimulation for Treatment of Major Depression.

BACKGROUND: Cognitive behavioral therapy (CBT) is effective in the treatment of major depressive disorder (MDD). Transcranial Direct Current Stimulation (tDCS) has demonstrated preliminary antidepressant effects and beneficial effects on cognitive function. OBJECTIVE: We investigated the feasibility and acceptability of using tDCS to enhance the effects of computer-based CBT for treatment of MDD. MATERIALS AND METHODS: In a randomized, double-blind, sham-controlled study, 14 patients with MDD on stable or no pharmacotherapy received active or sham bifrontal tDCS for four weeks with concurrent CBT. RESULTS: Ten participants completed the protocol. Three withdrew from the study because of lack of efficacy or dislike of the eCBT program. One was discontinued from the protocol by the investigators. Treatment was well tolerated, and most side-effects were mild and consistent with prior tDCS research. Pooled data from both groups showed significant baseline to endpoint improvement in depression (p = 0.008). Overall percent change on the HAMD-21 was 28.98%. The study was underpowered to detect differences in tDCS treatment groups. CONCLUSIONS: Combining tDCS with computer-based CBT is feasible for MDD. Further work is needed to evaluate potential synergistic effects of combined tDCS and CBT.

Noninvasive Brain Stimulation: Challenges and Opportunities for a New Clinical Specialty.

Noninvasive brain stimulation refers to a set of technologies and techniques with which to modulate the excitability of the brain via transcranial stimulation. Two major modalities of noninvasive brain stimulation are transcranial magnetic stimulation (TMS) and transcranial current stimulation. Six TMS devices now have approved uses by the U.S. Food and Drug Administration and are used in clinical practice: five for treating medication refractory depression and the sixth for presurgical mapping of motor and speech areas. Several large, multisite clinical trials are currently underway that aim to expand the number of clinical applications of noninvasive brain stimulation in a way that could affect multiple clinical specialties in the coming years, including psychiatry, neurology, pediatrics, neurosurgery, physical therapy, and physical medicine and rehabilitation. In this article, the authors review some of the anticipated challenges facing the incorporation of noninvasive brain stimulation into clinical practice. Specific topics include establishing efficacy, safety, economics, and education. In discussing these topics, the authors focus on the use of TMS in the treatment of medication refractory depression when possible, because this is the most widely accepted clinical indication for TMS to date. These challenges must be thoughtfully considered to realize the potential of noninvasive brain stimulation as an emerging specialty that aims to enhance the current ability to diagnose and treat disorders of the brain.

Patient- and Technician-Oriented Attitudes Toward Transcranial Magnetic Stimulation Devices.

Four transcranial magnetic stimulation (TMS) devices are currently approved for use in treatment-resistant depression. The authors present the first data-driven study examining the patient- and technician-experience using three of these distinct devices. A retrospective survey design with both patient and technician arms was utilized. The study population included patients who received TMS for treatment-resistant depression at the Berenson Allen Center for Noninvasive Brain Stimulation for the first time between 2013 and 2016 and technicians who worked in the program from 2009 to 2017. Statistical analysis included t tests and analyses of variance to assess differences between and across the multiple groups, respectively. Patients treated with the NeuroStar device reported greater confidence that the treatment was being performed correctly compared with those treated with the Magstim device. Conversely, with regard to tolerability, patients treated with the Magstim device reported less pain in the last week and less pain on average compared with those treated with the NeuroStar device. On average, technicians reported feeling that both the Magstim and NeuroStar devices were significantly easier to use than the Brainsway Deep TMS H-Coil device. Additionally, they found the former two devices to be more reliable and better tolerated. Furthermore, the technicians reported greater confidence in the Magstim and NeuroStar devices compared with the Brainsway Deep TMS H-Coil device and indicated that they would be more likely to recommend the two former devices to other treatment centers.