ABSTRACT
In schizophrenia, a disorder associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction, auditory cortical plasticity deficits have been indexed by the synchronized electroencephalographic (EEG) auditory steady-state gamma-band (40-Hz) response (ASSR) and the early auditory evoked gamma-band response (aeGBR), both considered to be target engagement biomarkers for NMDAR function, and potentially amenable to treatment by NMDAR modulators. As transcranial direct current stimulation (tDCS) is likely dependent on NMDAR neurotransmission, this preliminary study, conducted in 30 healthy volunteers, assessed the off-line effects of prefrontal anodal tDCS and sham (placebo) treatment on 40-Hz ASSR and aeGBR. Anodal tDCS failed to alter aeGBR but increased both 40-Hz ASSR power, as measured by event-related spectral perturbations (ERSP), and phase locking, as measured by inter-trial phase consistency (ITPC). Inter-individual differences in tDCS-induced increases in ERSP were negatively related to baseline ERSPs. These findings provide tentative support for further study of tDCS as a potential NMDAR neuromodulatory intervention for synchronized auditory gamma response deficits.
Subject(s)
Transcranial Direct Current Stimulation , Acoustic Stimulation , Biomarkers , Electroencephalography , Evoked Potentials, Auditory/physiology , Humans , Receptors, N-Methyl-D-AspartateABSTRACT
Deficits in early auditory sensory processing in schizophrenia have been linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction, but the role of NMDARs in aberrant auditory sensory gating (SG) in this disorder is unclear. This study, conducted in 22 healthy humans, examined the acute effects of a subanesthetic dose of the NMDAR antagonist ketamine on SG as measured electrophysiologically by suppression of the P50 event-related potential (ERP) to the second (S2) relative to the first (S1) of two closely paired (500 ms) identical speech stimuli. Ketamine induced impairment in SG indices at sensor (scalp)-level and at source-level in the auditory cortex (as assessed with eLORETA). Together with preliminary evidence of modest positive associations between impaired gating and dissociative symptoms elicited by ketamine, tentatively support a model of NMDAR hypofunction underlying disturbances in auditory SG in schizophrenia.
Subject(s)
Auditory Cortex , Ketamine , Acoustic Stimulation , Electroencephalography , Evoked Potentials, Auditory , Humans , Ketamine/pharmacology , Receptors, N-Methyl-D-Aspartate , Sensory Gating , SpeechABSTRACT
Impairments in auditory information processing in schizophrenia as indexed electrophysiologically by P300 deficits during novelty (P3a) and target (P3b) processing are linked to N -methyl- D -aspartate receptor (NMDAR) dysfunction. This study in 14 healthy volunteers examined the effects of a subanesthetic dose of the NMDAR antagonist ketamine on P300 and their relationship to psychomimetic symptoms and cortical source activity (with eLORETA). Ketamine reduced early (e- P3a) and late (l-P3a) novelty P300 at sensor (scalp)-level and at source-level in the salience network. Increases in dissociation symptoms were negatively correlated with ketamine-induced P3b changes, at sensor-level and source-level, in both salience and central executive networks. These P3a alterations during novelty processing, and the symptom-related P3b changes during target processing support a model of NMDAR hypofunction underlying disrupted auditory attention in schizophrenia.
Subject(s)
Event-Related Potentials, P300 , Ketamine/therapeutic use , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Schizophrenia/physiopathology , Acoustic Stimulation/methods , Adult , Attention , Auditory Perception , Cognition , Double-Blind Method , Electroencephalography/methods , Healthy Volunteers , Humans , Male , Young AdultABSTRACT
The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5â¯mg]; nicotine [6â¯mg]; and nicotineâ¯+â¯nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.
Subject(s)
Cannabinoid Receptor Agonists/pharmacology , Dronabinol/analogs & derivatives , Evoked Potentials, Auditory/drug effects , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Acoustic Stimulation/methods , Adult , Cannabinoid Receptor Agonists/administration & dosage , Double-Blind Method , Dronabinol/administration & dosage , Dronabinol/pharmacology , Drug Therapy, Combination/methods , Electroencephalography/methods , Electrooculography/methods , Frontal Lobe/drug effects , Healthy Volunteers , Humans , Male , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptors, Nicotinic/metabolism , Schizophrenia/drug therapy , Temporal Lobe/drug effects , Young AdultABSTRACT
Novel pharmacological treatments targeting alpha 7 nicotinic acetylcholine receptor (α7 nAChR) hypofunction in schizophrenia have shown mixed success in ameliorating cognitive impairments associated with this disorder. Choline, a selective agonist at α7 receptors is increased with oral administration of cytidine 5'-diphosphocholine (CDP-choline), the cognitive effects of which were assessed in healthy volunteers. Using the CogState test battery, behavioral performance in schizophrenia-relevant cognitive domains was assessed in 24 male participants following a single low (500mg) and moderate (1000mg) dose of CDP-choline. Relative to placebo, CDP-choline improved processing speed, working memory, verbal learning, verbal memory, and executive function in low baseline performers, while exerting no effects in medium baseline performers, and diminishing cognition in high baseline performers. Dose effects varied with cognitive domain but were evident with both the 500mg and 1000mg doses. These preliminary findings of cognitive enhancement in relatively impaired performers are consistent with the α7 receptor mechanism and support further trials with CDP-choline as a potential pro-cognitive strategy for cognitive impairment in schizophrenia.
Subject(s)
Choline/pharmacology , Cognition/drug effects , Nootropic Agents/pharmacology , Adolescent , Adult , Choline/administration & dosage , Cross-Over Studies , Double-Blind Method , Humans , Male , Neuropsychological Tests , Nootropic Agents/administration & dosage , Young AdultABSTRACT
Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (α7 nAChR), the targeting of which may have treatment potential. Choline is a selective α7 nAChR agonist and the aim of this study was to determine whether cytidine 5'-diphosphocholine (CDP-choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy.
Subject(s)
Cytidine Diphosphate Choline/pharmacology , Executive Function/drug effects , Inhibition, Psychological , Sensory Gating/drug effects , Cytidine Diphosphate Choline/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Evoked Potentials/physiology , Healthy Volunteers , Humans , Male , Nicotinic Agonists/adverse effects , Nicotinic Agonists/pharmacology , Young AdultABSTRACT
OBJECTIVE: Cognitive enhancement resulting from nicotinic acetylcholine receptor stimulation may be evidenced by increased efficiency of the auditory-frontal cortex network of auditory discrimination, which is impaired in schizophrenia, a cognitive disorder associated with excessive tobacco use. Investigating automatic (preattentive) detection of acoustic change with the mismatch negativity (MMN) brain event-related potential in response to nicotine in individuals with varying baseline levels of auditory discrimination may provide useful insight into the cholinergic regulation of this neural network and its potential amelioration with novel nicotinic agents. METHODS: Sixty healthy, non-smoking male volunteers were presented with an 'optimal' multi-feature MMN paradigm in a randomized, placebo controlled double-blind design with 6 mg of nicotine gum. RESULTS: Participants with low, medium, and high baseline amplitudes responded differently to nicotine (vs. placebo), and nicotine response was feature specific. Whereas MMN in individuals with high amplitudes was diminished by nicotine, MMN increased in those with low amplitudes. Nicotine effects were not shown in medium amplitude participants. CONCLUSIONS: These findings provide preliminary support for the role of nicotinic neurotransmission in sensory memory processing of auditory change and suggest that nicotinic receptor modulation can both enhance and diminish change detection, depending on baseline MMN and its eliciting stimulus feature.
Subject(s)
Auditory Perception/drug effects , Brain/drug effects , Nicotine/pharmacology , Psychotropic Drugs/pharmacology , Signal Detection, Psychological/drug effects , Acoustic Stimulation , Adolescent , Adult , Auditory Perception/physiology , Brain/physiology , Double-Blind Method , Electroencephalography , Evoked Potentials , Humans , Male , Nicotinic Agonists/pharmacology , Signal Detection, Psychological/physiology , Young AdultABSTRACT
Reduced suppression of the P50 auditory event-related potential in schizophrenia patients relative to normal controls is indicative of a sensory gating deficit and is one of the most robust findings reported for functional brain abnormalities in this disorder. However, there is considerable gating variability in patients and controls and there is little understanding as to how inter-individual differences moderate gating responses to drugs and nicotinic agonists in particular, which have shown potential to reverse gating deficits. In this study the effects of acutely administered nicotine (gum, 6 mg) on sensory gating in a paired (S1-S2) auditory stimulus paradigm were investigated in 57 healthy, non-smoking volunteers stratified as low (n = 19), medium (n = 19) and high (n = 19) P50 suppressors on the basis of three separate baseline derived gating indices, P50 ratios, P50 difference scores, and gating difference waveforms. Relative to placebo, nicotine consistently improved gating in low suppressors as stratified with all three gating indices, exerted no effects in medium suppressors and reduced gating in high suppressors. Analysis of individual stimulus (S2, S2) amplitudes showed distinctly different mechanisms of action underlying nicotine effects in individuals with low and high baseline suppression. The results parallel similar findings of baseline-dependency in the gating effects of several antipsychotic drugs in healthy volunteers and support the use of group segmentation as a translational model in novel cognitive drug development for schizophrenia.