Articulatory Gain Predicts Motor Cortex and Subthalamic Nucleus Activity During Speech.

Speaking precisely is important for effective verbal communication, and articulatory gain is one component of speech motor control that contributes to achieving this goal. Given that the basal ganglia have been proposed to regulate the speed and size of limb movement, that is, movement gain, we explored the basal ganglia contribution to articulatory gain, through local field potentials (LFP) recorded simultaneously from the subthalamic nucleus (STN), precentral gyrus, and postcentral gyrus. During STN deep brain stimulation implantation for Parkinson's disease, participants read aloud consonant-vowel-consonant syllables. Articulatory gain was indirectly assessed using the F2 Ratio, an acoustic measurement of the second formant frequency of/i/vowels divided by/u/vowels. Mixed effects models demonstrated that the F2 Ratio correlated with alpha and theta activity in the precentral gyrus and STN. No correlations were observed for the postcentral gyrus. Functional connectivity analysis revealed that higher phase locking values for beta activity between the STN and precentral gyrus were correlated with lower F2 Ratios, suggesting that higher beta synchrony impairs articulatory precision. Effects were not related to disease severity. These data suggest that articulatory gain is encoded within the basal ganglia-cortical loop.

Simultaneously recorded subthalamic and cortical LFPs reveal different lexicality effects during reading aloud.

Many language functions are traditionally assigned to cortical brain areas, leaving the contributions of subcortical structures to language processing largely unspecified. The present study examines a potential role of the subthalamic nucleus (STN) in lexical processing, specifically, reading aloud of words (e.g., 'fate') and pseudowords (e.g., 'fape'). We recorded local field potentials simultaneously from the STN and the cortex (precentral, postcentral, and superior temporal gyri) of 13 people with Parkinson's disease undergoing awake deep brain stimulation and compared STN's lexicality-related neural activity with that of the cortex. Both STN and cortical activity demonstrated significant task-related modulations, but the lexicality effects were different in the two brain structures. In the STN, an increase in gamma band activity (31-70 Hz) was present in pseudoword trials compared to word trials during subjects' spoken response. In the cortex, a greater decrease in beta band activity (12-30 Hz) was observed for pseudowords in the precentral gyrus. Additionally, 11 individual cortical sites showed lexicality effects with varying temporal and topographic characteristics in the alpha and beta frequency bands. These findings suggest that the STN and the sampled cortical regions are involved differently in the processing of lexical distinctions.

The AlzMatch Pilot Study - Feasibility of Remote Blood Collection of Plasma Biomarkers for Preclinical Alzheimer's Disease Trials.

BACKGROUND: Advances in plasma biomarkers to detect Alzheimer's disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer's Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD. OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individual's eligibility for AD preclinical trials. DESIGN: Pilot feasibility study with co-primary outcomes. SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility. PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months. MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aß42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study. RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials. CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.

Physiological identification of the human pedunculopontine nucleus.

BACKGROUND: The pedunculopontine nucleus (PPN) is a brainstem structure with widespread connections to the basal ganglia. Despite the recent introduction of PPN deep brain stimulation (DBS) for the treatment of gait disorders, little is known about its physiology in humans. METHODS: Single unit discharge characteristics of neurons in the PPN region were analysed in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson disease, and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas. RESULTS: Fifty-six units in the PPN region were studied, of which 32 mapped to within PPN boundaries. The mean (SD) discharge rate of neurons in the PPN was 23.2 (15.6) Hz. Spontaneous neuronal firing rate and burst discharge rate were significantly different between neurons in the region dorsal to PPN and those in the PPN. Responses to passive movement of contralateral and ipsilateral limbs were found. Theta and beta band oscillations were present in the PPN LFP. CONCLUSION: PPN discharge characteristics may prove useful in the electrophysiological identification of PPN during DBS implantation surgery.

Role of the posterior parietal cortex in updating reaching movements to a visual target.

The exact role of posterior parietal cortex (PPC) in visually directed reaching is unknown. We propose that, by building an internal representation of instantaneous hand location, PPC computes a dynamic motor error used by motor centers to correct the ongoing trajectory. With unseen right hands, five subjects pointed to visual targets that either remained stationary or moved during saccadic eye movements. Transcranial magnetic stimulation (TMS) was applied over the left PPC during target presentation. Stimulation disrupted path corrections that normally occur in response to target jumps, but had no effect on those directed at stationary targets. Furthermore, left-hand movement corrections were not blocked, ruling out visual or oculomotor effects of stimulation.

On-line motor control in patients with Parkinson's disease.

Recent models based, in part on a study of Huntington's disease, suggest that the basal ganglia are involved in on-line movement guidance. Two experiments were conducted to investigate this idea. First, we studied advanced Parkinson's disease patients performing a reaching task known to depend on on-line guidance. The task was to 'look and point' in the dark at visual targets displayed in the peripheral visual field. In some trials, the target location was slightly modified during saccadic gaze displacement (when vision is suppressed). In both patient and control groups, the target jump induced a gradual modification of the movement which diverged smoothly from its original path to reach the new target location. No deficit was found in the patients, except for an increased latency to respond to the target jump (Parkinson's disease: 243 ms; controls: 166 ms). A computational simulation indicated that this response slowing was likely to be a by-product of bradykinesia. The unexpected inconsistency between this result and previous reports was investigated in a second experiment. We hypothesized that the relevant factor was the characteristics of the corrections to be performed. To test this prediction, we investigated a task requiring corrections of the same type as investigated in Huntington's disease, namely large, consciously detected errors induced by large target jumps at hand movement onset. In contrast with the smooth adjustments observed in the first experiment, the subjects responded to the target jump by generating a discrete corrective sub-movement. While this iterative response was relatively rapid in the control subjects (220 ms), Parkinson's disease patients exhibited either dramatically late (>730 ms) or totally absent on-line corrections. When on-line corrections were absent, the initial motor response was completed before a second corrective response was initiated (the latency of the corrective response was the same as the latency of the initial response). Considered together, these results suggest that basal ganglia dependent circuits are not critical for feedback loops involving a smooth modulation of the ongoing command. These circuits may rather contribute to the generation of discrete corrective sub-movements. This deficit is in line with the general impairment of sequential and simultaneous actions in patients with basal ganglia disorders.

Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.

Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aß plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aß was detected at 4months in TgAPP and pre-plaque intracellular Aß accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1ß) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.

Cobra polypeptide cytotoxin I and marine worm polypeptide cytotoxin A-IV are potent and selective inhibitors of phospholipid-sensitive Ca2+-dependent protein kinase.

The effects of a number of polypeptide cytotoxins and neurotoxins on various protein kinases were examined. It was found that cobra cytotoxin I and marine worm cytotoxin A-IV effectively and specifically inhibited phospholipid-sensitive Ca2+-dependent protein kinase (PL-Ca-PK) relative to myosin light chain kinase and cyclic nucleotide-dependent protein kinases. Inhibition of PL-Ca-PK by these cytotoxins could be overcome by phosphatidylserine. Neurotoxins, in comparison, were much less effective inhibitors. The present findings indicated that these polypeptide cytotoxins, unlike other agents reported to date, were selective inhibitors of PL-Ca-PK and could be used to differentiate Ca2+-dependent events regulated by phospholipid or calmodulin.

Vaccinia virus serves as an efficient vector for expressing heterologous proteins in human NTera 2 neurons.

The human teratocarcinoma cell line NTera 2 (NT2) can be induced to differentiate into post-mitotic neurons possessing well-defined axonal and dendritic morphology. Highly enriched neurons (NT2-N cells) can be prepared in large numbers, thus combining many of the advantages of both primary and continuous cell culture systems. Unfortunately, it has proven difficult to express foreign genes in NT2-N cells. We examined whether vaccinia virus (VV) can express heterologous proteins in NT2-N cells and characterized the response of NT2-N cells to VV infection. NT2-N cells were infected with VV vectors expressing the envelope glycoprotein (gp160) from the human immunodeficiency type 1 virus (HIV 1). These vectors were chosen because VV-directed synthesis and post-translational processing of gp160 have been well characterized in many cell types. Approximately 85% of the neurons expressed gp160 which underwent native post-translational cleavage. The rate of gp160 synthesis was maximal at 5-48 hours postinfection, but was detectable for as long as 4 days. Surprisingly, NT2-N cells showed no VV-induced alterations in morphology, downregulation of host protein synthesis, or cytotoxicity, as measured by lactate dehydrogenase release. These results indicate that VV can serve as an efficient vector for introducing foreign genes in NT2-N cells without the cytotoxic effects often associated with VV infection. These properties, in conjunction with the advantages provided by NT2-N cells, provide new options for analyzing the cellular and molecular functions of human neurons.

Spontaneous intracranial hypotension causing reversible frontotemporal dementia.

Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache.

Probable diffuse Lewy body disease presenting as REM sleep behavior disorder.

Rapid eye movement sleep behavior disorder may herald several neurodegenerative disorders associated with parkinsonism, including Parkinson's disease. A 72-year-old man with a 17-year history of rapid eye movement sleep behavior disorder confirmed by polysomnography developed a progressive dementia that met operational clinical criteria for diffuse Lewy body disease. The differential diagnosis of progressive neurodegenerative disorders heralding as rapid eye movement sleep behavior disorder should now include diffuse Lewy body disease.

The pathology of REM sleep behavior disorder with comorbid Lewy body dementia.

A patient with REM sleep behavior disorder who subsequently developed probable Lewy body dementia is now reported to have a definite pathologic diagnosis of Lewy body dementia. Examination of brain revealed Lewy bodies as well as marked neuronal loss in brainstem monoaminergic nuclei-particularly locus coeruleus and substantia nigra-that inhibit cholinergic neurons in the pedunculopontine nucleus mediating atonia during REM sleep.

X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence.

The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. However, endocytic-competent APPswe Y743A had unique trafficking and metabolism including a prolonged half-life and increased secretion of catabolites compared with APPswe. In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.

Phospholipid-sensitive Ca2+-dependent protein kinase inhibition by R-24571, a calmodulin antagonist.

R-24571 (calmidazolium), a derivative of the antimycotic agent miconazole, inhibited phospholipid-sensitive Ca2+-dependent protein kinase (PL-Ca-PK), with an IC50 (the concentration causing 50% inhibition) of 5.3 microM. It also inhibited the calmodulin/Ca2+-stimulated enzymes, with IC50 values of 1.6 and 0.1 microM for myosin light chain kinase (MLCK) and phosphodiesterase respectively. Analysis of inhibition by R-24571 of PL-Ca-PK and MLCK revealed complex kinetics, suggesting that the agent interacted with the cofactors, the enzyme, and/or the cofactor-enzyme complexes. At saturating concentrations of the cofactors, R-24571 inhibited PL-Ca-PK and MLCK noncompetitively with their respective cofactors. Inhibition of MLCK by R-24571 was completely overcome by phosphatidylserine, indicating a strong hydrophobic interaction between R-24571 and the phospholipid in the presence of calmodulin. R-24571 also inhibited phosphorylation of various endogenous proteins in brain stimulated specifically by phosphatidylserine/Ca2+ or calmodulin/Ca2+. The present findings inducated that R-24571 has little specificity in inhibiting two types of Ca2+-dependent protein kinases sensitive to phospholipid or calmodulin.

Methionine-enkephalin and morphine: amount ejected microiontophoretically.

The microiontophoretic transport numbers of Met-enkephalin and morphine were determined by ejecting the tritiated compounds from both 5-barrel and 7-barrel micro-pipettes into a small volume of 0.9% NaCl, using a series of ejection currents and various timed durations. The transport number of Met-enkephalin was 2-4 times less than that for morphine in 5- and 7-barrel pipettes. The transport numbers of both drugs in 5-barrel pipettes were significantly greater than those in 7-barrel pipettes. These results indicate the need for caution in comparing the data derived from different studies that use microiontophoresis. The transport numbers for morphine and Met-enkephalin were used to compare the effects of these agents on neuronal firing.

Phospholipid/calcium-dependent protein kinase (protein kinase C) system: a major site of bioregulation.

The substrate specificity determinants of protein kinase C are probed using synthetic peptides encompassing the major phosphorylation site serine 115 in bovine MBP. The results indicate that basic residues arginine 107 and 113 N-terminal to the phosphorylation site are essential for the substrate activity of the peptides. Substitutions of these basic residues by alanine cause a marked decrease in their substrate activity and the resulting peptide analogs become specific and rather potent inhibitors of protein kinase C. Leukemic cells are particularly abundant in protein kinase C and its substrate proteins, and the enzyme system has been shown to play a key role in cell growth. The agents that stimulate protein kinase C include tumor promoting phorbol esters (such as TPA) and mezerein, and the putative second messenger diacylglycerol. Many antineoplastic agents, on the other hand, inhibit the enzyme which include adriamycin, tamoxifen, alkyl-lysophospholipid, selenium, retinal and lipoidal amine CP-46, 665-1. Immunocytochemical studies of protein kinase C in leukemic cells indicate that it is localized in the plasma membrane, cytoplasm, nucleus and Golgi apparatus, and the subcellular distribution of the enzyme might be related to the phases of the cell cycle. TPA induces translocation of the enzyme to plasma membrane, suggesting an additional mode of action for the tumor promotor.

Stability of phase recognition in complex spatial waveforms.

Observers viewed 200 msec presentations of gratings containing first (0.5 c/deg) and third (1.5 c/deg) harmonic components. The phase of the third harmonic and the absolute position of the grating on the screen varied randomly from trial to trial. Classification of the phase relation (0, 90, 180 or 270 deg was 99% perfect. When a 2 sec period of inspection of the grating or its fundamental preceded the test presentation, strong shifts in perceived waveform were observed that depended on the test grating's position relative to the inspection grating, and resembled the effects seen during continuous viewing. No phase-specific effects were obtained. The pattern of results was exactly that predicted by negative afterimage. Phase recognition at low contrast, and at a high frequency, was also good. Triangular-wave gratings were misperceived (the "square-wave illusion") only when real or simulated afterimages were present. We conclude that recognition of phase relations in a complex waveform is stable when the predictable variation due to afterimages is eliminated.

Afterimages of sinusoidal, square-wave and compound gratings.

Negative afterimages were observed after steady fixation of sinusoidal gratings at low spatial frequencies, and quantified using contrast-matching and cancellation methods. Afterimage contrast increased as a power function of "exposure", defined as the product of inspection contrast and inspection duration. A single function, linear on a log-log plot, describes the afterimages of gratings at different spatial frequencies, contrasts and durations. The matching method yielded a lower slope (about 0.42) than the cancellation method (0.62), probably because contrast adaptation attenuates perceived afterimage contrast in the first method, but not the second. Square-wave gratings, and those containing two or three harmonic components gave much weaker afterimages (assessed by contrast-matching) than sine-waves did. Contrast adaptation may again be responsible. Hemi-field asymmetries in contrast perception were noted. The contrast of real gratings and afterimages was nearly additive, especially at lower exposures, but the results cannot distinguish between linear filter and gain control models of "local adaptation".