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Objectives: This limited review examines the role of the reticular activating system (RAS), especially the pedunculopontine nucleus (PPN), one site of origin of bottom‐up gamma, in the symptoms of bipolar disorder (BD). Methods: The expression of neuronal calcium sensor protein 1 (NCS‐1) in the brains of BD patients is increased. It has recently been found that all PPN neurons manifest intrinsic membrane beta/gamma frequency oscillations mediated by high threshold calcium channels, suggesting that it is one source of bottom‐up gamma. This review specifically addresses the involvement of these channels in the manifestation of BD. Results: Excess NCS‐1 was found to dampen gamma band oscillations in PPN neurons. Lithium, a first line treatment for BD, was found to decrease the effects of NCS‐1 on gamma band oscillations in PPN neurons. Moreover, gamma band oscillations appear to epigenetically modulate gene transcription in PPN neurons, providing a new direction for research in BD. Conclusions: This is an area needing much additional research, especially since the dysregulation of calcium channels may help explain many of the disorders of arousal in, elicit unwanted neuroepigenetic modulation in, and point to novel therapeutic avenues for, BD. [ABSTRACT FROM AUTHOR]

This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca2+ channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle. [ABSTRACT FROM AUTHOR]

One element of the reticular activating system (RAS) is the pedunculopontine nucleus (PPN), which projects to the thalamus to trigger thalamocortical rhythms and the brainstem to modulate muscle tone and locomotion. The PPN is a posterior midbrain site known to induce locomotion in decerebrate animals when activated at 40-60 Hz, and has become a target for DBS in disorders involving gait deficits. We developed a research program using brainstem slices containing the PPN to study the cellular and molecular organization of this region. We showed that PPN neurons preferentially fire at gamma band frequency (30-60 Hz) when maximally activated, accounting for the effects of electrical stimulation. In addition, we developed the P13 midlatency auditory evoked potential, which is generated by PPN outputs, in freely moving rats. This allows the study of PPN cellular and molecular mechanisms in the whole animal. We also study the P50 midlatency auditory evoked potential, which is the human equivalent of the rodent P13 potential, allowing us to study PPN-related processes detected in vitro, confirmed in the whole animal, and tested in humans. Previous findings on the P50 potential in PD suggest that PPN output in this disorder is overactive. This translational research program led to the discovery of a novel mechanism of sleep-wake control based on electrical coupling, pointing the way to a number of new clinical applications in the development of novel stimulants (e.g., modafinil) and anesthetics. In addition, it provides methods for monitoring therapeutic efficacy of DBS in humans and animal models. [ABSTRACT FROM AUTHOR]

The article examines the application of genetics for predicting dangerous behavior. The U.S. courts' applications of future dangerous forecasts from genetics in sentencing and post-sentence commitment proceedings for sex offenders and murderers are discussed. It is argued that the courts' insistence on using future dangerousness predictions is unjustified both legally and scientifically.

Our discovery of low-threshold stimulation-induced locomotion in the pedunculopontine nucleus (PPN) led to the clinical use of deep brain stimulation (DBS) for the treatment of disorders such as Parkinson's disease (PD) that manifest gait and postural disorders. Three additional major discoveries on the properties of PPN neurons have opened new areas of research for the treatment of motor and arousal disorders. The description of (a) electrical coupling, (b) intrinsic gamma oscillations, and (c) gene regulation in the PPN has identified a number of novel therapeutic targets and methods for the treatment of a number of neurological and psychiatric disorders. We first delve into the circuit, cellular, intracellular, and molecular organization of the PPN, and then consider the clinical results to date on PPN DBS. This comprehensive review will provide valuable information to explain the network effects of PPN DBS, point to new directions for treatment, and highlight a number of issues related to PPN DBS. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN) is part of the reticular activating system (RAS) in charge of arousal and rapid eye movement sleep. The presence of high-frequency membrane oscillations in the gamma-band range in the PPN has been extensively demonstrated both in vivo and in vitro. Our group previously described histone deacetylation (HDAC) inhibition in vitro induced protein changes in F-actin cytoskeleton and intracellular Ca2+ concentration regulation proteins in the PPN. Here, we present evidence that supports the presence of a fine balance between HDAC function and calcium calmodulin kinase II-F-actin interactions in the PPN. We modified F-actin polymerization in vitro by using jasplakinolide (1 μM, a promoter of F-actin stabilization), or latrunculin-B (1 μM, an inhibitor of actin polymerization). Our results showed that shifting the balance in either direction significantly reduced PPN gamma oscillation as well as voltage-dependent calcium currents. [ABSTRACT FROM AUTHOR]

Leptin is an adipose-derived hormone that controls appetite and energy expenditure. Leptin receptors are expressed on extra-hypothalamic ventrobasal (VB) and reticular thalamic (RTN) nuclei from embryonic stages. Here, we studied the effects of pressure-puff, local application of leptin on both synaptic transmission and action potential properties of thalamic neurons in thalamocortical slices. We used whole-cell patch-clamp recordings of thalamocortical VB neurons from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We observed differences in VB neurons action potentials and synaptic currents kinetics when comparing WT vs. ob/ob. Leptin reduced GABA release onto VB neurons throughout the activation of a JAK2-dependent pathway, without affecting excitatory glutamate transmission. We observed a rapid and reversible reduction by leptin of the number of action potentials of VB neurons via the activation of large conductance Ca2+-dependent potassium channels. These leptin effects were observed in thalamocortical slices from up to 5-week-old WT but not in leptin-deficient obese mice. Results described here suggest the existence of a leptin-mediated trophic modulation of thalamocortical excitability during postnatal development. These findings could contribute to a better understanding of leptin within the thalamocortical system and sleep deficits in obesity. [ABSTRACT FROM AUTHOR]

The reticular activating system (RAS) is not an amorphous region but distinct nuclei with specific membrane properties that dictate their firing during waking and sleep. The locus coeruleus and raphe nucleus fire during waking and slow wave sleep, with the pedunculopontine nucleus (PPN) firing during both waking and REM sleep, the states manifesting arousal-related EEG activity. Two important discoveries in the PPN in the last 10 years are, 1) that some PPN cells are electrically coupled, and 2) every PPN cell manifests high threshold calcium channels that allow them to oscillate at beta/gamma band frequencies. The role of arousal in drug abuse is considered here in terms of the effects of drugs of abuse on these two mechanisms. Drug abuse and the perception of withdrawal/relapse are mediated by neurobiological processes that occur only when we are awake, not when we are asleep. These relationships focus on the potential role of arousal, more specifically of RAS electrical coupling and gamma band activity, in the addictive process as well as the relapse to drug use. [ABSTRACT FROM AUTHOR]

The relationship between arousal, perception, and visual neglect was examined in this case study. Cold pressor stimulation (CPS: immersing the foot in iced water) was used to manipulate arousal and to determine its effects on contralesional neglect, perception of stimulus intensity (magnitude estimation), reaction time, and an electrophysiological correlate of ascending reticular activating system activity (i.e., the P50 potential). Measures that normalized from baseline following CPS included contralesional neglect on a clock drawing test, perception of stimulus magnitude, and P50 amplitude. The P50 amplitude returned to its abnormally low baseline level 20 min after CPS ended, indicating that CPS increased arousal. [ABSTRACT FROM PUBLISHER]

Abstract: Gap junctions formed by expressing connexin subunits in Xenopus oocytes provide a valuable tool for revealing the gating properties of intercellular gap junctions in electrically coupled cells. We describe a new method that consists of simultaneous triple recordings from 3 apposed oocytes expressing exogenous connexins. The advantages of this method are that in one single experiment, 1 oocyte serves as control while a pair of oocytes, which have been manipulated differently, may be tested for different gap junctional properties. Moreover, we can study simultaneously the gap junctional coupling of 3 different pairs of oocytes in the same preparation. If the experiment consists of testing the effect of a single drug, this approach will reduce the time required, as background coupling in control pairs of oocytes does not need to be measured separately as with the conventional 2 oocyte pairing. The triplet approach also increases confidence that any changes seen in junctional communication are due to the experimental treatment and not variation in the preparation of oocytes or execution of the experiment. In this study, we show the example of testing the gap junctional properties among 3 oocytes, 2 of which are expressing rat connexin36. [Copyright &y& Elsevier]

Abstract: There is a growing interest both in identifying the neural mechanisms of magnitude estimation and in identifying forms of bias that can explain aspects of behavioral syndromes like unilateral neglect. Magnitude estimation is associated with activation of temporo-parietal cortex in both cerebral hemispheres of normal subjects; however, it is unclear if and how left hemisphere lesions bias magnitude estimation because the infrequency of neglect and the presence of aphasia in these subjects confound examination. In contrast, we examined magnitude estimation using 12 different types of sensory stimuli that spanned five sensory domains in two patients with very different clinical presentations following unilateral left hemisphere stroke. One patient had neglect sub-acutely without aphasia. The other had aphasia chronically after a temporo-parietal lesion but not neglect. The neglect patient was re-examined 48h after being treated with modafinil (Provigil) for decreased arousal. Both patients demonstrated bias in magnitude estimation relative to normal subjects (n =83). Alertness improved in the neglect patient after taking modafinil. His neglect also resolved and his magnitude estimates more closely resembled those of normal subjects. This is the first evidence, to our knowledge, that left hemisphere injury can bias magnitude estimation in a manner similar but not identical to that associated with right hemisphere injury. [Copyright &y& Elsevier]

GABAergic interneurons in the hippocampus are critically involved in almost all hippocampal circuit functions including coordinated network activity. Somatostatin-expressing oriens-lacunosum moleculare (O-LM) interneurons are a major subtype of dendritically projecting interneurons in hippocampal subregions (e.g., CA1), and express group I metabotropic glutamate receptors (mGluRs), specifically mGluR 1 and mGluR 5 . Group I mGluRs are thought to regulate hippocampal circuit functions partially through GABAergic interneurons. Previous studies suggest that a group I/II mGluR agonist produces slow supra-threshold membrane oscillations (<0.1 Hz), which are associated with high-frequency action potential (AP) discharges in O-LM interneurons. However, the properties and underlying mechanisms of these slow oscillations remain largely unknown. We performed whole-cell patch-clamp recordings from mouse interneurons in the stratum oriens/alveus (O/A interneurons) including CA1 O-LM interneurons. Our study revealed that the selective mGluR 1/5 agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced slow membrane oscillations (<0.1 Hz), which were associated with gamma frequency APs followed by AP-free perithreshold gamma oscillations. The selective mGluR 1 antagonist (S)-(+)-α-Amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) reduced the slow oscillations, and the selective mGluR 5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) partially blocked them. Blockade of nonselective cation-conducting transient receptor potential channels, L-type Ca 2+ channels, or ryanodine receptors all abolished the slow oscillations, suggesting the involvement of multiple mechanisms. Our findings suggest that group I mGluR activation in O/A interneurons may play an important role in coordinated network activity, and O/A interneuron vulnerability to excitotoxicity, in disease states like seizures, is at least in part due to an excessive rise in intracellular Ca 2+ . [ABSTRACT FROM AUTHOR]

Abstract Introduction Freezing of gait (FOG) is a debilitating, late motor complication of Parkinson's disease (PD) that occurs in 50–80% of patients. Gait freezing significantly worsens quality of life by decreasing mobility and increasing falls. Studies have shown that patients with episodic freezing episodes also have deficits in continuous gait. We evaluated whether there was an objective gait correlate to the increased stumbling reported by many patients with gait freezing. Methods PD subjects and healthy controls (HC) were enrolled after IRB approval. Subjects with more than 1 fall/day or a Montreal Cognitive Assessment score <10 were excluded. Subjects walked at their normal pace, 8 lengths of a 20 × 4 foot pressure-sensor mat. Data was collected and analyzed using PKMAS software (Protokinetics) and statistical analysis performed using SPSS 22 (IBM). Results 72 age matched subjects (22 PD FOG, 27 PD no-FOG, and 23 HC) were enrolled. Disease duration and Hoehn & Yahr scores were not significantly different between the PD groups. Mean dimensions of foot strike were not significantly different between groups, but PD FOG subjects had increased step-to-step variability in foot strike as measured by the percent coefficient of variation (%CV) in foot strike length compared to PD no-FOG and HC, independent of stride velocity. In PD no-FOG subjects, fallers also had higher variability in foot strike length compared to non-fallers. Conclusion PD subjects with FOG had increased variability in foot strike suggesting that in addition to stride length variability, foot strike variability could contribute to imbalance leading to falls. Highlights • Freezing of gait leads to decreased mobility and falls in Parkinson's disease. • Patients with gait freezing report stumbling even when medicated with levodopa. • We find increased variability in foot strike in patients with freezing of gait. • Increased foot strike variability also occurred in subjects reporting falls. • Foot strike variability could contribute to imbalance leading to falls. [ABSTRACT FROM AUTHOR]

The hippocampus plays a critical role in learning, memory, and spatial processing through coordinated network activity including theta and gamma oscillations. Recent evidence suggests that hippocampal subregions (e.g., CA1) can generate these oscillations at the network level, at least in part, through GABAergic interneurons. However, it is unclear whether specific GABAergic interneurons generate intrinsic theta and/or gamma oscillations at the single-cell level. Since major types of CA1 interneurons (i.e., parvalbumin-positive basket cells (PVBCs), cannabinoid type 1 receptor-positive basket cells (CB 1 BCs), Schaffer collateral-associated cells (SCAs), neurogliaform cells and ivy cells) are thought to play key roles in network theta and gamma oscillations in the hippocampus, we tested the hypothesis that these cells generate intrinsic perithreshold oscillations at the single-cell level. We performed whole-cell patch-clamp recordings from GABAergic interneurons in the CA1 region of the mouse hippocampus in the presence of synaptic blockers to identify intrinsic perithreshold membrane potential oscillations. The majority of PVBCs (83%), but not the other interneuron subtypes, produced intrinsic perithreshold gamma oscillations if the membrane potential remained above −45 mV. In contrast, CB 1 BCs, SCAs, neurogliaform cells, ivy cells, and the remaining PVBCs (17%) produced intrinsic theta, but not gamma, oscillations. These oscillations were prevented by blockers of persistent sodium current. These data demonstrate that the major types of hippocampal interneurons produce distinct frequency bands of intrinsic perithreshold membrane oscillations. [ABSTRACT FROM AUTHOR]

Human postmortem studies reported increased expression of neuronal calcium sensor protein 1 ( NCS-1) in the brains of some bipolar disorder patients, and reduced or aberrant gamma band activity is present in the same disorder. Bipolar disorder is characterized by sleep dysregulation, suggesting a role for the reticular activating system ( RAS). Lithium (Li+) has been shown to effectively treat the mood disturbances in bipolar disorder patients and was proposed to act by inhibiting the interaction between NCS-1 and inositol 1,4,5-triphosphate receptor protein (InsP3R). NCS-1 is known to enhance the activity of InsP3R, and of Ca2+-mediated gamma oscillatory activity in the pedunculopontine nucleus ( PPN), part of the RAS. This study aimed to determine the nature of some of the intracellular mechanisms of Li+ on rat PPN cells and to identify the interaction between Li+ and NCS-1. Since Li+ has been shown to act by inhibiting the enhancing effects of NCS-1, we tested the hypothesis that Li+ would reduced the effects of overexpression of NCS-1 and prevent the downregulation of gamma band activity. Li+ decreased gamma oscillation frequency and amplitude by downregulating Ca2+ channel activity, whereas NCS-1 reduced the effect of Li+ on Ca2+ currents. These effects were mediated by a G-protein overinhibition of Ca2+ currents. These results suggest that Li+ affected intracellular pathways involving the activation of voltage-gated Ca2+ channels mediated by an intracellular mechanism involving voltage-dependent activation of G proteins, thereby normalizing gamma band oscillations mediated by P/Q-type calcium channels modulated by NCS-1. [ABSTRACT FROM AUTHOR]

Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5- HT), dopamine, and noradrenaline, whereas caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5- HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus. We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (m IPSCs) in ventrobasal thalamic neurons during local ( puff) application of 5- HT in wild type ( WT) or knockout mice lacking 5- HT2A receptors (5- HT2A−/−). Inhibition of m IPSCs frequency by low (10 μM) and high (100 μM) 5- HT concentrations was observed in ventrobasal neurons from 5- HT2A−/− mice. In WT mice, only 100 μM 5- HT significantly reduced m IPSCs frequency. In 5- HT2A−/− mice, NAN-190, a specific 5- HT1A antagonist, prevented the 100 μM 5- HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 μM 5- HT were enhanced in cocaine binge-treated 5- HT2A−/− mice. Caffeine binge treatment did not affect 5- HT-mediated inhibition. Our findings suggest that both 5- HT1A and 5- HT2A receptors are present in pre-synaptic thalamic reticular nucleus terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. [ABSTRACT FROM AUTHOR]

Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus ( PPN) is part of the Reticular Activating System, and active during waking and REM sleep. Previous results showed that all PPN cells plateau at gamma frequencies and intrinsic membrane oscillations in PPN neurons are mediated by high-threshold N- and P/Q-type Ca2+ channels. The present study was designed to determine whether some PPN cells have only N-, only P/Q-, or both N- and P/Q-type Ca2+ channels. We used patch-clamp recordings in PPN cells in slices from anesthetized rat pups in the presence of synaptic receptor blockers ( SB) and Tetrodotoxin ( TTX), and applied ramps to induce intrinsic membrane oscillations. We found that all PPN cell types showed gamma oscillations in the presence of SB+ TTX when using current ramps. In 50% of cells, the N-type Ca2+ channel blocker ω-Conotoxin- GVIA ( ω-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker ω-Agatoxin- IVA ( ω-Aga) blocked the remaining oscillations. Another 20% manifested gamma oscillations that were not significantly affected by the addition of ω-CgTx, however, ω-Aga blocked the remaining oscillations. In 30% of cells, ω-Aga had no effect on gamma oscillations, while ω-CgTx blocked them. These novel results confirm the segregation of populations of PPN cells as a function of the calcium channels expressed, that is, the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N-type and P/Q-type Ca2+ channels. [ABSTRACT FROM AUTHOR]

Reduced levels of gamma-band activity are present in schizophrenia and bipolar disorder patients. In the same disorders, increased neuronal calcium sensor protein-1 (NCS-1) expression was reported in a series of postmortem studies. These disorders are also characterized by sleep dysregulation, suggesting a role for the reticular activating system (RAS). The discovery of gamma-band activity in the pedunculopontine nucleus (PPN), the cholinergic arm of the RAS, revealed that such activity was mediated by high-threshold calcium channels that are regulated by NCS-1. We hypothesized that NCS-1 normally regulates gamma-band oscillations through these calcium channels and that excessive levels of NCS-1, such as would be expected with overexpression, decrease gamma- band activity. We found that PPN neurons in rat brain slices mani- fested gamma-band oscillations that were increased by low levels of NCS-1 but suppressed by high levels of NCS-1. Our results suggest that NCS-1 overexpression may be responsible for the decrease in gamma-band activity present in at least some schizophrenia and bipolar disorder patients. [ABSTRACT FROM AUTHOR]

Background In recent years, 3D printing technology has become inexpensive and simple enough that any lab can own and use one of these printers. New method We explored the potential use of 3D printers for quickly and easily producing in vitro slice chambers for patch clamp electrophysiology. Slice chambers were produced using five available plastics: ABS, PLA, Nylon 618, Nylon 680, and T-glase. These “lab-made” chambers were also made using stereolithography through a professional printing service (Shapeways). This study measured intrinsic membrane properties of neurons in the brain stem pedunculopontine nucleus (PPN) and layer V pyramidal neurons in retrosplenial cortex. Results Nylon 680 and T-glase significantly hyperpolarized PPN neurons. ABS increased input resistance, decreased action potential amplitude, and increased firing frequency in pyramidal cortical neurons. To test long term exposure to each plastic, human neuroblastoma SHSY5Y cell cultures were exposed to each plastic for 1 week. ABS decreased cell counts while Nylon 618 and Shapeways plastics eliminated cells. Primary mouse pituitary cultures were also tested for 24-h exposure. ABS decreased cell counts while Nylon 618 and Shapeways plastics dramatically decreased cell counts. Comparison to existing methods Chambers can be quickly and inexpensively printed in the lab. ABS, PLA, Nylon 680, and T-glase plastics would suffice for many experiments instead of commercially produced slice chambers. Conclusions While these technologies are still in their infancy, they represent a powerful addition to the lab environment. With careful selection of print material, slice chambers can be quickly and inexpensively manufactured in the lab. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system, regulates waking and rapid eye movement sleep. Here, we demonstrate immunohistochemical labeling of the leptin receptor signaling isoform in PPN neurons, and investigated the effects of G-protein modulation and the leptin triple antagonist (TA) on the action of leptin in the PPN. Whole-cell patch clamp recordings were performed in rat brainstem slices from 9 to 17 day old pups. Previous results showed that leptin caused a partial blockade of sodium (INa) and h-current (IH) in PPN neurons. TA (100 nM) reduced the blockade of INa (~ 50% reduction) and IH (~ 93% reduction) caused by leptin. Intracellular guanosine 5′-[β-thio]diphosphate trilithium salt (a G-protein inhibitor) significantly reduced the effect of leptin on INa(~ 60% reduction) but not on IH (~ 25% reduction). Intracellular GTPγS (a G-protein activator) reduced the effect of leptin on both INa (~ 80% reduction) and IH (~ 90% reduction). These results suggest that the effects of leptin on the intrinsic properties of PPN neurons are leptin receptor- and G-protein dependent. We also found that leptin enhanced NMDA receptor-mediated responses in single neurons and in the PPN population as a whole, an effect blocked by TA. These experiments further strengthen the association between leptin dysregulation and sleep disturbances. [ABSTRACT FROM AUTHOR]

The parafascicular nucleus (Pf) is an ascending target of the pedunculopontine nucleus (PPN) and is part of the 'non-specific' intralaminar thalamus. The PPN, part of the reticular activating system, is mainly involved in waking and rapid eye movement sleep. Gamma oscillations are evident in all Pf neurons and mediated by high threshold voltage-dependent N- and P/Q-type calcium channels. We tested the hypothesis that high-speed calcium imaging would reveal calcium-mediated oscillations in synchrony with patch clamp recorded oscillations during depolarizing current ramps. Patch-clamped 9 to 19-day-old rat Pf neurons ( n = 148, dye filled n = 61, control n = 87) were filled with Fura 2, Bis Fura, or Oregon Green BAPTA-1. Calcium transients were generated during depolarizing current ramps and visualized with a high-speed, wide-field fluorescence imaging system. Cells manifested calcium transients with oscillations in both somatic and proximal dendrite fluorescence recordings. Fluorescent calcium transients were blocked with the nonspecific calcium channel blocker, cadmium, or the combination of ω-Agatoxin-IVA (AgA), a specific P/Q-type calcium channel blocker and ω-conotoxin-GVIA (CgTx), a specific N-type calcium channel blocker. We developed a viable methodology for studying high-speed oscillations without the use of multi-photon imaging systems. [ABSTRACT FROM AUTHOR]

Leptin, a hormone that regulates appetite and energy expenditure, is increased in obese individuals, although these individuals often exhibit leptin resistance. Obesity is characterized by sleep/wake disturbances, such as excessive daytime sleepiness, increased REM sleep, increased nighttime arousals, and decreased percentage of total sleep time. Several studies have shown that short sleep duration is highly correlated with decreased leptin levels in both animal and human models. Arousal and rapid eye movement (REM) sleep are regulated by the cholinergic arm of the reticular activating system, the pedunculopontine nucleus (PPN). The goal of this project was to determine the role of leptin in the PPN, and thus in obesity-related sleep disorders. Whole-cell patch-clamp recordings were conducted on PPN neurons in 9- to 17-day-old rat brainstem slices. Leptin decreased action potential (AP) amplitude, AP frequency, and h-current ( I). These findings suggest that leptin causes a blockade of Na channels. Therefore, we conducted an experiment to test the effects of leptin on Na conductance. To determine the average voltage dependence of this conductance, results from each cell were equally weighted by expressing conductance as a fraction of the maximum conductance in each cell. I amplitude was decreased in a dose-dependent manner, suggesting a direct effect of leptin on these channels. The average decrease in Na conductance by leptin was ~40 %. We hypothesize that leptin normally decreases activity in the PPN by reducing I and I currents, and that in states of leptin dysregulation (i.e., leptin resistance) this effect may be blunted, therefore causing increased arousal and REM sleep drive, and ultimately leading to sleep-related disorders. [ABSTRACT FROM AUTHOR]

Methylphenidate ( MPH) is widely used to treat children and adolescents diagnosed with attention deficit/hyperactivity disorder. Although MPH shares mechanistic similarities to cocaine, its effects on GABAergic transmission in sensory thalamic nuclei are unknown. Our objective was to compare cocaine and MPH effects on GABAergic projections between thalamic reticular and ventrobasal ( VB) nuclei. Mice (P18-30) were subjected to binge-like cocaine and MPH acute and sub-chronic administrations. Cocaine and MPH enhanced hyperlocomotion, although sub-chronic cocaine-mediated effects were stronger than MPH effects. Cocaine and MPH sub-chronic administration altered paired-pulse and spontaneous GABAergic input differently. The effects of cocaine on evoked paired-pulse GABA-mediated currents changed from depression to facilitation with the duration of the protocols used, while MPH induced a constant increase throughout the administration protocols. Thalamic reticular nucleus GAD67 and VB CaV3.1 protein levels were measured using western blot to better understand their link to increased GABA release. Both proteins were increased by sub-chronic administration of cocaine. MPH showed effects on GABAergic transmission that seems less disruptive than cocaine. Unique effects of cocaine on postsynaptic VB calcium currents might explain deleterious cocaine effects on sensory thalamic nuclei. These results suggest that cocaine and MPH produced distinct presynaptic alterations on GABAergic transmission. [ABSTRACT FROM AUTHOR]

Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 x 5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2 x 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum. [ABSTRACT FROM AUTHOR]

Abstract: Spasticity is a common disorder following spinal cord injury that can impair function and quality of life. While a number of mechanisms are thought to play a role in spasticity, the role of motoneuron persistent inward currents (PICs) is emerging as pivotal. The presence of PICs can be evidenced by temporal summation or wind-up of reflex responses to brief afferent inputs. In this study, a combined neurophysiological and novel biomechanical approach was used to assess the effects of passive exercise and modafinil administration on hyper-reflexia and spasticity following complete T-10 transection in the rat. Animals were divided into 3 groups (n =8) and provided daily passive cycling exercise, oral modafinil, or no intervention. After 6weeks, animals were tested for wind-up of the stretch reflex (SR) during repeated dorsiflexion stretches of the ankle. H-reflexes were tested in a subset of animals. Both torque and gastrocnemius electromyography showed evidence of SR wind-up in the transection only group that was significantly different from both treatment groups (p <0.05). H-reflex frequency dependent depression was also restored to normal levels in both treatment groups. The results provide support for the use of passive cycling exercise and modafinil in the treatment of spasticity and provide insight into the possible contribution of PICs. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated whether l-dopa (DOPA), locomotor-like passive exercise (Ex) using a motorized bicycle exercise trainer (MBET), or their combination in adult rats with complete spinal cord transection (Tx) preserves and restores low frequency-dependent depression (FDD) of the H-reflex. Adult Sprague–Dawley rats (n =56) transected at T8-9 had one of five treatments beginning 7 days after transection: Tx (transection only), Tx+Ex, Tx+DOPA, Tx+Ex+DOPA, and control (Ctl, no treatment) groups. After 30 days of treatment, FDD of the H-reflex was tested. Stimulation of the tibial nerve at 0.2, 1, 5, and 10Hz evoked an H-reflex that was recorded from plantar muscles of the hind paw. No significant differences were found at the stimulation rate of 1Hz. However, at 5Hz, FDD of the H-reflex in the Tx+Ex, Tx+DOPA and Ctl groups was significantly different from the Tx group (p <0.01). At 10Hz, all of the treatment groups were significantly different from the Tx group (p <0.01). No significant difference was identified between the Ctl and any of the treatment groups. These results suggest that DOPA significantly preserved and restored FDD after transection as effectively as exercise alone or exercise in combination with DOPA. Thus, there was no additive benefit when DOPA was combined with exercise. [ABSTRACT FROM AUTHOR]

Abstract: Hyperreflexia develops after spinal cord injury (SCI) in the human and in the spinal cord transected animal, and can be measured by the loss of low frequency-dependent depression of the H-reflex. Previous studies demonstrated normalization of low frequency-dependent depression of the H-reflex using passive exercise when initiated prior to the development of hyperreflexia. We examined the effects of passive exercise prior to compared to after the development of hyperreflexia in the transected rat. Adult female rats underwent complete transection (Tx) at T10. Frequency-dependence of the H-reflex was tested following passive exercise for 30 days, initiated prior to hyperreflexia in one group compared to initiation after hyperreflexia became established, and compared to intact and untreated Tx groups. An additional Tx group completed 60 days of exercise initiated after hyperreflexia was established. Lumbar enlargement tissue was harvested for western blot to compare Connexin-36 protein levels in control vs Tx animals vs Tx animals that were passively exercised. No differences in whole tissue were evident, although regional differences may still be present in Connexin-36 levels. Statistically significant decreases in low frequency-dependent depression of the H-reflex were observed following 30 days of exercise initiated prior to the onset of hyperreflexia, and also after 60 days of exercise when initiated after hyperreflexia had been established, compared with Tx only animals. We concluded that modulation of spinal circuitry by passive exercise took place when initiated before and after the onset of hyperreflexia, but different durations of exercise were required. [Copyright &y& Elsevier]

Abstract: Objective: Quantitative measures of pre-attentional, attentional and frontal lobe processes were compared to evaluate quantitative measures of these deficits in Ex-Preterm vs. Ex-Term adolescents. Methods: We compared 43 Ex-Preterm with 26 Ex-Term adolescents using the P50 auditory potential, the Psychomotor Vigilance Task (PVT), a reaction time (RT) test, and Near Infrared Spectroscopy (NIRS). Results: The mean amplitude (±SE) of the P50 amplitude was similar in the Ex-Preterm (1.8±1.4μV) vs. Ex-Term adolescents (1.8±0.6μV, df=68, F =0.05, p =0.8), but the Ex-Preterm group showed a trimodal distribution in amplitude (High, 3.3±0.4μV, df=42.25, F =19.2, p <0.01; Medium, 1.7±0.1μV, df=39, F =0.41, p =0.53; Low, 0.7±0.1μV, df=40, F =49.5, p <0.01) suggested by statistically significant variance between populations (Kolmogorov–Kuiper test, df=42.25, F =5.4, p <0.01). Mean RT was longer in Ex-Preterm (250±8ms) vs. Ex-Term subjects (200±5ms, df=68, F =18.8, p <0.001). PVT lapses were increased in Ex-Preterm subjects, and varied inversely with P50 amplitude (Overall Mean 17±5 lapses, df=67, F =5.34, p <0.05; Low P50 amplitude, 25±10, df=40, F =8.8, p <0.01; Medium, 21±11, df=38, F =5.37, p <0.05; High, 6±2, df=39, F =6.78, p <0.01) vs. Ex-Term subjects (2±0.4 lapses, p <0.01). NIRS levels did not differ statistically, but tended to correlate with P50 amplitude in the Ex-Preterm group. Conclusions: These findings suggest differential pre-attentional, attentional and frontal lobe dysfunction in Ex-Preterm adolescents. Significance: These measures could provide a means to objectively assess differential dysregulation of arousal and attention in Ex-Preterm adolescents, allowing optimization of therapeutic designs. [Copyright &y& Elsevier]

Abstract: The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system (RAS), is known to modulate waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, with the majority occurring between 12 and 21 days. We investigated the possibility that changes in the cholinergic, muscarinic and/or nicotinic, input to PPN neurons could explain at least part of the developmental decrease in REM sleep. We recorded intracellularly from PPN neurons in 12–21 day rat brainstem slices maintained in artificial cerebrospinal fluid (aCSF) and found that application of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) depolarized PPN neurons early in development, then hyperpolarized PPN neurons by day 21. Most of the effects of DMPP persisted following application of the sodium channel blocker tetrodotoxin (TTX), and in the presence of glutamatergic, serotonergic, noradrenergic and GABAergic antagonists, but were blocked by the nicotinic antagonist mecamylamine (MEC). The mixed muscarinic agonist carbachol (CAR) hyperpolarized all type II (A current) PPN cells and depolarized all type I (low threshold spike-LTS current) and type III (A+LTS current) PPN cells, but did not change effects during the period known for the developmental decrease in REM sleep. The effects of CAR persisted in the presence of TTX but were mostly blocked by the muscarinic antagonist atropine (ATR), and the remainder by MEC. We conclude that, while the nicotinic inputs to the PPN may help modulate the developmental decrease in REM sleep, the muscarinic inputs appear to modulate different types of cells differentially. [Copyright &y& Elsevier]

Sopite syndrome, characterized by loss of initiative, sensitivity to normally innocuous sensory stimuli, and impaired concentration amounting to a sensory gating deficit, is commonly associated with Space Motion Sickness (SMS). The amplitude of the P50 potential is a measure of level of arousal, and a paired-stimulus paradigm can be used to measure sensory gating. We used the rotary chair to elicit the sensory mismatch that occurs with SMS by overstimulating the vestibular apparatus. The effects of rotation on the manifestation of the P50 midlatency auditory evoked response were then assessed as a measure of arousal and distractibility. Results showed that rotation-induced motion sickness produced no change in the level of arousal but did produce a significant deficit in sensory gating, indicating that some of the attentional and cognitive deficits observed with SMS may be due to distractibility induced by decreased habituation to repetitive stimuli. [ABSTRACT FROM AUTHOR]

The P50 (or P1) potential is a midlatency auditory evoked response, believed to be partially generated by the cholinergic pedunculopontine nucleus (PPN) neurons that give rise to the ascending reticular activating system (RAS). We compared the P50 potential in 11 Huntington''s disease (HD) patients and 13 normal controls using a paired click stimulus paradigm. HD patients exhibited a P50 potential with reduced amplitude and increased latency to the first stimulus of the pair (first P50 potential), suggesting impaired ascending reticular activating system function, which may contribute to sleep disorders seen in HD. Sensory gating, measured as the percent ratio of the second P50 potential amplitude to the first P50 potential amplitude, was reduced at 250 and 500 ms interstimulus intervals (ISI), which may be related to disordered attention and anxiety in HD. [Copyright &y& Elsevier]

Propofol (2,6-diisopropylphenol) is a widely used anesthetic agent, but its mechanisms of action are poorly understood. In this report, the effects of three dose levels of propofol (5, 7.5, and 10 mg/kg) on the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential were investigated. The P13 potential is generated, at least in part, by the ascending cholinergic reticular activating system (RAS). The RAS is known to be affected by anesthetic agents. Intravenous injections of propofol were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. At 2 min post-injection, the mean P13 amplitude was suppressed to 40% of its pre-injection level by the lowest dose, but was suppressed to 10% of pre-injection levels by the two higher doses of propofol. The duration of the suppression of mean P13 potential amplitude was also dose-dependent such that complete recovery occurred by 5 min using 5 mg/kg, by 15 min using 7.5 mg/kg and by 30 min using 10 mg/kg of propofol. Using a paired stimulus paradigm, transient effects on habituation of the P13 potential were observed but only after the highest dose. Thus, one of the mechanisms of propofol may be to affect portions of the RAS which modulate the level of arousal. It may only transiently affect higher systems known to modulate the degree of habituation of responses by the RAS (i.e. processes which modulate habituation and may participate in sensory gating and distractibility). [Copyright &y& Elsevier]

The P13 mid-latency auditory evoked potential in Rat is a sleep state-dependent response thought to be equivalent to the human P50 potential, a measure of the output of the reticular activating system. The amplitude of these potentials can be considered a measure of level of arousal, while, using a paired stimulus paradigm, the degree of habituation of the responses also can be assessed. Different durations of rotation were found to reduce the amplitude of the P13 potential, which recovered in a duration-dependent manner. Different durations of rotation led to decreases in habituation of the P13 potential again in a duration-dependent manner. These results suggest that rotation may affect the level of arousal as well as habituation to repetitive sensory inputs. Such effects could be interpreted to imply the presence, following rotation of sufficient duration, of a deficit in sensory gating, or distractibility, and are relevant for the study of the effects of space motion sickness. [ABSTRACT FROM AUTHOR]

The percent of rapid eye movement (REM) sleep decreases dramatically between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus (PPN) is known to modulate waking and REM sleep. We recorded intracellularly from 127 neurons in the PPN in 12–21-day rat brainstem slices maintained in warmed, oxygenated artificial cerebrospinal fluid. We identified three types of PPN neurons based on intrinsic membrane properties, type I (LTS), type II (A) and type III (A+LTS), as previously described. The percent of type I neurons increased from 6% at 12 days to 17% by 21 days, while the percent of type III neurons decreased from 21% at 12–17 days, to 4% after 17 days. Thus, PPN neurons may differentiate into type I bursting neurons and type II slow-firing neurons across this critical stage in development. The 5-HT1 receptor agonist 5-carboxyamido-tryptamine (5-CT) was found to hyperpolarize 58% of 12–16-day PPN neurons, did not affect 25% and depolarized 17%. However, a higher percentage of 17–21-day PPN neurons were hyperpolarized (85%), and a lower percentage unaffected (10%) or depolarized (5%), suggesting that serotonergic responses switched from both excitatory and inhibitory before, to almost purely inhibitory after, 17 days. These findings indicate a reorganization of PPN intrinsic membrane properties and serotonergic responses occur across this stage, in keeping with the proposed presence of a REM sleep inhibitory process during development. We suggest that disturbances in this developmental process may lead to disorders marked by increased REM sleep drive. [Copyright &y& Elsevier]

The pedunculopontine nucleus (PPN) has long been known to be part of the reticular activating system (RAS) in charge of arousal and REM sleep. We previously showed that in vitro exposure to a HDAC Class I and II mixed inhibitor (TSA), or a specific HDAC class IIa inhibitor (MC 1568), decreased PPN gamma oscillations. Given the lack of information on systemic in vivo treatments on neuronal synaptic properties, the present study was designed to investigate the systemic effect of HDAC inhibitors (HDACi) on PPN rhythmicity. Rat pups were injected (acute, single dose) with TSA (4 or 20 mg/kg), MC1568 (4 or 20 mg/kg), or MS275 (20 or 100 mg/kg). Our results show that MC1568 (20 mg/kg) reduced mean frequency of PPN oscillations at gamma band, while increasing mean input resistance (Rm) of PPN neurons. For TSA (4 and 20 mg/kg), we observed reduced mean frequency of oscillations at gamma band and increased mean Rm of PPN neurons. Systemic administration of 20 mg/kg MC1568 and TSA effects on Rm were washed out after 60 min of in vitro incubation of PPN slices, suggesting an underlying functional recovery of PPN calcium-mediated gamma band oscillations over time. In addition, at a lower dose, 4 mg/kg, MC1568 and TSA induced higher mean amplitude gamma oscillations. Blocking HDAC class I might not have deleterious effects on gamma activity, but, more importantly, the inhibition of HDAC class I (at 100 mg/kg) increased gamma band oscillations. In conclusion, the present results in vivo validate our previous findings in vitro and further expand information on the effects of HDAC inhibition on PPN rhythmicity. PPN neurons require normal activity of HDAC class IIa in order to oscillate at gamma band. Red arrows represent statistical significant inhibition. Blue arrows represent statistical significant enhancement. ~ Represents absence of change.Our findings suggest that gamma oscillations in the PPN are finely tuned in vivo by the activity of HDAC class IIa. Sustained blocking of HDAC IIa blunted gamma band oscillations of PPN neurons. Blocking HDAC class I showed higher gamma band amplitudes. In conclusion, systemic administration of HDAC inhibitors might have either negative or positive effects on PPN rhythmicity depending of dose and group of HDAC affected. Image 105643 • HDAC class IIa inhibitors (acutely, i.p.) blunted PPN oscillations at gamma band. • HDAC class I inhibitors (100 mg/kg; i.p.) increased PPN gamma band oscillations. • We suggest the existence of a physiological HDAC class I/IIa balance in the PPN. [ABSTRACT FROM AUTHOR]

Gamma network oscillations in the brain are fast rhythmic network oscillations in the gamma frequency range (~30-100 Hz), playing key roles in the hippocampus for learning, memory, and spatial processing. There is evidence indicating that GABAergic interneurons, including parvalbumin-expressing basket cells (PVBCs), contribute to cortical gamma oscillations through synaptic interactions with excitatory cells. However, the molecular, cellular, and circuit underpinnings underlying generation and maintenance of cortical gamma oscillations are largely elusive. Recent studies demonstrated that intrinsic and synaptic properties of GABAergic interneurons and excitatory cells are regulated by a slowly inactivating or non-inactivating sodium current (i.e. , persistent sodium current, I NaP), suggesting that I NaP is involved in gamma oscillations. Here, we tested whether I NaP plays a role in hippocampal gamma oscillations using pharmacological, optogenetic, and electrophysiological approaches. We found that I NaP blockers, phenytoin (40 μM and 100 μM) and riluzole (10 μM), reduced gamma oscillations induced by optogenetic stimulation of CaMKII-expressing cells in CA1 networks. Whole-cell patch-clamp recordings further demonstrated that phenytoin (100 μM) reduced I NaP and firing frequencies in both PVBCs and pyramidal cells without altering threshold and amplitude of action potentials, but increased rheobase in both cell types. These results suggest that I NaP in pyramidal cells and PVBCs is required for hippocampal gamma oscillations, supporting a pyramidal-interneuron network gamma model. Phenytoin-mediated modulation of hippocampal gamma oscillations may be a mechanism underlying its anticonvulsant efficacy, as well as its contribution to cognitive impairments in epilepsy patients. • Phenytoin and riluzole reduce hippocampal gamma oscillations in the CA1 subregion. • Phenytoin blocks I NaP in parvalbumin-expressing basket cells (PVBCs). • Phenytoin increases rheobase and reduces firing frequency of PVBCs. • Phenytoin blocks I NaP in pyramidal cells. • Phenytoin increases rheobase and reduces firing frequency of pyramidal cells. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms (i.e., histone post-translational modification and DNA methylation) play a role in regulation of gene expression. The pedunculopontine nucleus (PPN), part of the reticular activating system, manifests intrinsic gamma oscillations generated by voltage-dependent, high threshold N- and P/Q-type Ca2+ channels. We studied whether PPN intrinsic gamma oscillations are affected by inhibition of histone deacetylation. We showed that, a) acute in vitro exposure to the histone deacetylation Class I and II inhibitor trichostatin A (TSA, 1 μM) eliminated oscillations in the gamma range, but not lower frequencies, b) pre-incubation with TSA (1 μM, 90-120 min) also decreased gamma oscillations, c) Ca2+ currents (ICa) were reduced by TSA, especially on cells with P/Q-type channels, d) a HDAC Class I inhibitor MS275 (500 nM), and a Class IIb inhibitor Tubastatin A (150-500 nM), failed to affect gamma oscillations, e) MC1568, a HDAC Class IIa inhibitor (1 μM), blocked gamma oscillations, and f) the effects of both TSA and MC1568 were blunted by blockade of CaMKII with KN-93 (1 μM). These results suggest a cell type specific effect on gamma oscillations when histone deacetylation is blocked, suggesting that gamma oscillations through P/Q-type channels modulated by CaMKII may be linked to processes related to gene transcription. [ABSTRACT FROM AUTHOR]

Introduction: Freezing of gait (FOG) is a debilitating, late motor complication of Parkinson's disease (PD) that occurs in 50-80% of patients. Gait freezing significantly worsens quality of life by decreasing mobility and increasing falls. Studies have shown that patients with episodic freezing episodes also have deficits in continuous gait. We evaluated whether there was an objective gait correlate to the increased stumbling reported by many patients with gait freezing.Methods: PD subjects and healthy controls (HC) were enrolled after IRB approval. Subjects with more than 1 fall/day or a Montreal Cognitive Assessment score <10 were excluded. Subjects walked at their normal pace, 8 lengths of a 20 × 4 foot pressure-sensor mat. Data was collected and analyzed using PKMAS software (Protokinetics) and statistical analysis performed using SPSS 22 (IBM).Results: 72 age matched subjects (22 PD FOG, 27 PD no-FOG, and 23 HC) were enrolled. Disease duration and Hoehn & Yahr scores were not significantly different between the PD groups. Mean dimensions of foot strike were not significantly different between groups, but PD FOG subjects had increased step-to-step variability in foot strike as measured by the percent coefficient of variation (%CV) in foot strike length compared to PD no-FOG and HC, independent of stride velocity. In PD no-FOG subjects, fallers also had higher variability in foot strike length compared to non-fallers.Conclusion: PD subjects with FOG had increased variability in foot strike suggesting that in addition to stride length variability, foot strike variability could contribute to imbalance leading to falls. [ABSTRACT FROM AUTHOR]