Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Cortical processing of speech and non-speech sounds in adults and newborns

Comprehension of a complex acoustic signal - speech - is vital for human communication, with numerous brain processes required to convert the acoustics into an intelligible message. In four studies in the present thesis, cortical correlates for different stages of speech processing in a mature linguistic system of adults were investigated. In two further studies, developmental aspects of cortical specialisation and its plasticity in adults were examined. In the present studies, electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings of the mismatch negativity (MMN) response elicited by changes in repetitive unattended auditory events and the phonological mismatch negativity (PMN) response elicited by unexpected speech sounds in attended speech inputs served as the main indicators of cortical processes. Changes in speech sounds elicited the MMNm, the magnetic equivalent of the electric MMN, that differed in generator loci and strength from those elicited by comparable changes in non-speech sounds, suggesting intra- and interhemispheric specialisation in the processing of speech and non-speech sounds at an early automatic processing level. This neuronal specialisation for the mother tongue was also reflected in the more efficient formation of stimulus representations in auditory sensory memory for typical native-language speech sounds compared with those formed for unfamiliar, non-prototype speech sounds and simple tones. Further, adding a speech or non-speech sound context to syllable changes was found to modulate the MMNm strength differently in the left and right hemispheres. Following the acoustic-phonetic processing of speech input, phonological effort related to the selection of possible lexical (word) candidates was linked with distinct left-hemisphere neuronal populations. In summary, the results suggest functional specialisation in the neuronal substrates underlying different levels of speech processing. Subsequently, plasticity of the brain's mature linguistic system was investigated in adults, in whom representations for an aurally-mediated communication system, Morse code, were found to develop within the same hemisphere where representations for the native-language speech sounds were already located. Finally, recording and localization of the MMNm response to changes in speech sounds was successfully accomplished in newborn infants, encouraging future MEG investigations on, for example, the state of neuronal specialisation at birth.

Cortical processing of speech and non-speech sounds in autism and Asperger syndrome

Autism and Asperger syndrome (AS) are neurodevelopmental disorders characterised by deficient social and communication skills, as well as restricted, repetitive patterns of behaviour. The language development in individuals with autism is significantly delayed and deficient, whereas in individuals with AS, the structural aspects of language develop quite normally. Both groups, however, have semantic-pragmatic language deficits. The present thesis investigated auditory processing in individuals with autism and AS. In particular, the discrimination of and orienting to speech and non-speech sounds was studied, as well as the abstraction of invariant sound features from speech-sound input. Altogether five studies were conducted with auditory event-related brain potentials (ERP); two studies also included a behavioural sound-identification task. In three studies, the subjects were children with autism, in one study children with AS, and in one study adults with AS. In children with autism, even the early stages of sound encoding were deficient. In addition, these children had altered sound-discrimination processes characterised by enhanced spectral but deficient temporal discrimination. The enhanced pitch discrimination may partly explain the auditory hypersensitivity common in autism, and it may compromise the filtering of relevant auditory information from irrelevant information. Indeed, it was found that when sound discrimination required abstracting invariant features from varying input, children with autism maintained their superiority in pitch processing, but lost it in vowel processing. Finally, involuntary orienting to sound changes was deficient in children with autism in particular with respect to speech sounds. This finding is in agreement with previous studies on autism suggesting deficits in orienting to socially relevant stimuli. In contrast to children with autism, the early stages of sound encoding were fairly unimpaired in children with AS. However, sound discrimination and orienting were rather similarly altered in these children as in those with autism, suggesting correspondences in the auditory phenotype in these two disorders which belong to the same continuum. Unlike children with AS, adults with AS showed enhanced processing of duration changes, suggesting developmental changes in auditory processing in this disorder.

Determinants of vascular cognitive impairment : White matter lesions, brain atrophy and their neuropsychological correlates

The concept of vascular cognitive impairment (VCI) covers a wide spectrum of cognitive dysfunctions related to cerebrovascular disease. Among the pathophysiological determinants of VCI are cerebral stroke, white matter lesions and brain atrophy, which are known to be important risk factors for dementia. However, the specific mechanisms behind the brain abnormalities and cognitive decline are still poorly understood. The present study investigated the neuropsychological correlates of particular magnetic resonance imaging (MRI) findings, namely, medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), general cortical atrophy and corpus callosum (CC) atrophy in subjects with cerebrovascular disease. Furthermore, the cognitive profile of subcortical ischaemic vascular disease (SIVD) was examined. This study was conducted as part of two large multidisciplinary study projects, the Helsinki Stroke Aging Memory (SAM) Study and the multinational Leukoaraiosis and Disability (LADIS) Study. The SAM cohort consisted of 486 patients, between 55 and 85 years old, with ischaemic stroke from the Helsinki University Hospital, Helsinki, Finland. The LADIS Study included a mixed sample of subjects (n=639) with age-related WMH, between 65 and 84 years old, gathered from 11 centres around Europe. Both studies included comprehensive clinical and neuropsychological assessments and detailed brain MRI. The relationships between the MRI findings and the neuropsychological test performance were analysed by controlling for relevant confounding factors such as age, education and other coexisting brain lesions. The results revealed that in elderly patients with ischaemic stroke, moderate to severe MTA was specifically related to impairment of memory and visuospatial functions, but mild MTA had no clinical relevance. Instead, WMH were primarily associated with executive deficits and mental slowing. These deficits mediated the relationship between WMH and other, secondary cognitive deficits. Cognitive decline was best predicted by the overall degree of WMH, whereas the independent contribution of regional WMH measures was low. Executive deficits were the most prominent cognitive characteristic in SIVD. Compared to other stroke patients, the patients with SIVD also presented more severe memory deficits, which were related to MTA. The cognitive decline in SIVD occurred independently of depressive symptoms and, relative to healthy control subjects, it was substantial in severity. In stroke patients, general cortical atrophy also turned out to be a strong predictor of cognitive decline in a wide range of cognitive domains. Moreover, in elderly subjects with WMH, overall CC atrophy was related to reduction in mental speed, while anterior CC atrophy was independently associated with frontal lobe-mediated executive functions and attention. The present study provides cross-sectional evidence for the involvement of WMH, MTA, general cortical atrophy and CC atrophy in VCI. The results suggest that there are multifaceted pathophysiological mechanisms behind VCI in the elderly, including both vascular ischaemic lesions and neurodegenerative changes. The different pathological changes are highly interrelated processes and together they may produce cumulative effects on cognitive decline.

Social perception and cognition : processing of gestures, postures and facial expressions in the human brain

Humans are a social species with the internal capability to process social information from other humans. To understand others behavior and to react accordingly, it is necessary to infer their internal states, emotions and aims, which are conveyed by subtle nonverbal bodily cues such as postures, gestures, and facial expressions. This thesis investigates the brain functions underlying the processing of such social information. Studies I and II of this thesis explore the neural basis of perceiving pain from another person s facial expressions by means of functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). In Study I, observing another s facial expression of pain activated the affective pain system (previously associated with self-experienced pain) in accordance with the intensity of the observed expression. The strength of the response in anterior insula was also linked to the observer s empathic abilities. The cortical processing of facial pain expressions advanced from the visual to temporal-lobe areas at similar latencies (around 300 500 ms) to those previously shown for emotional expressions such as fear or disgust. Study III shows that perceiving a yawning face is associated with middle and posterior STS activity, and the contagiousness of a yawn correlates negatively with amygdalar activity. Study IV explored the brain correlates of interpreting social interaction between two members of the same species, in this case human and canine. Observing interaction engaged brain activity in very similar manner for both species. Moreover, the body and object sensitive brain areas of dog experts differentiated interaction from noninteraction in both humans and dogs whereas in the control subjects, similar differentiation occurred only for humans. Finally, Study V shows the engagement of the brain area associated with biological motion when exposed to the sounds produced by a single human being walking. However, more complex pattern of activation, with the walking sounds of several persons, suggests that as the social situation becomes more complex so does the brain response. Taken together, these studies demonstrate the roles of distinct cortical and subcortical brain regions in the perception and sharing of others internal states via facial and bodily gestures, and the connection of brain responses to behavioral attributes.

Cortical processing of musical pitch as reflected by behavioural and electrophysiological evidence

In a musical context, the pitch of sounds is encoded according to domain-general principles not confined to music or even to audition overall but common to other perceptual and cognitive processes (such as multiple pattern encoding and feature integration), and to domain-specific and culture-specific properties related to a particular musical system only (such as the pitch steps of the Western tonal system). The studies included in this thesis shed light on the processing stages during which pitch encoding occurs on the basis of both domain-general and music-specific properties, and elucidate the putative brain mechanisms underlying pitch-related music perception. Study I showed, in subjects without formal musical education, that the pitch and timbre of multiple sounds are integrated as unified object representations in sensory memory before attentional intervention. Similarly, multiple pattern pitches are simultaneously maintained in non-musicians' sensory memory (Study II). These findings demonstrate the degree of sophistication of pitch processing at the sensory memory stage, requiring neither attention nor any special expertise of the subjects. Furthermore, music- and culture-specific properties, such as the pitch steps of the equal-tempered musical scale, are automatically discriminated in sensory memory even by subjects without formal musical education (Studies III and IV). The cognitive processing of pitch according to culture-specific musical-scale schemata hence occurs as early as at the sensory-memory stage of pitch analysis. Exposure and cortical plasticity seem to be involved in musical pitch encoding. For instance, after only one hour of laboratory training, the neural representations of pitch in the auditory cortex are altered (Study V). However, faulty brain mechanisms for attentive processing of fine-grained pitch steps lead to inborn deficits in music perception and recognition such as those encountered in congenital amusia (Study VI). These findings suggest that predispositions for exact pitch-step discrimination together with long-term exposure to music govern the acquisition of the automatized schematic knowledge of the music of a particular culture that even non-musicians possess.

Human brain mechanisms of auditory and audiovisual selective attention

Selective attention refers to the process in which certain information is actively selected for conscious processing, while other information is ignored. The aim of the present studies was to investigate the human brain mechanisms of auditory and audiovisual selective attention with functional magnetic resonance imaging (fMRI), electroencephalography (EEG) and magnetoencephalography (MEG). The main focus was on attention-related processing in the auditory cortex. It was found that selective attention to sounds strongly enhances auditory cortex activity associated with processing the sounds. In addition, the amplitude of this attention-related modulation was shown to increase with the presentation rate of attended sounds. Attention to the pitch of sounds and to their location appeared to enhance activity in overlapping auditory-cortex regions. However, attention to location produced stronger activity than attention to pitch in the temporo-parietal junction and frontal cortical regions. In addition, a study on bimodal attentional selection found stronger audiovisual than auditory or visual attention-related modulations in the auditory cortex. These results were discussed in light of Näätänen s attentional-trace theory and other research concerning the brain mechanisms of selective attention.

Cortical representations for phonological quantity

Different languages use temporal speech cues in different linguistic functions. In Finnish, speech-sound duration is used as the primary cue for the phonological quantity distinction ― i.e., a distinction between short and long phonemes. For the second-language (L2) learners of Finnish, quantity is often difficult to master if speech-sound duration plays a less important role in the phonology of their native language (L1). The present studies aimed to investigate the cortical representations for phonological quantity in native speakers and L2 users of Finnish by using behavioral and electrophysiological methods. Since long-term memory representations for different speech units have been previously shown to participate in the elicitation of the mismatch negativity (MMN) brain response, MMN was used to compare the neural representation for quantity between native speakers and L2 users of Finnish. The results of the studies suggested that native Finnish speakers' MMN response to quantity was determined by the activation of native-language phonetic prototypes rather than by phoneme boundaries. In addition, native speakers seemed to process phoneme quantity and quality independently from each other by separate brain representations. The cross-linguistic MMN studies revealed that, in native speakers of Finnish, the MMN response to duration or quantity-degree changes was enhanced in amplitude selectively in speech sounds, whereas this pattern was not observed in L2 users. Native speakers' MMN enhancement is suggested to be due to the pre-attentive activation of L1 prototypes for quantity. In L2 users, the activation of L2 prototypes or other L2 learning effects were not reflected in the MMN, with one exception. Even though L2 users failed to show native-like brain responses to duration changes in a vowel that was similar in L1 and L2, their duration MMN response was native-like for an L2 vowel with no counterpart in L1. Thus, the pre-attentive activation of L2 users' representations was determined by the degree of similarity of L2 sounds to L1 sounds. In addition, behavioral experiments suggested that the establishment of representations for L2 quantity may require several years of language exposure.

Cellular Mechanisms of Sleep Homeostasis : Studies on Brain Energy Metabolism and Aging

Sleep is governed by a homeostatic process in which the duration and quality of previous wake regulate the subsequent sleep. Active wakefulness is characterized with high frequency cortical oscillations and depends on stimulating influence of the arousal systems, such as the cholinergic basal forebrain (BF), while cessation of the activity in the arousal systems is required for slow wave sleep (SWS) to occur. The site-specific accumulation of adenosine (a by-product of ATP breakdown) in the BF during prolonged waking /sleep deprivation (SD) is known to induce sleep, thus coupling energy demand to sleep promotion. The adenosine release in the BF is accompanied with increases in extracellular lactate and nitric oxide (NO) levels. This thesis was aimed at further understanding the cellular processes by which the BF is involved in sleep-wake regulation and how these processes are affected by aging. The BF function was studied simultaneously at three levels of organization: 1) locally at a cellular level by measuring energy metabolites 2) globally at a cortical level (the out-put area of the BF) by measuring EEG oscillations and 3) at a behavioral level by studying changes in vigilance states. Study I showed that wake-promoting BF activation, particularly with glutamate receptor agonist N-methyl-D-aspatate (NMDA), increased extracellular adenosine and lactate levels and led to a homeostatic increase in the subsequent sleep. Blocking NMDA activation during SD reduced the high frequency (HF) EEG theta (7-9 Hz) power and attenuated the subsequent sleep. In aging, activation of the BF during SD or experimentally with NMDA (studies III, IV), did not induce lactate or adenosine release and the increases in the HF EEG theta power during SD and SWS during the subsequent sleep were attenuated as compared to the young. These findings implicate that increased or continuous BF activity is important for active wake maintenance during SD as well as for the generation of homeostatic sleep pressure, and that in aging these mechanisms are impaired. Study II found that induction of the inducible NO synthase (iNOS) during SD is accompanied with activation of the AMP-activated protein kinase (AMPK) in the BF. Because decreased cellular energy charge is the most common cause for AMPK activation, this finding implicates that the BF is selectively sensitive to the metabolic demands of SD as increases were not found in the cortex. In aging (study III), iNOS expression and extracellular levels of NO and adenosine were not significantly increased during SD in the BF. Furthermore, infusion of NO donor into the BF did not lead to sleep promotion as it did in the young. These findings indicated that the NO (and adenosine) mediated sleep induction is impaired in aging and that it could at least partly be due to the reduced sensitivity of the BF to sleep-inducing factors. Taken together, these findings show that reduced sleep promotion by the BF contributes to the attenuated homeostatic sleep response in aging.

Developmental, functional brain imaging and electrophysiological evidence of visual and auditory working memory

Intact function of working memory (WM) is essential for children and adults to cope with every day life. Children with deficits in WM mechanisms have learning difficulties that are often accompanied by behavioral problems. The neural processes subserving WM, and brain structures underlying this system, continue to develop during childhood till adolescence and young adulthood. With functional magnetic resonance imaging (fMRI) it is possible to investigate the organization and development of WM. The present thesis aimed to investigate, using behavioral and neuroimaging methods, whether mnemonic processing of spatial and nonspatial visual information is segregated in the developing and mature human brain. A further aim in this research was to investigate the organization and development of audiospatial and visuospatial information processing in WM. The behavioral results showed that spatial and nonspatial visual WM processing is segregated in the adult brain. The fMRI result in children suggested that memory load related processing of spatial and nonspatial visual information engages common cortical networks, whereas selective attention to either type of stimuli recruits partially segregated areas in the frontal, parietal and occipital cortices. Deactivation mechanisms that are important in the performance of WM tasks in adults are already operational in healthy school-aged children. Electrophysiological evidence suggested segregated mnemonic processing of visual and auditory location information. The results of the development of audiospatial and visuospatial WM demonstrate that WM performance improves with age, suggesting functional maturation of underlying cognitive processes and brain areas. The development of the performance of spatial WM tasks follows a different time course in boys and girls indicating a larger degree of immaturity in the male than female WM systems. Furthermore, the differences in mastering auditory and visual WM tasks may indicate that visual WM reaches functional maturity earlier than the corresponding auditory system. Spatial WM deficits may underlie some learning difficulties and behavioral problems related to impulsivity, difficulties in concentration, and hyperactivity. Alternatively, anxiety or depressive symptoms may affect WM function and the ability to concentrate, being thus the primary cause of poor academic achievement in children.

Brain imaging of chronic pain

Acute pain has substantial survival value because of its protective function in the everyday environment. Instead, chronic pain lacks survival and adaptive function, causes great amount of individual suffering, and consumes the resources of the society due to the treatment costs and loss of production. The treatment of chronic pain has remained challenging because of inadequate understanding of mechanisms working at different levels of the nervous system in the development, modulation, and maintenance of chronic pain. Especially in unclear chronic pain conditions the treatment may be suboptimal because it can not be targeted to the underlying mechanisms. Noninvasive neuroimaging techniques have greatly contributed to our understanding of brain activity associated with pain in healthy individuals. Many previous studies, focusing on brain activations to acute experimental pain in healthy individuals, have consistently demonstrated a widely-distributed network of brain regions that participate in the processing of acute pain. The aim of the present thesis was to employ non-invasive brain imaging to better understand the brain mechanisms in patients suffering from chronic pain. In Study I, we used magnetoencephalography (MEG) to measure cortical responses to painful laser stimulation in healthy individuals for optimization of the stimulus parameters for patient studies. In Studies II and III, we monitored with MEG the cortical processing of touch and acute pain in patients with complex regional pain syndrome (CRPS). We found persisting plastic changes in the hand representation area of the primary somatosensory (SI) cortex, suggesting that chronic pain causes cortical reorganization. Responses in the posterior parietal cortex to both tactile and painful laser stimulation were attenuated, which could be associated with neglect-like symptoms of the patients. The primary motor cortex reactivity to acute pain was reduced in patients who had stronger spontaneous pain and weaker grip strength in the painful hand. The tight coupling between spontaneous pain and motor dysfunction supports the idea that motor rehabilitation is important in CRPS. In Studies IV and V we used MEG and functional magnetic resonance imaging (fMRI) to investigate the central processing of touch and acute pain in patients who suffered from recurrent herpes simplex virus infections and from chronic widespread pain in one side of the body. With MEG, we found plastic changes in the SI cortex, suggesting that many different types of chronic pain may be associated with similar cortical reorganization. With fMRI, we found functional and morphological changes in the central pain circuitry, as an indication of central contribution for the pain. These results show that chronic pain is associated with morphological and functional changes in the brain, and that such changes can be measured with functional imaging.

Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.