Bereitschaftspotential and lateralized readiness potential in children with attention deficit hyperactivity disorder: altered motor system activation and effects of methylphenidate.

Attention deficit hyperactivity disorder (ADHD) has been linked to abnormal functioning of cortical motor areas such as the supplementary motor area, the premotor cortex and primary motor cortex (MI). The Bereitschaftspotential (BP) and lateralized readiness potential (LRP) are movement-related potentials generated by cortical motor areas. We hypothesized that the BP and LRP would be altered in children with ADHD. A group of 17 children with ADHD (mean age: 11.5 ±â€¯1.9 years) and a control group of 16 typically developing children (mean age: 12.2 ±â€¯2.0 years) performed movements at self-chosen irregular intervals while a 64-channel DC-EEG was registered. BP and LRP were calculated from the EEG. The ADHD group had significantly lower and on average positive BP amplitudes at Cz. In agreement with age-dependent maturation effects the LRP had a positive polarity in both groups, but lower amplitudes were found in the ADHD group without medication. The control group showed a mid-central negativity and a positivity over motor areas contra-lateral to the side of movement, whereas no negativity over Cz and a more diffuse positivity was found in the ADHD group. LRP group differences diminished after MPH administration as indicated by an interaction between group and time of measurement/medication. The cortical motor system shows altered functioning during movement preparation and initiation in children affected by ADHD. Positive Bereitschaftspotential polarities may represent delayed cortical maturation. Group differences of LRP were pharmacologically modulated by the catecholaminergic agent MPH.

Characteristic Scent from the Tahitian Liverwort, Cyathodium foetidissimum.

The volatile components of the Tahitian liverwort Cyathodium foetidissimum was analyzed using headspace solid phase micro-extraction (SPME) and GC-MS. Three volatile components, 4-methoxystyrene (24.4%), 3,4-dimethoxystyrene (28.7%), and skatole (15.9%) were identified as the major components from the fresh C. foetidissimum, along with several aliphatic aldehydes, n-octanal, n-nonanal, and n-decanal. However, (E)-2-nonenal recognized as aged malodor was not identified. In GC-O analysis, 2-aminoacetophenone was detected as one of the minor components with a strong aging note. In fact, C. foetidissimum showed the characteristic aging odor reminiscent the damp smell from old chest of drawers, or the civet like note with very strong feces and urine odor. The mixture consisted of 4-methoxystyrene, 3,4-dimethoxystyrene, and skatole in the detected ratio showed the sedative effect on CNV (contingent negative variation) measurement.

Identification of TAAR5 Agonist Activity of Alpha-NETA and Its Effect on Mismatch Negativity Amplitude in Awake Rats.

Mismatch negativity (MMN) is a well-defined component of human event-related potentials that reflects the pre-attentive, stimulus-discrimination process and is associated with involuntary switching of attention. MMN-like responses detected in animal models provide an opportunity to investigate the neural mechanisms of this process that involves several neurotransmitter and neuromodulator systems. Trace amines are believed to play a significant role in neuromodulation of synaptic transmission. The present study aimed to determine the role of trace amine-associated receptor 5 (TAAR5) in the MMN-like response in rats. First, using a bioluminescence resonance energy transfer (BRET) cAMP biosensor, we performed unbiased screening of TAAR5 ligands from a commercially available compound library (661 compounds) and identified 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) as a potent (EC50 150 nM) TAAR5 agonist. Then, we recorded auditory event-related potentials during an oddball paradigm in awake freely moving rats that were intraperitoneally injected with a vehicle or two doses of the putative TAAR5 agonist alpha-NETA. The MMN-like response was increased by alpha-NETA 3 mg/kg dose, but not by 1 mg/kg dose or 0.9% saline solution. These results suggest that the MMN-like response in rats may be modulated, at least in part, through TAAR5-dependent processes.

Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms.

BACKGROUND: Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder. METHODS: Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor. RESULTS: Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN. CONCLUSIONS: These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).

The effects of glycine on auditory mismatch negativity in schizophrenia.

Glycine increases N-methyl-d-aspartate receptor (NMDAR) mediated glutamatergic function. Mismatch negativity (MMN) is a proposed biomarker of glutamate-induced improvements in clinical symptoms, however, the effect of glycine-mediated NMDAR activation on MMN in schizophrenia is not well understood. This study aimed to determine the effects of acute and 6-week chronic glycine administration on MMN in schizophrenia patients. MMN amplitude was compared at baseline between 22 patients (schizophrenia or schizoaffective disorder; receiving stable antipsychotic medication; multi-centre recruitment) and 21 age- and gender-matched controls. Patients underwent a randomised, double-blind, placebo-controlled clinical trial with glycine added to their regular antipsychotic medication (placebo, n=10; glycine, n=12). MMN was reassessed post-45-minutes of first dose (0.2g/kg) and post-6-weeks treatment (incremented to 0.6g/kg/day). Clinical symptoms were assessed at baseline and post-6-weeks treatment. At baseline, duration MMN was smaller in schizophrenia compared to controls. Acute glycine increased duration MMN (compared to placebo), whilst this difference was absent post-6-weeks treatment. Six weeks of chronic glycine administration improved PANSS-Total, PANSS-Negative and PANSS-General symptoms compared to placebo. Smaller baseline duration MMN was associated with greater PANSS-Negative symptoms and predicted (at trend level) PANSS-Negative symptom improvement post-6-weeks glycine treatment (not placebo). These findings support the benefits of chronic glycine administration and demonstrate, for the first time, that acute glycine improves duration MMN in schizophrenia. This result, together with smaller baseline duration MMN predicting greater clinical treatment response, suggests the potential for duration MMN as a biomarker of glycine-induced improvements in negative symptoms in schizophrenia.

Late deviance detection in rats is reduced, while early deviance detection is augmented by the NMDA receptor antagonist MK-801.

One of the most robust electrophysiological features of schizophrenia is reduced mismatch negativity, a component of the event related potential (ERP) induced by rare and unexpected stimuli in an otherwise regular pattern. Emerging evidence suggests that mismatch negativity (MMN) is not the only ERP index of deviance detection in the mammalian brain and that sensitivity to deviant sounds in a regular background can be observed at earlier latencies in both the human and rodent brain. Pharmacological studies in humans and rodents have previously found that MMN reductions similar to those seen in schizophrenia can be elicited by N-methyl-d-aspartate (NMDA) receptor antagonism, an observation in agreement with the hypothesised role of NMDA receptor hypofunction in schizophrenia pathogenesis. However, it is not known how NMDA receptor antagonism affects early deviance detection responses. Here, we show that NMDA antagonism impacts both early and late deviance detection responses. By recording EEG in awake, freely-moving rats in a drug-free condition and after varying doses of NMDA receptor antagonist MK-801, we found the hypothesised reduction of deviance detection for a late, negative potential (N55). However, the amplitude of an early component, P13, as well as deviance detection evident in the same component, were increased by NMDA receptor antagonism. These findings indicate that late deviance detection in rats is similar to human MMN, but the surprising effect of MK-801 in increasing ERP amplitudes as well as deviance detection at earlier latencies suggests that future studies in humans should examine ERPs over early latencies in schizophrenia and after NMDA antagonism.

Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia.

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction has been implicated in the pathophysiology of schizophrenia, including auditory processing abnormalities reflected by the mismatch negativity (MMN) event-related potential component. Evidence suggesting cognitive benefits from nicotine administration, together with the high rate of cigarette use in patients with schizophrenia, has stimulated interest in whether nicotine modulates NMDAR hypofunction. We examined the interactive effects of ketamine, an NMDAR antagonist that produces transient schizophrenia-like neurophysiological effects, and nicotine, a nicotinic acetylcholine receptor (nAChR) agonist, in 30 healthy volunteers to determine whether nicotine prevents or attenuates MMN abnormalities. Secondary analyses compared the profile of ketamine and schizophrenia effects on MMN using previously reported data from 24 schizophrenia patients (Hay et al. 2015). Healthy volunteers completed four test days, during which they received ketamine/placebo and nicotine/placebo in a double-blind, counterbalanced design. MMN to intensity, frequency, duration, and frequency+duration double deviant sounds was assessed each day. Ketamine decreased intensity, frequency, and double deviant MMN amplitudes, whereas nicotine increased intensity and double deviant MMN amplitudes. A ketamine×nicotine interaction indicated, however, that nicotine failed to attenuate the decrease in MMN associated with ketamine. Although the present dose of ketamine produced smaller decrements in MMN than those associated with schizophrenia, the profile of effects across deviant types did not differ between ketamine and schizophrenia. Results suggest that while ketamine and schizophrenia produce similar profiles of MMN effects across deviant types, nicotinic agonists may have limited potential to improve these putative NMDAR hypofunction-mediated impairments in schizophrenia.

Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.

Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.

Changes of auditory event-related potentials in ovariectomized rats injected with d-galactose: Protective role of rosmarinic acid.

Rosmarinic acid (RA), which has multiple bioactive properties, might be a useful agent for protecting central nervous system against age related alterations. In this context, the purpose of the present study was to investigate possible protective effects of RA on mismatch negativity (MMN) component of auditory event-related potentials (AERPs) as an indicator of auditory discrimination and echoic memory in the ovariectomized (OVX) rats injected with d-galactose combined with neurochemical and histological analyses. Ninety female Wistar rats were randomly divided into six groups: sham control (S); RA-treated (R); OVX (O); OVX+RA-treated (OR); OVX+d-galactose-treated (OD); OVX+d-galactose+RA-treated (ODR). Eight weeks later, MMN responses were recorded using the oddball condition. An amplitude reduction of some components of AERPs was observed due to ovariectomy with or without d-galactose administiration and these reduction patterns were diverse for different electrode locations. MMN amplitudes were significantly lower over temporal and right frontal locations in the O and OD groups versus the S and R groups, which was accompanied by increased thiobarbituric acid reactive substances (TBARS) and hydroxy-2-nonenal (4-HNE) levels. RA treatment significantly increased AERP/MMN amplitudes and lowered the TBARS/4-HNE levels in the OR and ODR groups versus the O and OD groups, respectively. Our findings support the potential benefit of RA in the prevention of auditory distortion related to the estrogen deficiency and d-galactose administration at least partly by antioxidant actions.

Neurophysiological evidence of impaired self-monitoring in schizotypal personality disorder and its reversal by dopaminergic antagonism.

BACKGROUND: Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder characterized by odd or bizarre behavior, strange speech, magical thinking, unusual perceptual experiences, and social anhedonia. Schizophrenia proper has been associated with anomalies in dopaminergic neurotransmission and deficits in neurophysiological markers of self-monitoring, such as low amplitude in cognitive event-related brain potentials (ERPs) like the error-related negativity (ERN), and the error positivity (Pe). These components occur after performance errors, rely on adequate fronto-striatal function, and are sensitive to dopaminergic modulation. Here we postulated that analogous to observations in schizophrenia, SPD individuals would show deficits in self-monitoring, as measured by the ERN and the Pe. We also assessed the capacity of dopaminergic antagonists to reverse these postulated deficits. METHODS: We recorded the electroencephalogram (EEG) from 9 SPD individuals and 12 healthy controls in two separate experimental sessions while they performed the Eriksen Flanker Task, a classical task recruiting behavioral monitoring. Participants received a placebo or 1 mg risperidone according to a double-blind randomized design. RESULTS: After placebo, SPD individuals showed slower reaction times to hits, longer correction times following errors and reduced ERN and Pe amplitudes. While risperidone impaired performance and decreased ERN and Pe in the control group, it led to behavioral improvements and ERN amplitude increases in the SPD individuals. CONCLUSIONS: These results indicate that SPD individuals show deficits in self-monitoring analogous to those in schizophrenia. These deficits can be evidenced by neurophysiological measures, suggest a dopaminergic imbalance, and can be reverted by dopaminergic antagonists.

Temporal lobe impairment in West syndrome: event-related potential evidence.

OBJECTIVE: This study investigates auditory processing in infants with West syndrome (WS) using event-related potentials (ERPs). METHODS: ERPs were measured in 25 infants with mainly symptomatic WS (age range = 3-10 months) and 26 healthy term infants (age range = 3-9 months) using an auditory novelty oddball paradigm. The ERP recordings were made during wakefulness and repeated in stage II sleep. RESULTS: The obligatory components (P150, N250, P350) and novelty response components (P300, Nc) were recordable during both sleep and wakefulness in patients and controls. All ERP latencies decreased with age in controls but not in the WS group (age × group interaction, F = 22.3, p < 0.0001). These ERP latency alterations were not affected by pharmacological treatment for WS. INTERPRETATION: This study demonstrated a persistently altered ERP signature in patients with a recent history of infantile spasms. The prolongation of auditory obligatory and novelty ERPs in WS patients indicates a severe failure of temporal lobe maturation during infancy. It remains to be investigated whether this predicts long-term cognitive impairments characteristic for this epileptic encephalopathy.

Cognitive training enhances pre-attentive neurophysiological responses in older adults 'at risk' of dementia.

BACKGROUND: With predicted increases in dementia incidence, interventions targeting neuroplasticity and neuroprotection are required. Cognitive Training (CT) is an intervention which has been shown to improve aspects of cognition, but the pathophysiological mechanisms contributing to its efficacy are unknown. OBJECTIVE: We aimed to explore the neurobiological correlates of CT using Mismatch Negativity (MMN), a neurophysiological marker of pre-attentive information processing, which in turn, is postulated to underpin higher-order cognitive processes. METHODS: As part of a larger randomized controlled trial, forty 'at risk' (i.e., mild cognitive impairment or late-life depression) participants aged 51-79 years underwent neurophysiological, neuropsychological, and psychiatric assessments before and after a multi-faceted seven-week CT program or a 'treatment-as-usual' seven-week waitlist period. RESULTS: The treatment group demonstrated significantly increased fronto-central MMN responses (p < 0.05), as well as improved phonemic verbal fluency (p < 0.05) and decreased self-rated memory difficulties (p < 0.05) following CT, in comparison to the waitlist control group. However, there were no significant correlations between enhanced MMN and cognitive/psychosocial outcomes. CONCLUSIONS: Results from this preliminary investigation indicate that CT is associated with enhanced neurophysiological mechanisms suggestive of improved pre-attentive processing, which may reflect alterations in underlying neurobiology. Further research is warranted to confirm these findings, to explicate whether CT is associated with restorative or compensatory neuroplastic processes and to determine whether MMN is a useful biomarker for treatment response.

Tyrosine ameliorates heat induced delay in event related potential P300 and contingent negative variation.

The efficacy of tyrosine, a catecholamine precursor, as a countermeasure in the reduction of cognitive decline during heat exposure (HE) using event-related potential P300, and contingent negative variation (CNV) was evaluated. Ten healthy males, age 20-30years participated in the study. Volunteers received placebo or tyrosine (6.5g) 90min prior to HE (1.5h in 45°C+30% RH). P300 latency was significantly increased (p<0.01) during exposure with placebo, which was reduced significantly (p<0.01) after tyrosine supplementation. There was an increase in CNV M100 latency (p<0.05) and reaction time (p<0.01) and decrease in M100 amplitude (p<0.01) during HE with placebo, which returns to near normal level with the tyrosine administration. A significantly higher plasma norepinephrine (p<0.05), dopamine and epinephrine levels were detected in tyrosine supplemented group post heat exposure. HE increases the brain catecholamine activity thereby reduces the plasma norepinephrine and dopamine level leading to a reduction in cognitive performances. Tyrosine supplementation increases the catecholamine level and reduces the impairment of cognitive performance during HE.

Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.

Cross-diagnostic comparison of duration mismatch negativity and P3a in bipolar disorder and schizophrenia.

OBJECTIVES: Bipolar disorder and schizophrenia share common pathophysiological processes and may have similar perceptual abnormalities. Mismatch negativity (MMN) and P3a - event-related potentials associated with auditory preattentional processing - have been extensively studied in schizophrenia, but rarely in bipolar disorder. Furthermore, MMN and P3a have not been examined between diagnostic subgroups of patients with bipolar disorder. We evaluated MMN and P3a in patients with bipolar disorder compared to patients with schizophrenia and healthy controls. METHODS: MMN and P3a were assessed in 52 bipolar disorder patients, 30 schizophrenia patients, and 27 healthy control subjects during a duration-deviant auditory oddball paradigm. RESULTS: Significant MMN and P3a amplitude reductions were present in patients with bipolar disorder and schizophrenia relative to controls. The MMN reduction was more prominent in patients with schizophrenia than bipolar disorder, at a trend level. P3a did not differ significantly between patient groups. There were no MMN or P3a differences between patients with bipolar I (n = 34) and bipolar II (n = 18) disorder. Patients with bipolar I disorder failed to show lateralized MMN, in contrast to the other groups. No MMN or P3a differences were found between patients with bipolar disorder taking (n = 12) and not taking (n = 40) lithium, as well as between those taking (n = 30) and not taking (n = 22) antipsychotic medications. CONCLUSIONS: Patients with bipolar disorder showed deficits in preattentive auditory processing, including MMN deficits that are less severe and P3a deficits that are slightly more pronounced, than those seen in schizophrenia.

Nicotine and the hallucinating brain: effects on mismatch negativity (MMN) in schizophrenia.

Elevated smoking rates have been noted in schizophrenia, and it has been hypothetically attributed to nicotine's ameliorating abnormal brain processes in this illness. There is some preliminary evidence that nicotine may alter pre-attentive auditory change detection, as indexed by the EEG-derived mismatch negativity (MMN), but no previous study has examined what role auditory verbal hallucinations (AVH) may have on these effects. The objective of this study was to examine MMN-indexed acoustic change detection in schizophrenia (SZ) following nicotine administration and elucidate its association with AVH. Using a modified multi-feature paradigm, MMNs to duration, frequency and intensity deviants were recorded in 12 schizophrenia outpatients (SZ) with persistent AVHs following nicotine (6mg) and placebo administration. Electrical activity was recorded from 32 scalp electrodes; MMN amplitudes and latencies for each deviant were compared between treatments and were correlated with trait (PSYRATS) and state measures of AVH severity and Positive and Negative Syndrome Scale (PANSS) ratings. Nicotine administration resulted in a shortened latency for intensity MMN. Additionally, nicotine-related change in MMN amplitude was correlated with nicotine-related change in subjective measures of hallucinatory state. In summary, nicotine did not affect MMN amplitudes in schizophrenia patients with persistent AVHs, however this study reports accelerated auditory change detection to intensity deviants with nicotine in this group. Additionally, nicotine appeared to induce a generalized activation of the auditory cortex in schizophrenia, resulting in a concurrent increase in intensity MMN amplitude and subjective clarity of AVHs.

Alcohol use and mismatch negativity in young patients with psychotic disorder.

Mismatch negativity (MMN) is a neurophysiological indicator of the brain's ability to extract relevant information from an irrelevant background. MMN has been described as a reliable biomarker of schizophrenia and more recently it has found to be impaired in the early stages of psychosis. In addition, drugs (including alcohol) that block glutamate's N-methyl-D-aspartate receptor have been shown to reduce MMN. This study aims to determine whether risky alcohol consumption in young patients with psychotic disorder further impacts or changes their MMN response. Patients with high-alcohol use were found to show reduced temporal MMN amplitudes compared with patients with low-alcohol use and controls. In contrast, early psychosis patients with low-alcohol use showed reduced fronto-central MMN amplitudes compared with controls; whereas patients with high-alcohol use showed an intermediate response at these sites. Correlational analysis revealed distinct patterns of association between MMN and alcohol use in patients with early psychosis compared with controls. This study shows that early psychosis outpatients who engaged in risky drinking have decreased temporal MMN amplitudes, compared with their peers. This may reflect an additive effect of N-methyl-D-aspartate receptor hypofunction and high-alcohol consumption.

Interplay of neuronal processes during response inhibition: results from a combined event-related potentials (ERPs)/transcranial magnetic stimulation (TMS) study on methylphenidate.

The neuronal processes underlying response inhibition are often studied using either event-related potentials (ERPs) or by applying transcranial magnetic stimulation (TMS) to investigate excitatory and inhibitory processes in the motor system. We performed a more refined analysis of response inhibition by combining both approaches with the aim of identifying an interplay between ERPs and TMS parameters. During a go/nogo task, motor system excitability was measured using TMS single and double pulses and brain electrical activity was recorded in healthy adults (n=14). Each participant completed two testing sessions, once on placebo and once on methylphenidate (double-blind, crossover design). Studying the effects of methylphenidate served as an example application for this combined approach. Developing regression models, inhibition-related TMS measures (e.g., short intracortical inhibition) and the contingent negative variation explained about 85% of the variance of the nogo-P3 under both MPH and placebo medication. The smaller the inhibitory effect in the motor system, the more terminal response control was required and the more resources were allocated for the evaluation of the inhibitory process, respectively, as indicated by a larger P3. Thus, an interplay between processes in the motor system (cortex) and control processes with sources in the prefrontal cortex and the anterior cingulate cortex (ACC) may take place, acting complementarily to facilitate a correct nogo-response. While ERPs rather represent initiation and monitoring of inhibitory processes and response control, motor inhibition may be best analyzed using TMS. A combined ERP/TMS analysis may allow for the development of distinct models concerning the interplay of processes involved in response inhibition.

Contingent negative variation as a dopaminergic biomarker: evidence from dose-related effects of methylphenidate.

RATIONALE: The basal ganglia play an important role in motor control, which is dependent on dopaminergic input. Preparation of a motor response has been associated with dopamine release in the basal ganglia, and response readiness may therefore serve as a pharmacodynamic marker of dopamine activity. METHODS: We measured response readiness using the amplitude of the contingent negative variation (CNV), a slow negative shift in the electroencephalogram. The CNV is evoked in a paradigm in which a warning stimulus (S1) signals the occurrence of the imperative stimulus (S2) 4 s later, to which the participant has to respond. CNV was assessed in healthy volunteers after administration of placebo or 10, 20 or 40 mg of methylphenidate, a catecholamine re-uptake blocker which primarily enhances the synaptic concentration of dopamine and to a lesser extent also noradrenaline. In addition, participants filled out two visual analogue scales measuring subjective ratings of mood and alertness: Profile of Mood States and Bond and Lader. RESULTS: Methylphenidate dose dependently increased CNV amplitude and decreased reaction times. Furthermore, participants reported improved mood, feeling more alert, vigorous and content and less angry and tired after methylphenidate. CONCLUSIONS: These results indicate that dopamine availability increases response readiness as measured by the CNV paradigm. The CNV appears to be a good candidate biomarker for assessing changes in dopaminergic function by treatments that either directly or indirectly target the dopaminergic system.

MMN responsivity to manipulations of frequency and duration deviants in chronic, clozapine-treated schizophrenia patients.

Event-related potential (ERP) probing of abnormal sensory processes in schizophrenia with the mismatch negativity (MMN) has shown impairments in auditory change detection, but knowledge of the acoustic features leading to this deficit is incomplete. Changes in the duration and frequency properties of sound stimuli result in diminished MMNs in schizophrenia but it is unclear as to whether this reduced responsiveness is seen with more subtle changes in sound frequency. In a sample of 19 healthy controls and 21 patients with chronic schizophrenia treated with clozapine, MMN was assessed in response to tone frequency changes of 5%, 10% and 20%, and to tone duration changes. Patients exhibited reduced amplitudes and shorter latencies than controls to all frequency changes, and attenuated amplitudes to tone duration increments and decrements. Clozapine dose was related to MMN, with increasing dose being positively associated with frequency-MMN amplitudes (10% ∆f, 20% ∆f) and negatively associated with the amplitude and latency of duration-MMNs. These data support the well-established findings of auditory sensory abnormality in schizophrenia and underscore the sensitivity of MMN to relatively small auditory change detection deficits that may appear to characterize chronic schizophrenia.