Faculty Bibliography

Low-frequency repetitive transcranial magnetic stimulation (1-Hz rTMS) is a promising noninvasive tool for the treatment of depression. Hippocampal neuronal plasticity is thought to play a pivotal role in the pathophysiology of depressive disorders and the mechanism of action of antidepressant treatments. We investigated the effect of 1-Hz rTMS treatment on hippocampal dentate gyrus structural plasticity and related emotional behaviors modifications. Experimentally, adult male mice received either five days of 1-Hz rTMS or Sham stimulation. After stimulation, the mice underwent a battery of tests for anxiety-like and depression-like behaviors. We also tested the effect of treatment on mature and newly generated granule cell dendritic complexity. Our data showed that 1-Hz rTMS induced structural plasticity in mature granule cells, as evidenced by increased dendritic length and number of intersections. However, the stimulation did not increase the proliferation of the dentate gyrus progenitor cells. On the contrary, the stimulated mice showed increased dendritic complexity of newly generated neurons. Moreover, 1-Hz rTMS resulted in antidepressant-like effects in the tail suspension test, but it did not affect anxiety-like behaviors. Therefore, our results indicate that 1-Hz rTMS modulates dentate gyrus morphological plasticity in mature and newly generated neurons. Furthermore, our data provide some evidence of an association between the antidepressant-like activity of 1-Hz rTMS and structural plasticity in the hippocampus.

Food portion size influences energy intake, and sustained high-energy intake often leads to obesity. Virtual portion creation tasks (VPCTs), in which a participant creates portions of food on a computer screen, predict intake in healthy individuals. The objective of this study was to determine whether portions created in VPCTs are stable over time (test-retest reliability) and responsive to factors known to influence food intake, such as eating contexts and food types, and to determine if virtual portions can predict weight loss. Patients with obesity scheduled for bariatric surgery (n=29), and individuals with a normal BMI (18.5-24.9 kg/m², controls, n=29), were instructed to create virtual portions of eight snack foods, which varied in energy density (low and high) and taste (sweet and salty). Portions were created in response to the following eating situations, or "contexts": What they would a) eat to stay healthy (healthy), b) typically eat (typical), c) eat to feel comfortably satisfied (satisfied), d) consider the most that they could tolerate eating (maximum), and e) eat if nothing was limiting them (desired). Tasks were completed before and 3 months after surgery in patients, and at two visits, 3 months apart, in controls. Body weight (kg) was recorded at both visits. Virtual portions differed significantly across groups, visits, eating contexts, energy densities (low vs. high), and tastes (sweet vs. salty). Portions created by controls did not change over time while portions created by patients decreased significantly after surgery, for all contexts except healthy. For patients, desired and healthy portions predicted 3-month weight loss. VPCTs are replicable, responsive to foods and eating contexts, and predict surgical weight loss. These tasks could be useful for individual assessment of expectations of amounts that are eaten in health and disease and for prediction of weight loss.

OBJECTIVE:To assess the proportion of pediatric patients who develop post-traumatic stress disorder (PTSD) attributed to traumatic brain injury (TBI). METHODS:PubMed and Embase were searched from database inception until January 26, 2019. Two independent investigators screened titles, abstracts, and subsequently, full-text articles. Following this, the same investigators also extracted data relevant for the scope of this review. RESULTS:Ten articles were included in this review. In these, six unique cohorts were described, with relative frequencies of PTSD attributed TBI ranging from 3.3% to 48.5%. Two studies also found that PTSD was more common in children after TBI compared to pediatric orthopedic controls. Study quality was determined as high or very high for all six included cohorts, although the studies differed considerably in terms of methodology. CONCLUSIONS:Methodological variations confound comparisons of relative frequency assessments of PTSD attributed to TBI. However, PTSD is associated with considerable long-term disability and undetected PTSD in children should raise public concern. Thus, large scale, prospective studies are needed to ascertain the clinical course of PTSD attributed to TBI in children and adolescence.

Enrichment of sodium channels at nodes of Ranvier, a hallmark of myelinated axons, underlies effective saltatory conduction. In this issue of Neuron, Eshed-Eisenbach et al. (2020) demonstrate that proteolysis of gliomedin, which drives initial channel clustering, provides a novel mechanism to ensure fidelity of channel localization to nodes.

OBJECTIVE:To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs. METHODS:In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment. RESULTS:< 0.0001). Focal seizures with motor component, impaired awareness, and focal to bilateral tonic-clonic seizures were significantly reduced with cenobamate vs placebo. During maintenance, 28.3% of cenobamate-treated and 8.8% of placebo-treated patients were seizure-free. Treatment-emergent adverse events reported in >10% in either group (cenobamate vs placebo) were somnolence (22.1% vs 11.9%), dizziness (22.1% vs 16.5%), headache (12.4% vs 12.8%), nausea (11.5% vs 4.6%), and fatigue (10.6% vs 6.4%). CONCLUSION/CONCLUSIONS:Adjunctive treatment with cenobamate 200 mg/d significantly improved seizure control in adults with uncontrolled focal seizures and was well tolerated. CLINICALTRIALSGOV IDENTIFIER/UNASSIGNED:NCT01397968. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that, for patients with uncontrolled focal seizures, adjunctive cenobamate reduces seizures.

It is a commonplace that evolution proceeds by selection of the fittest with elimination of organisms less well adapted to the environment. Along with this, the appearance of novel form arises from preliminary stages in growth, not as additions to the endpoints of prior specialization. The mechanisms of evolutionary change, from earlier form-building layers and specification by elimination, have been described in morphogenesis as prolongation of pre-terminal stages in development and winnowing of redundancy to achieve specific-ity. In earlier writings, these trends in evolutionary and developmental growth were the basis of an account of the nature of the symptom (error) with focal brain lesion. This paper extends the argument from pathology to subjective experience, namely that patterns in evolutionary and fetal growth that are carried over into adult cognition can explain the emergence of intrapersonal phenomena in human mind conceived as a kind of organism, with activity in the mental (mind/brain) state interpreted as a dynamic process of growth.

Neurons are highly polarized cells organized into functionally and molecularly distinct domains. A key question is whether the multiprotein complexes that comprise these domains are preassembled, transported, and inserted as a complex or whether their components are transported independently and assemble locally. Here, we have dynamically imaged, in pairwise combinations, the vesicular transport of fluorescently tagged components of the nodes of Ranvier and other myelinated axonal domains in sensory neurons cultured alone or together with Schwann cells at the onset of myelination. In general, most proteins are transported independently in the anterograde direction. In contrast, there is substantial cotransport of proteins from distinct domains in the retrograde direction likely due to coendocytosis along the axon. Early myelination did not substantially change these patterns of transport, although it increased the overall numbers of axonal transport vesicles. Our results indicate domain components are transported in separate vesicles for local assembly, not as preformed complexes, and implicate endocytosis along axons as a mechanism of clearance.

BACKGROUND:Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum. OBJECTIVES:We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication. METHODS:A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements. RESULTS:Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication. CONCLUSIONS:Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.