Sakari Leino

Representation of harmony rules in the human brain: Further evidence from event-related potentials

In Western tonal music, the rules of harmony determine the order and music-structural importance of events in a musical piece: for instance, the tonic chord, built on the first note of the diatonic scale, is usually placed at the end of chord sequences. A brain response termed the early right anterior negativity (ERAN) is elicited when a harmonically incongruous chord is inserted within or at the end of a musical sequence. The present study was conducted to test whether the ERAN reflects the processing of harmony rather than the building of a tonal context and whether the ERAN is also elicited by violations of the tuning of the sounds upon which harmony is based. To this aim, ten subjects listened to musical sequences containing either expected chords only, a harmonically incongruous chord in one of three positions within the cadence, or a harmonically congruous but mistuned chord in one of the three positions. Simultaneously, the electroencephalograph (EEG) was recorded. Incongruous chords violating the rules of harmony elicited a bilateral early anterior negativity, the amplitude of which depended on the degree of the harmony violation. On the contrary, mistuned chords, violating the rule of relations between all the sounds in the sequences, elicited a bilateral fronto-central negativity (the mismatch negativity, or MMN). The MMN was not modulated by the position of the violation within the musical sequence and had a longer peak latency than the anterior negativity elicited by the harmony rule violations. In conclusion, violations of the harmony and tuning rules of Western tonal music were found to generate specific and distinct electric responses in the human brain.

Event-related potentials suggest early interaction between syntax and semantics during on-line sentence comprehension.

Event-related potentials (ERPs) were used to investigate interaction between syntactic parsing and semantic integration processes during a visual sentence comprehension task. The linguistic stimuli were Finnish five-word sentences containing morphosyntactic and/or semantic violations. Single morphosyntactic violations evoked left anterior negativity (LAN) and P600 components. Single semantic violations elicited a robust N400 effect over the left hemisphere. A later and weaker N400-like response was also observed in the right hemisphere, left-right hemispheric latency difference being 40 ms. Combined morphosyntactic and semantic violations elicited a P600 component and a negative ERP component within the latency range of the LAN and N400 components. Further analysis of these ERP effects provided evidence for early processual interaction between syntax and semantics during on-line sentence comprehension. The hemispheric distribution of the LAN and N400 components was taken to suggest lateralization of initial morphosyntactic parsing and semantic integration processes to the left hemisphere. In contrast, the later syntax-related P600 component was observed as being more pronounced over the posterior areas of the right hemisphere.

Distinct neural responses to chord violations: A multiple source analysis study

The human brain is constantly predicting the auditory environment by representing sequential similarities and extracting temporal regularities. It has been proposed that simple auditory regularities are extracted at lower stations of the auditory cortex and more complex ones at other brain regions, such as the prefrontal cortex. Deviations from auditory regularities elicit a family of early negative electric potentials distributed over the frontal regions of the scalp. In this study, we wished to disentangle the brain processes associated with sequential vs. hierarchical auditory regularities in a musical context by studying the event-related potentials (ERPs), the behavioral responses to violations of these regularities, and the localization of the underlying ERP generators using two different source analysis algorithms. To this aim, participants listened to musical cadences constituted by seven chords, each containing either harmonically congruous chords, harmonically incongruous chords, or harmonically congruous but mistuned chords. EEG was recorded and multiple source analysis was performed. Incongruous chords violating the rules of harmony elicited a bilateral ERAN, whereas mistuned chords within chord sequences elicited a right-lateralized MMN. We found that the dominant cortical sources for the ERAN were localized around Brocas area and its right homolog, whereas the MMN generators were localized around the primary auditory cortex. These findings suggest a predominant role of the auditory cortices in detecting sequential scale regularities and the posterior prefrontal cortex in parsing hierarchical regularities in music.

Cortical sensitivity to periodicity of speech sounds

Previous non-invasive brain research has reported auditory cortical sensitivity to periodicity as reflected by larger and more anterior responses to periodic than to aperiodic vowels. The current study investigated whether there is a lower fundamental frequency (F0) limit for this effect. Auditory evoked fields (AEFs) elicited by natural-sounding 400 ms periodic and aperiodic vowel stimuli were measured with magnetoencephalography. Vowel F0 ranged from normal male speech (113 Hz) to exceptionally low values (9 Hz). Both the auditory N1m and sustained fields were larger in amplitude for periodic than for aperiodic vowels. The AEF sources for periodic vowels were also anterior to those for the aperiodic vowels. Importantly, the AEF amplitudes and locations were unaffected by the F0 decrement of the periodic vowels. However, the N1m latency increased monotonically as F0 was decreased down to 19 Hz, below which this trend broke down. Also, a cascade of transient N1m-like responses was observed in the lowest F0 condition. Thus, the auditory system seems capable of extracting the periodicity even from very low F0 vowels. The behavior of the N1m latency and the emergence of a response cascade at very low F0 values may reflect the lower limit of pitch perception.

The right-hemispheric auditory cortex in humans is sensitive to degraded speech sounds

We investigated how degraded speech sounds activate the auditory cortices of the left and right hemisphere. To degrade the stimuli, we introduce uniform scalar quantization, a controlled and replicable manipulation, not used before, in cognitive neuroscience. Three Finnish vowels (/a/, /e/ and /u/) were used as stimuli for 10 participants in magnetoencephalography registrations. Compared with the original vowel sounds, the degraded sounds increased the amplitude of the right-hemispheric N1m without affecting the latency whereas the amplitude and latency of the N1m in the left hemisphere remained unaffected. Although the participants were able to identify the stimuli correctly, the increased degradation led to increased reaction times which correlated positively with the N1m amplitude. Thus, the auditory cortex of right hemisphere might be particularly involved in processing degraded speech and possibly compensates for the poor signal quality by increasing its activity.

Low micromolar Ba2+ potentiates glutamate transporter current in hippocampal astrocytes

Glutamate uptake, mediated by electrogenic glutamate transporters largely localized in astrocytes, is responsible for the clearance of glutamate released during excitatory synaptic transmission. Glutamate uptake also determines the availability of glutamate for extrasynaptic glutamate receptors. The efficiency of glutamate uptake is commonly estimated from the amplitude of transporter current recorded in astrocytes. We recorded currents in voltage-clamped hippocampal CA1 stratum radiatum astrocytes in rat hippocampal slices induced by electrical stimulation of the Schaffer collaterals. A Ba2+-sensitive K+ current mediated by inward rectifying potassium channels (Kir) accompanied the transporter current. Surprisingly, Ba2+ not only suppressed the K+ current and changed holding current (presumably, mediated by Kir) but also increased the transporter current at lower concentrations. However, Ba2+ did not significantly increase the uptake of aspartate in cultured astrocytes, suggesting that increase in the amplitude of the transporter current does not always reflect changes in glutamate uptake.

Effects of antidyskinetic nicotine treatment on dopamine release in dorsal and ventral striatum

The treatment of Parkinsons disease is often complicated by levodopa-induced dyskinesia (LID), and antidyskinetic treatment options are currently sparse. Nicotinic acetylcholine receptors have been suggested as potential targets for treatment of LID, as nicotinic agonists have been reported to alleviate LID in animal models. We aimed at the first independent replication of an antidyskinetic effect by nicotine using a mouse model of LID, and at investigation of its mechanisms by studying the release of [3H]dopamine from synaptosomes prepared from the dorsal and ventral striatum. Chronic nicotine treatment in drinking water inhibited the development of LID in mice lesioned unilaterally with 6-hydroxydopamine and treated chronically with levodopa and benserazide. The antidyskinetic nicotine treatment had no effect on [3H]dopamine release mediated by α4β2* nicotinic receptors, but decreased α6β2*-mediated [3H]dopamine release in the lesioned dorsal striatum and the ventral striatum. In addition, nicotine treatment restored [3H]dopamine release in the lesioned ventral striatum to intact levels. The results support a role for nicotinic receptors as drug targets for treatment of LID, and suggest that striatal presynaptic α6β2* receptors are important mediators of nicotines antidyskinetic effect.

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons

Histamine H3 receptors are widely distributed Gi-coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H3-modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons.

Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit

ABSTRACT Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinsons disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of &agr;5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinsons disease and levodopa‐induced dyskinesia. Unilateral dopaminergic lesions were induced in wild‐type and &agr;5‐KO mice by 6‐hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa‐induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of &agr;5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian &agr;5‐KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa‐induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in &agr;5‐KO mice. Decreased striatal dopamine uptake in &agr;5‐KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild‐type but not &agr;5‐KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian &agr;5‐KO mice suggests potential for &agr;5 subunit‐containing nicotinic receptors as a novel target in the treatment of Parkinsons disease. HIGHLIGHTSLessened amphetamine‐induced rotational behavior in &agr;5‐KO animals.Reduced levodopa‐induced dyskinesia in &agr;5‐KO animals.Less severe dopaminergic cell loss in the medial substantia nigra in &agr;5‐KO animals.Attenuated hemiparkinsonism suggests &agr;5 as a treatment target for Parkinsons disease.