Human brain networks of auditory attention and working memory

This thesis examines brain networks involved in auditory attention and auditory working memory using measures of task performance, brain activity, and neuroanatomical connectivity. Auditory orienting and maintenance of attention were compared with visual orienting and maintenance of attention, and top-down controlled attention was compared to bottom-up triggered attention in audition. Moreover, the effects of cognitive load on performance and brain activity were studied using an auditory working memory task. Corbetta and Shulman s (2002) model of visual attention suggests that what is known as the dorsal attention system (intraparietal sulcus/superior parietal lobule, IPS/SPL and frontal eye field, FEF) is involved in the control of top-down controlled attention, whereas what is known as the ventral attention system (temporo-parietal junction, TPJ and areas of the inferior/middle frontal gyrus, IFG/MFG) is involved in bottom-up triggered attention. The present results show that top-down controlled auditory attention also activates IPS/SPL and FEF. Furthermore, in audition, TPJ and IFG/MFG were activated not only by bottom-up triggered attention, but also by top-down controlled attention. In addition, the posterior cerebellum and thalamus were activated by top-down controlled attention shifts and the ventromedial prefrontal cortex (VMPFC) was activated by to-be-ignored, but attention-catching salient changes in auditory input streams. VMPFC may be involved in the evaluation of environmental events causing the bottom-up triggered engagement of attention. Auditory working memory activated a brain network that largely overlapped with the one activated by top-down controlled attention. The present results also provide further evidence of the role of the cerebellum in cognitive processing: During auditory working memory tasks, both activity in the posterior cerebellum (the crus I/II) and reaction speed increased when the cognitive load increased. Based on the present results and earlier theories on the role of the cerebellum in cognitive processing, the function of the posterior cerebellum in cognitive tasks may be related to the optimization of response speed.

Temporal acuity in developmental dyslexia across the life span : Tactile, auditory, visual, and crossmodal estimations

Taustaa Kehityksellinen dysleksia (lukivaikeus) on erityinen lukemaan oppimisen vaikeus, johon liittyy usein myös vaikeuksia kirjoittamaan oppimisessa. Lukivaikeuden oletetaan useissa tapauksissa johtuvan vaikeudesta käsitellä kielen äännerakenteita (fonologinen prosessointi). Tämä poikkeavuus voi olla joko lukivaikeuden perimmäinen syy tai vaihtoehtoisesti ongelmat äänteiden käsittelyssä voivat heijastaa jotain vielä perustavamman tason vaikeutta. Eräs tällainen ehdotettu perustavan tasoin syy on poikkeavuus aistien toiminnoissa, erityisesti aistien aikatarkkuudessa. Aikatarkkuudella tarkoitetaan kykyä ja rajoja siinä, kuinka nopeasti esitettyä aistitiedon virtaa henkilö kykenee vastaanottamaan ja käsittelemään. Monet arjen toiminnot lukemisen rinnalla edellyttävät aistien erittäin tarkkaa ajallista erottelukykyä (esimerkiksi kuulo puheen ymmärtämisessä, tunto pintamateriaalin tunnistamisessa). Aikatarkkuusvaikeuksien esiintyvyyttä lukivaikeudessa on tutkittu aiemminkin, mutta yksimielisyyteen ei ole päästy siitä, onko kaikilla lukivaikeuksisilla näitä ongelmia tai mihin aisteihin vaikeudet mahdollisesti rajoittuvat. Myöskään ei tiedetä, havaitaanko aikatarkkuuden ongelmia kaiken ikäisillä lukivaikeuksisilla vai vaihteleeko mahdollinen ongelmien kuva iän mukana. Lisäksi on epäselvää, kuinka aikatarkkuuden ongelmat itseasiassa ovat yhteydessä kielen käsittelyn ja varsinaisen lukemisen vaikeuksiin. Tutkimussarjan aihe Tässä tutkimussarjassa aikatarkkuutta tutkittiin kolmessa yksittäisessä aistissa, joita olivat tunto, näkö ja kuulo, sekä kolmessa aistien välisessä yhdistelmässä, joita olivat audiotaktiilinen (kuulo-tunto), visuotaktiilinen (näkö-tunto) ja audiovisuaalinen (näkö-kuulo). Aikatarkkuutta arvioitiin kahdella eri menetelmällä, jotta saataisiin lisää tietoa siitä, missä tietyssä aikatarkkuuden osa-alueessa lukivaikeuksisilla mahdollisesti on vaikeuksia. Ensimmäisessä tehtävässä tutkittavan tuli arvioida, ovatko esitetyt ei-kielelliset ärsykkeet samanaikaisia vai eriaikaisia. Toisessa tehtävässä koehenkilön tuli arvioida esitettyjen ei-kielellisten ärsykkeiden esitysjärjestys. Molemmissa tehtävissä määriteltiin millisekuntitasolla (sekunnin tuhannesosa) se esitysnopeus, jolla koehenkilö kykeni arvioimaan ärsykkeiden ajalliset suhteet oikein. Englanninkielinen demonstraatio aikatarkkuustehtävistä löytyy internetistä (http://www.helsinki.fi/hum/ylpsy/neuropsy). Itse aikatarkkuustehtävien lisäksi tutkimussarjassa arvioitiin tutkimushenkilöiden päättelykykyä, kielellisiä toimintoja ja lukemista. Tutkimushenkilöt Tutkimuksiin osallistui 53 lukivaikeuksista ja 66 sujuvaa lukijaa, jotka oli jaettu kolmeen pääikäryhmään: lapset (8-12 vuotta), nuoret aikuiset (20-36 vuotta) ja ikääntyneemmät aikuiset (20-59 vuotta). Ikääntyneempien aikuisten ryhmä oli edelleen jaettu ikävuosikymmenluokkiin, mikä mahdollisti sen tutkimisen, vaikuttaako lisääntyvä aikuisikä lukivaikeuksisten aikatarkkuuteen (20-29, 30-39, 40-49 ja 50-59 -vuotiaat). Tutkimussarjan tulokset Aikatarkkuuden ongelmat lukivaikeuksisilla olivat yleistyneitä yli iän, aistien ja tehtävien Lukivaikeuksiset kaikissa pääikäryhmissä (lapset, nuoret aikuiset, ikääntyneemmän aikuiset) tarvitsivat samanikäisiä sujuvia lukijoita hitaamman esitystahdin, jotta he kykenivät arvioimaan ei-kielellisten ärsykkeiden ajallisen esitystavan oikein. Tämä aikatarkkuuden ongelma havaittiin lukivaikeuksisilla kaikissa aisteissa (tunto, kuulo, näkö) ja niiden yhdistelmissä (audiotaktiilinen, visuotaktiilinen, audiovisuaalinen). Lukivaikeuksisten aikatarkkuusongelmat ilmenivät edelleen molemmissa tehtävätyypeissä (samanaikaisuuden ja järjestyksen arvioinnissa). Aikatarkkuus ja sen ongelmat olivat yhteydessä äänteiden käsittelyyn Aikatarkkuus oli yhteydessä äänteiden käsittelykykyyn (fonologiseen prosessointiin), niin lapsilla kuin aikuisillakin, kaikissa aisteissa, niiden yhdistelmissä ja tehtävätyypeissä. Yhteys ei-kielellisen aikatarkkuuden ja kielellisten toimintojen välillä oli kuitenkin selkeämpi lukivaikeuksisilla kuin sujuvilla lukijoilla. Tämä tarkoittaa, että etenkin lukivaikeuksisilla ryhmätason huono aikatarkkuus oli yhteydessä huonoon äänteiden käsittelyyn (fonologiseen prosessointiin) ja päinvastoin. Suoraa yhteyttä lukemisen ja aikatarkkuuden välillä ei kuitenkaan havaittu. Lisääntyvä aikuisikä heikensi lukivaikeuksisten aikatarkkuutta suhteettoman paljon Tiedonkäsittelyn nopeuden on toistuvasti osoitettu hidastuvan normaalissa ikääntymisessä. Lisääntyvä aikuisikä (20-59 -vuotiailla) heikensikin sekä sujuvien että lukivaikeuksisten aikatarkkuutta. Toisin sanoen, mitä iäkkäämmästä aikuisesta oli kysymys, sitä hitaammin hänelle tuli esittää ärsykkeet, jotta hän kykeni arvioimaan niiden ajalliset suhteet oikein. Tämä ikään liittyvä tavanomainen hidastuminen oli kuitenkin yllättäen suhteettoman nopeaa lukivaikeuksisilla. Toisin sanoen, jo nuorilla lukivaikeuksisilla havaittu aikatarkkuuden vaikeus (ryhmäero verrattuna sujuviin lukijoihin) ei pysynyt saman suuruisena, vaan ryhmien ero kasvoi aikuisiän lisääntyessä. Tulosten merkitys Lukivaikeuden osoitettiin tässä tutkimussarjassa olevan yhteydessä yleistyneeseen vaikeuteen käsitellä ajassa nopeasti muuttuvaa ei-kielellistä aistitietoa (yli aistien ja niiden yhdistelmien, tehtävätyyppien, tutkittavien iän). Tämä osoittaa, että lukivaikeus ei ole ongelma, joka rajoittuu vain kielellisen materiaalin käsittelyn vaikeuksiin (äänteiden käsittely, lukeminen, kirjoittaminen). Nyt havaitut vaikeudet eivät myöskään rajoittuneet vain niihin aisteihin, jotka selkeimmin liittyvät lukemiseen (näkö) ja puhuttuun kieleen (kuulo); Ongelmia esiintyi myös muissa aisteissa (tunto). Lukivaikeuksisten lukijoiden ryhmätasolla havaittu aikatarkkuuden ongelma ei kuitenkaan heijastunut yksilötasolle; Jokainen lukivaikeuksinen ei ollut huono aikatarkkuustehtävissä. Näin ollen ei siis voida väittää, että kaikkien lukivaikeuksisten äänteiden käsittelyn tai lukemaan oppimisen vaikeudet voisivat selittyä aistien toimintojen poikkeavuudella. Aikatarkkuuden ongelmat eivät olleet yhteydessä varsinaiseen lukemiseen. Sekä lukivaikeuksisilla lapsilla että aikuisilla todettiin kuitenkin selkeä yhteys aikatarkkuuden ongelmien ja lukemaan oppimisen keskeisen ennakkoehdon, fonologisen prosessoinnin, välillä. Saattaa siis olla, että synnynnäinen aistien toimintojen poikkeavuus vaikuttaa yksilön suoriutumiseen jo ennen varsinaista lukemaan oppimista, kun ne taidot kehittyvät (fonologinen prosessointi), joille myöhempi lukemaan oppiminen perustuu. Ikäännyttäessä havaittu lukivaikeuksisten suhteettoman nopea aikatarkkuuden heikkeneminen osoittaa, että lukivaikeus ei voi olla ongelma, joka koskee vain lapsuusikää, tai vaikeus, joka johtuu vain kehityksen viivästymästä joka kurottaisiin iän myötä umpeen. Tulosten ymmärtämiseksi onkin muistettava kaksi seikkaa. Lukivaikeus on ensinnäkin yhdistetty synnynnäisiin, pieniin, poikkeavuuksiin aivojen rakenteissa ja toiminnoissa. Toisaalta tavanomaiseen ikääntymiseen liittyy se, että aivot kykenevät yhä huonommin korjaamaan ja kiertämään (kompensoimaan) pieniä vaurioita. Tämän perusteella tutkimussarjan tuloksista voidaan päätellä, että lukivaikeuksisten jo synnynnäisesti heikentyneet aivojen kompensointimahdollisuudet eivät ole yhtä tehokkaita puskuroimaan ikääntymisen tavanomaisia vaikutuksia kuin sujuvilla lukijoilla. Yllättävää kuitenkin on, että tämä korostunut heikkeneminen havaittiin jo suhteellisen nuorilla, työikäisillä, lukivaikeuksisilla, ennen 60 ikävuotta. Samanlaista ikäännyttäessä korostuvaa vaikeutta ei lukivaikeuksilla kuitenkaan havaittu päättelyssä, kielellisissä toiminnoissa tai itse lukemisessa. Vaikuttaakin siis siltä, että ne toiminnot, joita on harjaannutettu aktiivisesti, eivät heikkene kasvavan aikuisiän myötä yhtä suhteettomasti. Alkuperäiset artikkelit Laasonen M, Tomma-Halme J, Lahti-Nuuttila P, Service E, and Virsu V (2000) Rate of information segregation in developmentally dyslexic children, Brain and Language, 75(1), 66-81. Laasonen M, Service E, and Virsu V (2001) Temporal order and processing acuity of visual, auditory, and tactile perception in developmentally dyslexic young adults, Cognitive, Affective, and Behavioral Neuroscience, 1(4), 394-410. Laasonen M, Service E, and Virsu V (2002) Crossmodal temporal order and processing acuity in developmentally dyslexic young adults, Brain and Language, 80(3), 340-354. Laasonen M, Lahti-Nuuttila P, and Virsu V (2002) Developmentally impaired processing speed decreases more than normally with age, NeuroReport, 13(9), 1111-1113.

Neurochemical regulation of auditory information processing studied with EEG/MEG: application to schizophrenia

Cognitive impairments of attention, memory and executive functions are a fundamental feature of the pathophysiology of schizophrenia. The neurophysiological and neurochemical changes in the auditory cortex are shown to underlie cognitive impairmentsin schizophrenia patients. Functional state of the neural substrate of auditory information processing could be objectively and non-invasively probed with auditory event-related potentials (ERPs) and event- related fields (ERFs). In the current work, we explored the neurochemical effect on the neural origins of auditory information processing in relation to schizophrenia. By means of ERPs/ERFs we aimed to determine how neural substrates of auditory information processing are modulated by antipsychotic medication in schizophrenia spectrum patients (Studies I, II) and by neuropharmacological challenges in healthy human subjects (Studies III, IV). First, with auditory ERPs we investigated the effects of olanzapine (Study I) and risperidone (Study II) in a group of patients with schizophrenia spectrum disorders. After 2 and 4 weeks of treatment, olanzapine has no significant effects on mismatch negativity(MMN) and P300, which, as it has been suggested, respectively reflect preattentive and attention-dependent information processing. After 2 weeks of treatment, risperidone has no significant effect on P300, however risperidone reduces P200 amplitude. This latter effect of risperidone on neural resources responsible for P200 generation could be partly explained through the action of dopamine. Subsequently, we used simultaneous EEG/MEG to investigate the effects of memantine (Study III) and methylphenidate (Study IV) in healthy subjects. We found that memantine modulates MMN response without changing other ERP components. This could be interpreted as being due to the possible influence of memantine through the NMDA receptors on auditory change- detection mechanism, with processing of auditory stimuli remaining otherwise unchanged. Further, we found that methylphenidate does not modulate the MMN response. This finding could indicate no association between catecholaminergic activities and electrophysiological measures of preattentive auditory discrimination processes reflected in the MMN. However, methylphenidate decreases the P200 amplitudes. This could be interpreted as a modulation of auditory information processing reflected in P200 by dopaminergic and noradrenergic systems. Taken together, our set of studies indicates a complex pattern of neurochemical influences produced by the antipsychotic drugs in the neural substrate of auditory information processing in patients with schizophrenia spectrum disorders and by the pharmacological challenges in healthy subjects studied with ERPs and ERFs.

Auditory - Visual Matching in Learning Disabilities : Intervention Studies from Finland and Sweden

The present thesis discusses relevant issues in education: 1) learning disabilities including the role of comorbidity in LDs, and 2) the use of research-based interventions. This thesis consists of a series of four studies (three articles), which deepens the knowledge of the field of special education. Intervention studies (N=242) aimed to examine whether training using a nonverbal auditory-visual matching computer program had a remedial effect in different learning disabilities, such as developmental dyslexia, Attention Deficit Disorder (ADD) and Specific Language Impairment (SLI). These studies were conducted in both Finland and Sweden. The intervention’s non-verbal character made an international perspective possible. The results of the intervention studies confirmed, that the auditory-visual matching computer program, called Audilex had positive intervention effects. In Study I of children with developmental dyslexia there were also improvements in reading skills, specifically in reading nonsense words and reading speed. These improvements in tasks, which are thought to rely on phonological processing, suggest that such reading difficulties in dyslexia may stem in part from more basic perceptual difficulties, including those required to manage the visual and auditory components of the decoding task. In Study II the intervention had a positive effect on children with dyslexia; older students with dyslexia and surprisingly, students with ADD also benefited from this intervention. In conclusion, the role of comorbidity was apparent. An intervention effect was evident also in students’ school behavior. Study III showed that children with SLI experience difficulties very similar to those of children with dyslexia in auditory-visual matching. Children with language-based learning disabilities, such as dyslexia and SLI benefited from the auditory-visual matching intervention. Also comorbidity was evident among these children; in addition to formal diagnoses, comorbidity was explored with an assessment inventory, which was developed for this thesis. Interestingly, an overview of the data of this thesis shows positive intervention effects in all studies despite learning disability, language, gender or age. These findings have been described by a concept inter-modal transpose. Self-evidently these issues need further studies. In learning disabilities the aim in the future will also be to identify individuals at risk rather than by deficit; this aim can be achieved by using research-based interventions, intensified support in general education and inclusive special education. Keywords: learning disabilities, developmental dyslexia, attention deficit disorder, specific language impairment, language-based learning disabilities, comorbidity, auditory-visual matching, research-based interventions, inter-modal transpose

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.

Risk factors associated with corneal nerve alteration in type 1 diabetes in the absence of neuropathy: A longitudinal in vivo corneal confocal microscopy study

Purpose The aim of this study was to determine alterations to the corneal subbasal nerve plexus (SNP) over four years using in vivo corneal confocal microscopy (IVCM) in participants with type 1 diabetes and to identify significant risk factors associated with these alterations. Methods A cohort of 108 individuals with type 1 diabetes and no evidence of peripheral neuropathy at enrollment underwent laser-scanning IVCM, ocular screening, and health and metabolic assessment at baseline and the examinations continued for four subsequent annual visits. At each annual visit, eight central corneal images of the SNP were selected and analyzed to quantify corneal nerve fiber density (CNFD), branch density (CNBD) and fiber length (CNFL). Linear mixed model approaches were fitted to examine the relationship between risk factors and corneal nerve parameters. Results A total of 96 participants completed the final visit and 91 participants completed all visits. No significant relationships were found between corneal nerve parameters and time, sex, duration of diabetes, smoking, alcohol consumption, blood pressure or BMI. However, CNFD was negatively associated with HbA1c (β=-0.76, P<0.01) and age (β=-0.13, P<0.01) and positively related to high density lipids (HDL) (β=2.01, P=0.03). Higher HbA1c (β=-1.58, P=0.04) and age (β=-0.23, P<0.01) also negatively impacted CNBD. CNFL was only affected by higher age (β=-0.06, P<0.01). Conclusions Glycemic control, HDL and age have significant effects on SNP structure. These findings highlight the importance of diabetic management to prevent corneal nerve damage as well as the capability of IVCM for monitoring subclinical alterations in the corneal SNP in diabetes.

Corneal confocal microscopy detects neuropathy in patients with type 1 diabetes without retinopathy or microalbuminuria

Objective Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria. Materials and Methods All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)]. Results 53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria. Conclusions IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.

The inferior whorl for detecting diabetic peripheral neuropathy using corneal confocal microscopy

PURPOSE: In vivo corneal confocal microscopy (CCM) is increasingly used as a surrogate endpoint in studies of diabetic polyneuropathy (DPN). However, it is not clear whether imaging the central cornea provides optimal diagnostic utility for DPN. Therefore, we compared nerve morphology in the central cornea and the inferior whorl, a more distal and densely innervated area located inferior and nasal to the central cornea. METHODS: A total of 53 subjects with type 1/type 2 diabetes and 15 age-matched control subjects underwent detailed assessment of neuropathic symptoms (NPS), deficits (neuropathy disability score [NDS]), quantitative sensory testing (vibration perception threshold [VPT], cold and warm threshold [CT/WT], and cold- and heat-induced pain [CIP/HIP]), and electrophysiology (sural and peroneal nerve conduction velocity [SSNCV/PMNCV], and sural and peroneal nerve amplitude [SSNA/PMNA]) to diagnose patients with (DPN+) and without (DPN-) neuropathy. Corneal nerve fiber density (CNFD) and length (CNFL) in the central cornea, and inferior whorl length (IWL) were quantified. RESULTS: Comparing control subjects to DPN- and DPN+ patients, there was a significant increase in NDS (0 vs. 2.6 ± 2.3 vs. 3.3 ± 2.7, P < 0.01), VPT (V; 5.4 ± 3.0 vs. 10.6 ± 10.3 vs. 17.7 ± 11.8, P < 0.01), WT (°C; 37.7 ± 3.5 vs. 39.1 ± 5.1 vs. 41.7 ± 4.7, P < 0.05), and a significant decrease in SSNCV (m/s; 50.2 ± 5.4 vs. 48.4 ± 5.0 vs. 39.5 ± 10.6, P < 0.05), CNFD (fibers/mm2; 37.8 ± 4.9 vs. 29.7 ± 7.7 vs. 27.1 ± 9.9, P < 0.01), CNFL (mm/mm2; 27.5 ± 3.6 vs. 24.4 ± 7.8 vs. 20.7 ± 7.1, P < 0.01), and IWL (mm/mm2; 35.1 ± 6.5 vs. 26.2 ± 10.5 vs. 23.6 ± 11.4, P < 0.05). For the diagnosis of DPN, CNFD, CNFL, and IWL achieved an area under the curve (AUC) of 0.75, 0.74, and 0.70, respectively, and a combination of IWL-CNFD achieved an AUC of 0.76. CONCLUSIONS: The parameters of CNFD, CNFL, and IWL have a comparable ability to diagnose patients with DPN. However, IWL detects an abnormality even in patients without DPN. Combining IWL with CNFD may improve the diagnostic performance of CCM.

Small fibre neuropathy in patients with latent autoimmune diabetes in adults

The prevalence of latent autoimmune diabetes in adults (LADA) in patients diagnosed with type 2 diabetes mellitus (T2DM) ranges from 7 to 10% (1). They present at a younger age and have a lower BMI but poorer glycemic control, which may increase the risk of complications (2). However, a recent analysis of the Collaborative Atorvastatin Diabetes Study (CARDS) has demonstrated no difference in macrovascular or microvascular events between patients with LADA and T2DM, but neuropathy was not assessed (3). Previous studies quantifying neuropathy in patients with LADA are limited. In this study, we aimed to accurately quantify neuropathy in subjects with LADA compared with matched patients with T2DM.

Research update: LANDMark study: Longitudinal assessment of neuropathy in diabetes using novel ophthalmic MARKers

The eye is a simple, non-invasive location for screening, diagnosing and follow up of diabetic peripheral neuropathy.

Tactile processing in human somatosensory and auditory cortices

Tactile sensation plays an important role in everyday life. While the somatosensory system has been studied extensively, the majority of information has come from studies using animal models. Recent development of high-resolution anatomical and functional imaging techniques has enabled the non-invasive study of human somatosensory cortex and thalamus. This thesis provides new insights into the functional organization of the human brain areas involved in tactile processing using magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). The thesis also demonstrates certain optimizations of MEG and fMRI methods. Tactile digit stimulation elicited stimulus-specific responses in a number of brain areas. Contralateral activation was observed in somatosensory thalamus (Study II), primary somatosensory cortex (SI; I, III, IV), and post-auditory belt area (III). Bilateral activation was observed in secondary somatosensory cortex (SII; II, III, IV). Ipsilateral activation was found in the post-central gyrus (area 2 of SI cortex; IV). In addition, phasic deactivation was observed within ipsilateral SI cortex and bilateral primary motor cortex (IV). Detailed investigation of the tactile responses demonstrated that the arrangement of distal-proximal finger representations in area 3b of SI in humans is similar to that found in monkeys (I). An optimized MEG approach was sufficient to resolve such fine detail in functional organization. The SII region appeared to contain double representations for fingers and toes (II). The detection of activations in the SII region and thalamus improved at the individual and group levels when cardiac-gated fMRI was used (II). Better detection of body part representations at the individual level is an important improvement, because identification of individual representations is crucial for studying brain plasticity in somatosensory areas. The posterior auditory belt area demonstrated responses to both auditory and tactile stimuli (III), implicating this area as a physiological substrate for the auditory-tactile interaction observed in earlier psychophysical studies. Comparison of different smoothing parameters (III) demonstrated that proper evaluation of co-activation should be based on individual subject analysis with minimal or no smoothing. Tactile input consistently influenced area 3b of the human ipsilateral SI cortex (IV). The observed phasic negative fMRI response is proposed to result from interhemispheric inhibition via trans-callosal connections. This thesis contributes to a growing body of human data suggesting that processing of tactile stimuli involves multiple brain areas, with different spatial patterns of cortical activation for different stimuli.