Effects of Metabotropic Glutamate Receptor 3 Genotype on Phonetic Mismatch Negativity

BACKGROUND: The genetic and molecular basis of glutamatergic dysfunction is one key to understand schizophrenia, with the identification of an intermediate phenotype being an essential step. Mismatch negativity (MMN) or its magnetic counterpart, magnetic mismatch field (MMF) is an index of preattentive change detection processes in the auditory cortex and is generated through glutamatergic neurotransmission. We have previously shown that MMN/MMF in response to phoneme change is markedly reduced in schizophrenia. Variations in metabotropic glutamate receptor (GRM3) may be associated with schizophrenia, and has been shown to affect cortical function. Here we investigated the effect of GRM3 genotypes on phonetic MMF in healthy men. METHODS: MMF in response to phoneme change was recorded using magnetoencephalography in 41 right-handed healthy Japanese men. Based on previous genetic association studies in schizophrenia, 4 candidate SNPs (rs6465084, rs2299225, rs1468412, rs274622) were genotyped. RESULTS: GRM3 rs274622 genotype variations significantly predicted MMF strengths (p = 0.009), with C carriers exhibiting significantly larger MMF strengths in both hemispheres compared to the TT subjects. CONCLUSIONS: These results suggest that variations in GRM3 genotype modulate the auditory cortical response to phoneme change in humans. MMN/MMF, particularly those in response to speech sounds, may be a promising and sensitive intermediate phenotype for clarifying glutamatergic dysfunction in schizophrenia

Doctor of Philosophy

dissertationAbnormalities in language and communication, auditory sensitivity, and complex information processing are associated with autism, yet the neural underpinnings are unknown. The studies in this dissertation examine neurodevelopment of several brain regions implicated in these abnormalities. We first examine age-related changes in midsagittal corpus callosum area in a large cross-sectional cohort from early childhood to adulthood. Increased variability in total corpus callosum area and atypical regional development in the rostrum and isthmus are found in autism compared with typical controls. In autism, larger areas are associated with reduced severity of autism behaviors, higher intelligence, and faster speed of processing, providing support to theories of underconnectivity in the autism brain. Longitudinal maturation of Heschl's gyrus gray matter and white matter and planum temporale during childhood and adolescence in autism and a typically developing sample are then described. Despite previous crosssectional studies reporting typical Heschl's gyrus structure in autism, reduced developmental trajectories in the right gray matter and atypical white matter maturation are identified. Our longitudinal findings also expand on previous reports of reduced planum temporale asymmetry in autism by showing that the reduced asymmetry develops during later childhood and adolescence. In addition to the case-control comparisons, different developmental trajectories in those individuals with autism with delayed versus early language onset in Heschl's gyrus white matter and planum temporale asymmetry iv are apparent. Finally, individuals with autism exhibit associations between smaller Heschl's gyrus volumes and reduced auditory sensitivity and higher language function, and smaller planum temporale volumes associated with increased vocabulary aptitude. Our findings highlight the importance of longitudinal studies of brain development and examining behavioral profiles of individuals to identify functional and maladaptive pathological neurodevelopment

Cognitive Impairments in Schizophrenia as Assessed Through Activation and Connectivity Measures of Magnetoencephalography (MEG) Data

The cognitive dysfunction present in patients with schizophrenia is thought to be driven in part by disorganized connections between higher-order cortical fields. Although studies utilizing electroencephalography (EEG), PET and fMRI have contributed significantly to our understanding of these mechanisms, magnetoencephalography (MEG) possesses great potential to answer long-standing questions linking brain interactions to cognitive operations in the disorder. Many experimental paradigms employed in EEG and fMRI are readily extendible to MEG and have expanded our understanding of the neurophysiological architecture present in schizophrenia. Source reconstruction techniques, such as adaptive spatial filtering, take advantage of the spatial localization abilities of MEG, allowing us to evaluate which specific structures contribute to atypical cognition in schizophrenia. Finally, both bivariate and multivariate functional connectivity metrics of MEG data are useful for understanding how these interactions in the brain are impaired in schizophrenia, and how cognitive and clinical outcomes are affected as a result. We also present here data from our own laboratory that illustrates how some of these novel functional connectivity measures, specifically imaginary coherence (IC), are quite powerful in relating disconnectivity in the brain to characteristic behavioral findings in the disorder

Mismatch Negativity as a Psychophysiological Index of Cognitive Function in Schizophrenia

It is now widely accepted that cognitive deficits, beyond other psychiatric symptoms (e.g., delusion, hallucination, emotional flattening, social withdrawal and apathy), is far most relevant to social functional outcome in schizophrenia. Accordingly, the treatment target has been shifted to the area, developing new drugs that facilitate cognitive function and building up new psychosocial rehabilitation programs that directly approach the cognitive deficits. Despite the desirability to target these deficits, no standard neuropsychological test batteries exist for assessing the level of cognitive function. Mismatch negativity (MMN), an auditory event-related potential component, is a measure of preattentive information processing and its amplitude has repeatedly been demonstrated to be reduced in schizophrenia. MMN deficits are a robust feature in chronic schizophrenia and indicate abnormalities in automatic context-dependent auditory information processing and auditory sensory memory in schizophrenia. Moreover, the deficits have been related to poor social functioning level and social skills acquisition, hypofunction of NMDA system, and illness duration, which indicate the validity of accepting MMN as a biomarker of the disease. In this article, we present a summary of the discussions about the plausibility of MMN to be used as a neurobiological index for assessing the cognitive function and also its predictability of social functional outcome in schizophrenia

Impairment in predictive processes during auditory mismatch negativity in ScZ: evidence from event-related fields

Patients with schizophrenia (ScZ) show pronounced dysfunctions in auditory perception but the underlying mechanisms as well as the localization of the deficit remain unclear. To examine these questions, the current study examined whether alterations in the neuromagnetic mismatch negativity (MMNm) in ScZ-patients could involve an impairment in sensory predictions in local sensory and higher auditory areas. Using a whole-head MEG-approach, we investigated the MMNm as well as P300m and N100m amplitudes during a hierarchical auditory novelty paradigm in 16 medicated ScZ-patients and 16 controls. In addition, responses to omitted sounds were investigated, allowing for a critical test of the predictive coding hypothesis. Source-localization was performed to identify the generators of the MMNm, omission responses as well as the P300m. Clinical symptoms were examined with the positive and negative syndrome scale. Event-related fields (ERFs) to standard sounds were intact in ScZ-patients. However, the ScZ-group showed a reduction in the amplitude of the MMNm during both local (within trials) and global (across trials) conditions as well as an absent P300m at the global level. Importantly, responses to sound omissions were reduced in ScZ-patients which overlapped both in latency and generators with the MMNm sources. Thus, our data suggest that auditory dysfunctions in ScZ involve impaired predictive processes that involve deficits in both automatic and conscious detection of auditory regularities

The neurochemical basis of human cortical auditory processing: combining proton magnetic resonance spectroscopy and magnetoencephalography

BACKGROUND: A combination of magnetoencephalography and proton magnetic resonance spectroscopy was used to correlate the electrophysiology of rapid auditory processing and the neurochemistry of the auditory cortex in 15 healthy adults. To assess rapid auditory processing in the left auditory cortex, the amplitude and decrement of the N1m peak, the major component of the late auditory evoked response, were measured during rapidly successive presentation of acoustic stimuli. We tested the hypothesis that: (i) the amplitude of the N1m response and (ii) its decrement during rapid stimulation are associated with the cortical neurochemistry as determined by proton magnetic resonance spectroscopy. RESULTS: Our results demonstrated a significant association between the concentrations of N-acetylaspartate, a marker of neuronal integrity, and the amplitudes of individual N1m responses. In addition, the concentrations of choline-containing compounds, representing the functional integrity of membranes, were significantly associated with N1m amplitudes. No significant association was found between the concentrations of the glutamate/glutamine pool and the amplitudes of the first N1m. No significant associations were seen between the decrement of the N1m (the relative amplitude of the second N1m peak) and the concentrations of N-acetylaspartate, choline-containing compounds, or the glutamate/glutamine pool. However, there was a trend for higher glutamate/glutamine concentrations in individuals with higher relative N1m amplitude. CONCLUSION: These results suggest that neuronal and membrane functions are important for rapid auditory processing. This investigation provides a first link between the electrophysiology, as recorded by magnetoencephalography, and the neurochemistry, as assessed by proton magnetic resonance spectroscopy, of the auditory cortex

Hallucination Proneness and Musical Aptitude: Functional and Microstructural Underpinnings

The current thesis aimed to explore links between hallucination proneness and musical aptitude utilising a variety of brain imaging methodologies to characterise associated functional and microstructural individual variabilities. A further aim was to investigate whether a short duration of musical training could be used to modulate functional activity and microstructure in regions associated with hallucinatory experiences. It was hypothesised that hallucination proneness and musical aptitude would be negatively associated with each other and inversely related to underlying functional activity and microstructure within a shared network of brain regions. Moreover, it was hypothesised that musical training would lead to changes in functional activity and microstructure within this shared network of regions. Measures of musical aptitude and hallucination proneness were assessed in conjunction with diffusion imaging models which enabled the characterisation of the microstructural features of the corpus callosum. Results revealed an inverse relationship between musical aptitude and hallucination proneness, with a mediating effect of musical aptitude on hallucination proneness through the microstructure of the corpus callosum. The use of a multi-shell biophysical model, based on neurite orientation dispersion density imaging, further revealed that the relationship between hallucination proneness and musical aptitude was primarily due to callosal neurite orientation dispersion rather than neurite density. With the addition of functional connectivity MRI the degree of callosal neurite orientation dispersion also shown to impact on the functional connectivity during a musical categorisation task, such that higher neurite alignment was associated with increased ROI- ROI fronto-temporal functional connectivity. Hallucination proneness was shown to be negatively associated with performance on a speech perception task and functional connectivity between the left IFG and the superior temporal gyrus (STG) (bilaterally) during task completion. Dendritic complexity within the STG grey matter was also found to be negatively associated with individual variability in propensity to hallucinate. Investigations of the effects of exposure to a short musical training session (learning to tap polyrhythms for one hour) provided evidence of an increase in ROI-ROI function within a bilateral network of fronto-temporal regions following training. Moreover, using three distinct but complimentary diffusion imaging models, polyrhythm training was shown to facilitate a decrease in extra-axonal space diffusion in the central portions of the CC which correlated with performance gains on the polyrhythm discrimination task. The overall results of this thesis therefore support the hypothesis that musical aptitude and hallucination proneness are linked and associated with the underlying microstructure of the CC. Moreover, musical aptitude was shown to be positively associated with task based functional fronto-temporal connectivity whereas hallucination proneness was shown to be negatively associated. Hallucination proneness was further shown to be related to microstructure of the STG with orientation dispersion deemed the most sensitive metric for assessing this relationship. Importantly, results offer evidence that musical training may offer a novel approach for improving fronto-temporal functional connectivity and the microstructure of the corpus callosum, providing an initial foundation for investigation of future novel interventions for hallucinatory experiences

Noise sensitivity in the function and structure of the brain

Exposure to noise has a negative influence on human health, including an increased occurrence of cardiovascular diseases. Susceptibility to the harmful effects of noise can be further moderated by a personal trait called noise sensitivity (NS). It is not understood what makes some individuals more sensitive to noise than others. So far, the research on this topic has been largely limited to perceptual and population studies. The aim of this thesis was to broaden the understanding of NS by addressing its biological mechanisms. Thus, this thesis investigated the neuroanatomical correlates of NS and its effects on auditory processing. The thesis consists of three studies. The first study examines whether NS can be developed as the result of musical training (Study I). The other two studies investigate whether NS is reflected in the functioning of the central auditory system (Study II) and whether it is related to the morphology of cortical and subcortical brain structures (Study III). The research was conducted using questionnaires, combined magneto- and electroencephalography (MEG/EEG) and magnetic resonance imaging (MRI). The findings of this thesis suggest that NS moderates how and why individuals listen to music. However, NS is not associated with musical training and thus does not seem to relate to fine perceptual skills (Study I). An investigation of the central auditory processing in Study II, however, revealed compromised sound feature encoding and automatic discrimination skills in noise-sensitive individuals. Study III showed that NS is also associated with the structural organization of the brain. Noise-sensitive individuals were found to have enlarged volumes of the auditory cortical areas and hippocampus as well as thicker right anterior insular cortex. These results suggest that NS is related to the structures involved with auditory perceptual, emotional, and interoceptive processing. Overall, this thesis proposes that NS is not merely an attitudinal phenomenon but instead has underlying neuronal mechanisms.Altistuminen melulle vaikuttaa negatiivisesti ihmisten terveyteen, muun muassa kohonneena riskinä sydän- ja verisuonitaudeille. Meluherkkyys on persoonallisuuden piirre, joka voi vaikuttaa alttiuteen melusta koituville haitoille. Syytä sille, mikä tekee toisista herkempiä melulle, ei tiedetä. Tähän mennessä asiaa on selvitetty lähinnä melun havaintokykyä ja sen esiintymistä väestössä kartoittavien tutkimusten avulla. Tämän väitöskirjan tavoitteena oli lisätä tietoa meluherkkyyden biologisista mekanismeista. Väitöskirjassa tutkittiin meluherkkyyteen liittyviä aivojen rakenteita sekä meluherkkyyden vaikutusta kuulotiedon käsittelyyn. Väitöskirja koostuu kolmesta osatutkimuksesta. Ensimmäisessä tutkimuksessa selvitettiin, voiko meluherkkyys kehittyä musiikin harjoittelun seurauksena (Tutkimus I). Kahdessa muussa osatutkimuksessa selvitettiin, heijastuuko meluherkkyys aivojen kuulojärjestelmän toimintaan (Tutkimus II), ja liittyykö se aivokuoren ja sen alaisiin rakenteisiin (Tutkimus III). Tutkimukset suoritettiin käyttämällä kyselytutkimuksia, yhdistettyä aivosähkökäyrää ja sen magneettista vastinetta, eli elektro- ja magnetoenkefalografiaa (EEG/MEG), sekä aivojen magneettikuvausta (MRI). Tämän väitöskirjan tulosten mukaan meluherkkyys vaikuttaa siihen, miten ja miksi ihmiset kuuntelevat musiikkia. Meluherkkyys ei kuitenkaan liity musiikin harjoitteluun eikä täten liene yhteydessä hienovaraiseen kuulohavaintokykyyn (Tutkimus I). Tutkimus II kuitenkin paljasti, että äänten erottelukyky ja äänipiirteiden koodaus aivoissa on heikentynyttä meluherkillä yksilöillä. Tutkimuksessa III osoitettiin, että meluherkkyys on myös yhteydessä aivorakenteiden järjestäytymiseen. Meluherkillä löydettiin suurentunut kuuloaivokuoren ja hippokampuksen tilavuus sekä paksumpi oikean etuaivopuoliskon aivosaari. Näiden tulosten mukaan meluherkkyys on yhteydessä rakenteisiin, jotka osallistuvat äänten havaitsemiseen sekä niiden tunneperäistä ja elimellistä tietoa välittävään tiedonkäsittelyyn. Kaiken kaikkiaan tässä väitöskirjassa esitetään, että meluherkkyydellä on hermostollista taustaa eikä se ole pelkästään negatiivinen asenne melua kohtaan