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Four major discoveries on the function of the pedunculopontine nucleus (PPN) have significantly advanced our understanding of the role of arousal in neurodegenerative disorders. The first was the finding that stimulation of the PPN-induced controlled locomotion on a treadmill in decerebrate animals, the second was the revelation of electrical coupling in the PPN and other arousal and sleep-wake control regions, the third was the determination of intrinsic gamma band oscillations in PPN neurons, and the last was the discovery of gene transcription resulting from the manifestation of gamma activity in the PPN. These discoveries have led to novel therapies such as PPN deep brain stimulation (DBS) for Parkinson's disease (PD), identified the mechanism of action of the stimulant modafinil, determined the presence of separate mechanisms underlying gamma activity during waking versus REM sleep, and revealed the presence of gene transcription during the manifestation of gamma band oscillations. These discoveries set the stage for additional major advances in the treatment of a number of disorders., (© 2019 Wiley Periodicals, Inc.)

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., (Copyright © 2017. Published by Elsevier B.V.)

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.

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.

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+/-1.4 microV) vs. Ex-Term adolescents (1.8+/-0.6 microV, df = 68, F = 0.05, p = 0.8), but the Ex-Preterm group showed a trimodal distribution in amplitude (High, 3.3+/-0.4 microV, df=42.25, F=19.2, p < 0.01; Medium, 1.7+/-0.1 microV, df = 39, F = 0.41, p = 0.53; Low, 0.7+/-0.1 microV, 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+/-8 ms) vs. Ex-Term subjects (200+/-5 ms, 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.

Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. The pedunculopontine nucleus (PPN), as the cholinergic arm of the reticular activating system (RAS), is known to modulate arousal, waking and REM sleep. Rapid eye movement (REM) sleep decreases between 10 and 30 days postnatally in the rat, with the greatest decrease occurring at 12-21 days. Pregnant dams were exposed to 150 ml of cigarette smoke for 15 min, three times per day, from day E14 until parturition, and the pups allowed to mature. We analyzed (a) intrinsic membrane properties of PPN neurons in slices from pups aged 12-21 days, and (b) the sleep state-dependent P13 auditory evoked potential, which is generated by PPN outputs, in animals allowed to age to adolescence. We found significant changes in the intrinsic membrane properties of PPN cells in prenatally exposed animals compared to intact ones, rendering these cells more excitable. In addition, we found disturbances in the habituation to repetitive stimulation in adolescent, freely moving animals, suggestive of a deficit in the process of sensory gating. These findings could explain some of the differences seen in individuals whose parents smoked during pregnancy, especially in terms of their hypervigilance and increased propensity for attentional deficits and cognitive/behavioral disorders.

We investigated the effects of tinnitus on measures of arousal and attention at various levels of the neuraxis to derive a profile of the pathophysiology of tinnitus. Individuals with tinnitus of at least 6 months' duration (14 male, 15 female) and healthy controls (14 male, 21 female) were tested for arousal and habituation to repetitive stimulation at the brainstem-thalamus level by measuring the P50 potential, a scalp-recorded, auditory-evoked response, using pairs of click stimuli. We used the psychomotor vigilance task, a reaction-time test, to assess attentional processes mediated by thalamocortical functions. We then correlated deficits in arousal and attention, as measured by these tests, with perceived tinnitus severity. Results showed no difference between tinnitus patients and controls in level of arousal or habituation to repetitive sensory stimulation, as measured by the amplitude of the P50 potential and the ability to suppress a second, closely paired stimulus, respectively. However, reaction-time assessments showed that patients with tinnitus have attentional deficits relative to controls (p = .02). We found no significant correlation between sleep disturbance or tinnitus severity and reaction-time testing.

We identified a potential novel site of action for nicotine (NIC) since (a) systemic injection of NIC led to a dose-dependent decrease in the amplitude of the sleep state-dependent, vertex-recorded, P13 midlatency auditory evoked potential (generated by the reticular activating system, RAS), (b) localized injections of a nicotinic receptor antagonist into the pedunculopontine nucleus (PPN, the cholinergic arm of the RAS) blocked the effects of systemic NIC on the P13 potential (a measure of level of arousal), and (c) localized injection of a nicotinic receptor agonist into the PPN also led to a decrease in the amplitude of the P13 potential, an effect blocked by PPN injection of a nicotinic receptor antagonist. There were minor changes in the manifestation of the startle response (SR) at the concentrations used; however, NIC did decrease the hippocampal N40 potential, although its effects were not affected by antagonist or agonist injections into the PPN. These results suggest a potential mechanism underlying the anxiolytic effects of NIC-suppression of the cholinergic arm of the RAS.

An intrinsic function of the reticular activating system (RAS) is its participation in fight vs. flight responses such that alerting stimuli simultaneously activate thalamocortical systems, as well as postural and locomotor systems, in order to enable an appropriate response. The P50 midlatency auditory-evoked potential appears to be an ascending manifestation of the cholinergic arm of the RAS in eliciting changes in arousal state. Abnormalities in the manifestation of the P50 potential are present in disorders which include: (1) dysregulation of sleep-wake cycles; (2) abnormalities in reflex/postural, especially, startle, responses; and (3) malfunctions in flight vs. flight responses. In general, the P50 potential appears to be upregulated (increased amplitude and/or decreased sensory gating) in disorders which are marked by upregulation of RAS outputs (hypervigilance), and downregulated in disorders characterized by decreased RAS outputs (hypovigilance). Many of the disorders discussed have a developmental etiology and a postpubertal age of onset.

Much of the controversy surrounding the induction of locomotion following stimulation of mesopontine sites, including the pedunculopontine nucleus (PPN), appears based on procedural differences, including stimulus onset, delay preceding stepping, and frequency of stimuli. The results reviewed in this chapter address these issues and provide novel information suggesting that descending projections from the PPN may exert a frequency-dependent effect. Stimulation at approximately 60 Hz (which induces prolonged tonic firing) may exercise a "push" towards locomotion (activation of pontine interneurons) as well as a "pull" away from decreased muscle tone (inhibiting giant pontine reticulospinal cells). Higher frequencies of stimulation (> 100 Hz, which induces phasic burst-like activity) may "push" towards decreases in muscle tone, including the atonia of rapid eye movement sleep (activating giant pontine reticulospinal cells).

This review describes the role of the pedunculopontine nucleus (PPN) in various functions, including sleep-wake mechanisms, arousal, locomotion and in several pathological conditions. Special emphasis is placed on the auditory input to the PPN and the possible role of this nucleus in the manifestation of the P1 middle latency auditory evoked response. The importance of these considerations is evident because the PPN is part of the cholinergic arm of the reticular activating system. As such, the auditory input to this region may modulate the level of arousal of the CNS and, consequently, abnormalities in the processing of this input can be expected to have serious consequences on the level of excitability of the CNS. The involvement of the PPN in such disorders as schizophrenia, anxiety disorder and narcolepsy is discussed.

The authors provide evidence that four mesencephalic nuclei, two of which are cholinergic and two of which are catecholaminergic, serve as oscillators capable of modulating a number of interrelated rhythmic functions. These include sleep-wake cycles, locomotion, blood pressure, respiratory rate, heart rate, mastication, micturition, and saccadic eye movements. The P1 auditory evoked potential is generated by ascending cholinergic projections from one of these nuclei, the pedunculopontine nucleus, and thus serves as a clinical tool to monitor the integrity of this system.

This review highlights the most important discovery in the reticular activating system (RAS) in the last 10 years, the manifestation of gamma (γ) band activity in cells of the RAS, especially in the pedunculopontine nucleus (PPN), which is in charge of the high frequency states of waking and rapid eye movement sleep. This discovery is critical to understanding the modulation of movement by the RAS and how it sets the background over which we generate voluntary and triggered movements. The presence of γ band activity in the RAS is proposed to participate in the process of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. Early findings using stimulation of this region to induce arousal, and also to elicit stepping, are placed in this context. This finding also helps explain the novel use of PPN deep brain stimulation for the treatment of Parkinson’s disease, although considerable work remains to be done.

• Good evidence relates the pedunculopontine nucleus (PPN) to control of reflex reactions, sleep-wake cycles, posture and gait. • The PPN has become a target for deep brain stimulation for the treatment of Parkinson's disease. • This review is intended to provide a framework for future research. The pedunculopontine nucleus (PPN) is located in the mesopontine tegmentum and is best delimited by a group of large cholinergic neurons adjacent to the decussation of the superior cerebellar peduncle. This part of the brain, populated by many other neuronal groups, is a crossroads for many important functions. Good evidence relates the PPN to control of reflex reactions, sleep-wake cycles, posture and gait. However, the precise role of the PPN in all these functions has been controversial and there still are uncertainties in the functional anatomy and physiology of the nucleus. It is difficult to grasp the extent of the influence of the PPN, not only because of its varied functions and projections, but also because of the controversies arising from them. One controversy is its relationship to the mesencephalic locomotor region (MLR). In this regard, the PPN has become a new target for deep brain stimulation (DBS) for the treatment of parkinsonian gait disorders, including freezing of gait. This review is intended to indicate what is currently known, shed some light on the controversies that have arisen, and to provide a framework for future research. [ABSTRACT FROM AUTHOR]

The dorsal subcoeruleus nucleus (SubCD) is involved in generating two signs of rapid eye movement (REM) sleep: muscle atonia and ponto-geniculo-occipital (PGO) waves. We tested the hypothesis that single cell and/or population responses of SubCD neurons are capable of generating gamma frequency activity in response to intracellular stimulation or receptor agonist activation. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. All SubCD neurons (n = 103) fired at gamma frequency when subjected to depolarizing steps. Two statistically distinct populations of neurons were observed, which were distinguished by their high (>80 Hz, n = 24) versus low (35-80 Hz, n = 16) initial firing frequencies. Both cell types exhibited subthreshold oscillations in the gamma range (n = 43), which may underlie the gamma band firing properties of these neurons. The subthreshold oscillations were blocked by the sodium channel blockers tetrodotoxin (TTX, n = 21) extracellularly and N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314) intracellularly (n = 5), indicating they were sodium channel dependent. Gamma frequency subthreshold oscillations were observed in response to the nonspecific cholinergic receptor agonist carbachol (CAR, n = 11, d = 1.08) and the glutamate receptor agonists N-methyl-d-aspartic acid (NMDA, n = 12, d = 1.09) and kainic acid (KA, n = 13, d = 0.96), indicating that cholinergic and glutamatergic inputs may be involved in the activation of these subthreshold currents. Gamma band activity also was observed in population responses following application of CAR (n = 4, P < 0.05), NMDA (n = 4, P < 0.05) and KA (n = 4, P < 0.05). Voltage-sensitive, sodium channel-dependent gamma band activity appears to be a part of the intrinsic membrane properties of SubCD neurons. [ABSTRACT FROM AUTHOR]

Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states by activation of such descending targets as the caudal pons and the medioventral medulla (MED). Previously, PPN stimulation was reported to induce prolonged responses (PRs) in intracellularly recorded caudal pontine neurons in vitro. The present study used intracellular recordings in semihorizontal slices from rat brain stem (postnatal days 12-21) to determine responses in MED neurons following PPN stimulation. One-half (40/81) of MED neurons showed PRs after PPN stimulation. MED neurons with PRs had shorter duration action potential, longer duration afterhyperpolarization, and higher amplitude afterhyperpolarization than non-PR MED neurons. PR MED neurons were significantly larger (568 ± 44 μm²) than non-PR MED neurons (387 ± 32 μm²). The longest mean duration PRs and maximal firing rates during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. The muscarinic cholinergic agonist carbachol induced depolarization in all PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked carbachol- and PPN stimulation-induced PRs in all MED neurons tested. These findings suggest that PPN stimulation-induced PRs may be due to activation of muscarinic receptor-sensitive channels, allowing MED neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs in large MED neurons using parameters known best to induce locomotion. [ABSTRACT FROM AUTHOR]

We found a shift in the responsiveness of pedunculopontine neurons from N-methyl-d-aspartic acid (NMDA) to kainic acid (KA) regulation around 15 days of age. While rapid eye movement (REM) sleep in humans decreases from 50 to 15% of sleep time between birth and the end of puberty, a similar decrease in the rat occurs from 10 to 30 days postnatally. Intracellularly recorded type II cholinergic PPN neurons, known to modulate waking and REM sleep, showed a gradual decrease in responsiveness to NMDA, and an increase in responsiveness to KA, during this period. Non-cholinergic PPN neurons did not show a developmental-dependent change in responsiveness. These results do not help explain if KA and NMDA control the developmental decrease in REM sleep, however, the data indicate that the shift at ∼15 days suggests that REM sleep becomes selectively modulated by KA receptors in the adult. Therefore, given development of appropriate compounds, KA receptor antagonism may become an effective treatment for disorders that manifest increased REM sleep drive and produce frequent nocturnal arousals and awakenings, e.g. schizophrenia, anxiety, insomnia, etc. [Copyright &y& Elsevier]

This mini-review considers certain factors related to the developmental decrease in rapid eye movement (REM) sleep, including its timing, its relationship to other developmental changes, factors that may influence its progress and its potential role in brain development. Specifically, we discuss some of the theories proposed for its occurrence and agree with the classic notion that REM sleep is, at least, an active mechanism that may play a role in the maturation of the central nervous system (CNS), specifically contributing to the maturation of thalamocortical pathways. The developmental decrease in REM sleep occurs gradually from birth until after puberty in the human, but in other mammals it is brief and coincides with eye and ear opening and the beginning of massive exogenous activation. This purported role for REM sleep may change to involve a number of other functions with age. We describe recent findings showing that intrinsic morphological and physiological properties as well as serotonergic, n-methyl-d-aspartic acid (NMDA) and kainic acid (KA) synaptic inputs to mesopontine cholinergic neurons change dramatically at this critical period in development, perhaps driving what has been proposed as a REM sleep inhibitory process (RIP). We hypothesize that a dysregulation of this process could result in life-long disturbances in REM sleep drive, leading to hypervigilance or hypovigilance such as that observed in a number of disorders which have a mostly postpubertal age of onset. Finally, we also hypothesize that the role of normal cyclic increases in vigilance, observable during both sleep and waking, may be related, at least in part, to cortical blood flow. [Copyright &y& Elsevier]

The P50 potential is a midlatency auditory evoked response which is sleep state-dependent, habituates rapidly and is blocked by the muscarinic cholinergic antagonist scopolamine. It is thought to be generated, at least in part, by ascending projections of the reticular activating system. The amplitude of the P50 potential can be used as a measure of level of arousal, while the degree of habituation to repetitive stimulation can be used as a measure of sensory gating. We studied these processes in three conditions which show sleep-wake cycle dysregulation and attentional disturbance, but differ greatly in their etiology, depression, Huntington’s disease and rotation-induced motion sickness. Subjects with depression and rotation-induced motion sickness showed significant decreases in the habituation of the second of paired evoked responses, while Huntington’s disease subjects showed decreased amplitude as well as decreases in the habituation of the second P50 potential. This waveform may represent the manifestation of pre-attentional processes, and may become a useful measure for monitoring the severity, progression and/or remission of disorders which affect these processes. [Copyright &y& Elsevier]

In this review, we discuss first an example of one of the symptoms of PD, freezing of gait (FOG), then we will turn to the use of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) to treat PD, and the original studies that led to identification of the PPN as one source of locomotor control and why stimulation frequency is critical, and then describe the intrinsic properties of PPN neurons that require beta/gamma stimulation in order to fully activate all types of PPN neurons. Finally, we will describe recent findings on the proteomic and molecular consequences of gamma band activity in PPN neurons, with emphasis on the potential neuroepigenetic sequelae. These considerations will provide essential information for the appropriate refining and testing of PPN DBS as a potential therapy for PD, as well as alternative options. [ABSTRACT FROM AUTHOR]

Abstract: Rapid eye movement sleep decreases between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus is known to modulate waking and rapid eye movement sleep, and pedunculopontine nucleus neurons are thought to be hyperpolarized by noradrenergic input from the locus coeruleus. The goal of the study was to investigate the possibility that a change in α-2 adrenergic inhibition of pedunculopontine nucleus cells during this period could explain at least part of the developmental decrease in rapid eye movement sleep. We, therefore, recorded intracellularly in 12–21 day rat brainstem slices maintained in oxygenated artificial cerebrospinal fluid. Putative cholinergic vs. non-cholinergic pedunculopontine nucleus neurons were identified using nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and intracellular injection of neurobiotin (Texas Red immunocytochemistry). Pedunculopontine nucleus neurons also were identified by intrinsic membrane properties, type I (low threshold spike), type II (A) and type III (A+low threshold spike), as previously described. Clonidine (20 μM) hyperpolarized most cholinergic and non-cholinergic pedunculopontine nucleus cells. This hyperpolarization decreased significantly in amplitude (mean±S.E.) from −6.8±1.0 mV at 12–13 days, to −3.0±0.7 mV at 20–21 days. However, much of these early effects (12–15 days) were indirect such that direct effects (tested following sodium channel blockade with tetrodotoxin (0.3 μM)) resulted in hyperpolarization averaging −3.4±0.5 mV, similar to that evident at 16–21 days. Non-cholinergic cells were less hyperpolarized than cholinergic cells at 12–13 days (−1.6±0.3 mV), but equally hyperpolarized at 20–21 days (−3.3±1.3 mV). In those cells tested, hyperpolarization was blocked by yohimbine, an α-2 adrenergic receptor antagonist (1.5 μM). These results suggest that the α-2 adrenergic receptor on cholinergic pedunculopontine nucleus neurons activated by clonidine may play only a modest role, if any, in the developmental decrease in rapid eye movement sleep. Clonidine blocked or reduced the hyperpolarization-activated inward cation conductance, so that its effects on the firing rate of a specific population of pedunculopontine nucleus neurons could be significant. In conclusion, the α-2 adrenergic input to pedunculopontine nucleus neurons appears to consistently modulate the firing rate of cholinergic and non-cholinergic pedunculopontine nucleus neurons, with important effects on the regulation of sleep–wake states. [Copyright &y& Elsevier]

Abstract: Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. The pedunculopontine nucleus (PPN), as the cholinergic arm of the reticular activating system (RAS), is known to modulate arousal, waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, especially at 12–21 days. Pregnant dams were exposed to 350 ml of cigarette smoke for 15 min, 3 times per day, from day E14 until birth, and the pups allowed to mature. Intracellularly recorded PPN neurons in 12–21 day rat brainstem slices were tested for intrinsic membrane properties, including the hyperpolarization-activated cation current I h, which is known to drive oscillatory activity. Type II (A-current) PPN cells from 12–16 day old offspring of treated animals had a 1/2max I h amplitude of (mean± SE) 4.1±0.9 mV, while 17–21 day cells had a higher 1/2max I h of 9.9±1.1 mV (p <0.0001). Cells from 12–16 day old control brainstems had a 1/2max I h of 1.3±0.1 mV, which was lower (p <0.05) than in cells from prenatally treated offspring; while 17–21 day old cells from controls had a 1/2max I h of 3.3±0.3 mV, which was also lower (p <0.01) than in cells from prenatally treated offspring. In addition, changes in resting membrane potential [control −65.±0.9 mV (n =32); exposed −55.0±1.4 mV (n =27) (p <0.0001)], and action potential (AP) threshold [control −56.5±0.7 mV (n =32), exposed −47.0±1.4 mV (n =27) (p <0.0001)], suggest that prenatal exposure to cigarette smoke induced marked changes in cells in the cholinergic arm of the RAS, rendering them more excitable. Such data could partially explain the differences seen in individuals whose parents smoked during pregnancy, especially in terms of their hypervigilance and increased propensity for attentional deficits and cognitive/behavioral disorders. [Copyright &y& Elsevier]

Abstract: Objective: Patients with Chronic Low Back Pain (CLBP) show arousal, attentional and cognitive disturbances. The sleep state-dependent P50 midlatency auditory evoked potential was used to determine if patients with CLBP [with and without co-morbid depression (DEP)] show quantitative disturbances in the manifestation of the P50 potential. Methods: P50 potential latency, amplitude and habituation to repetitive stimuli at 250, 500 and 1000ms interstimulus intervals (ISIs) was recorded, along with the McGill Pain Questionnaire-Short Form (MPQ-SF). CLBP subjects (n=42) were compared with Controls (n=43), and with subjects with DEP only (n=6). Of the CLBP subjects, 20/42 had clinical depression (CLBP+DEP); 8/20 were taking anti-depressant medication (CLBP+DEP+med), the others were not (CLBP+DEP−med). Results: There were no differences (ANOVA) in age, sex or P50 potential latency, although there was a trend towards increased latencies in CLBP groups. P50 potential amplitude was lower in CLBP groups, but not in sub-groups, again indicating a trend. P50 potential habituation was decreased in the DEP only subjects at the 250m ISI, and decreased in CLBP+DEP−med subjects at the 500ms ISI. This difference was not present in CLBP+DEP+med subjects. The MPQ-SF revealed that patients with CLBP and CLBP+DEP−med showed lower pain scores than CLBP+DEP+med patients. Conclusions: There is decreased habituation of the P50 potential habituation in unmedicated patients with CLBP+DEP compared to Controls. Significance: Patients with CLBP+DEP−med may be less able to disregard incoming sensory information, including painful sensations, but anti-depressant medications help correct this deficit. However, their perception of pain may be increased by medication. [Copyright &y& Elsevier]