Gamma-Aminobutyric Acid and Glutamate Concentrations in the Striatum and Anterior Cingulate Cortex Not Found to Be Associated with Cognitive Flexibility

Behavioral flexibility and goal-directed behavior heavily depend on fronto-striatal networks. Within these circuits, gamma-aminobutyric acid (GABA) and glutamate play an important role in (motor) response inhibition, but it has remained largely unclear whether they are also relevant for cognitive inhibition. We hence investigated the functional role of these transmitters for cognitive inhibition during cognitive flexibility. Healthy young adults performed two paradigms assessing different aspects of cognitive flexibility. Magnetic resonance spectroscopy (MRS) was used to quantify GABA+ and total glutamate/glutamine (Glx) levels in the striatum and anterior cingulate cortex (ACC) referenced to N-acetylaspartate (NAA). We observed typical task switching and backward inhibition effects, but striatal and ACC concentrations of GABA+/NAA and Glx/NAA were not associated with cognitive flexibility in a functionally relevant manner. The assumption of null effects was underpinned by Bayesian testing. These findings suggest that behavioral and cognitive inhibition are functionally distinct faculties, that depend on (at least partly) different brain structures and neurotransmitter systems. While previous studies consistently demonstrated that motor response inhibition is modulated by ACC and striatal GABA levels, our results suggest that the functionally distinct cognitive inhibition required for successful switching is not, or at least to a much lesser degree, modulated by these factors

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

The role of ventrolateral prefrontal cortex in performance of spatial self-ordered response sequences in the marmoset

The ventrolateral prefrontal cortex (vlPFC) in primates plays an important role in cognitive control and working memory, but as argued in the Introduction its contribution to those aspects of goal-directed behaviour such as planning and executing spatial response sequences requires further analysis, using more refined methods than have been employed hitherto. These studies investigated the role of vlPFC in performance of self-ordered response sequences using intra-cerebral microinfusions of specific pharmacologic agents in the common marmoset. Following a description of the necessary methodology, including behavioural training and surgical details (Chapter 2), a causal role for vlPFC in performance of spatial-self ordered sequences was confirmed in Chapter 3 by demonstrating that local inactivation of vlPFC using muscimol/baclofen infusions impairs sequencing. This effect was shown to be selective to performance of sequences that varied spatially from trial to trial; thus, no effects of vlPFC inactivation were observed for performance of a fixed response sequence. Once animals could learn a heuristical strategy for a self-ordered fixed sequence, vlPFC inactivation no longer impaired performance. Chapter 4 investigated the effects of the chemical neuromodulation of vlPFC on self-ordered sequencing using microinfusions of dopamine receptor D2 antagonist, sulpiride, and 5HT2A receptor antagonist, M100907 on performance of variable sequences. These drugs produced contrasting, dose-dependent impairments. M100907 impaired accuracy, while sulpiride impaired error correction. Chapter 5 studied effects of blocking glutamatergic receptors in a region of the caudate nucleus to which the vlPFC projects, but no significant effects on sequencing accuracy were observed, although there were large effects on perseverative errors in 2 out of 3 animals. The findings are discussed in Chapter 6 in terms of the functioning of the vlPFC and its possible role in controlling flexible response sequencing and working memory. The findings are shown to be of relevance for psychiatric disorders such as obsessive compulsive disorder (OCD) and schizophrenia, which show functional dysconnectivity of the vlPFC in association with response sequencing impairments

BIOLOGICAL BASIS OF VARIABILITY IN DOPAMINE AVAILABILITY ON FRONTOSTRIATAL BRAIN FUNCTION IN ADOLESCENCE

Neurodevelopmental studies indicate a protracted development through adolescence of brain systems underlying incentive-driven behaviors including prefrontal cortex (PFC) and the striatum. These systems support the executive control of behavior as well as motivationally driven behaviors and may contribute to vulnerabilities in the emergence of psychopathology. The PFC and striatum may support cognition and motivation through the function of the neurotransmitter dopamine. Dopamine (DA) availability is increased during the adolescent period in human and animals and play an important role in mediating individual differences in risk-taking behaviors. This dissertation seeks to examine the moderating role of genetically mediated DA availability on frontostriatal brain function in adolescence. To this end, we genotyped individuals between the ages of 10 and 20 for common functional polymorphisms in three genes that have a direct influence on synaptic DA availability. In addition, we calculated a multilocus composite score in order to assess additive effects of our three genetic loci. We used functional magnetic resonance imaging (fMRI) to assess brain function. The purpose of our first study was to examine the integrity of frontostriatal networks using resting state functional connectivity. We then look more directly at the role of frontostriatal brain function on incentive-driven behaviors using a rewarded inhibitory control task that has a known developmental signature . Overall we found a moderating influence of DA availability on age-related changes in key frontostriatal circuitry suggesting that the maturation of brain function in adolescence may in part be mediated by inter-individual variability in DA signaling. Overall, the genotypes by age interactions highlight a unique DA-driven brain profile in adolescence. This suggests that a genetically mediated brain phenotype characterized in adolescence may differ significantly from that in adulthood. This has strong implications regarding the variability observed in adolescent risk-taking behaviors as well as predictions of later adult behavior

The relationship between higher-order cognition and personality.

A latent variable approach was used to (1) examine the relationship between working memory capacity and fluid intelligence, (2) compare the relationship between fluid intelligence and two measures of working memory capacity (complex span and n-back), (3) identify higher-order personality factors and (4) determine the relationship between higher-order personality factors, working memory capacity and fluid intelligence. Confirmatory factor analysis followed by structural equation modeling described the complex span and n-back as highly correlated yet distinct constructs. Consistent with previous research, both measures correlated highly with fluid intelligence. Four higher-order personality factors best modeled the structure of personality. Moreover, these four factors had differential relationship to cognitive constructs. The current research provides a deeper understanding of the relationship between working memory capacity and fluid intelligence, including discrepancies considering the magnitude of the relationship between two types of working memory measures and fluid intelligence, and finally, the influence of a diverse personality structure on working memory capacity and fluid intelligence. Importantly, the study examined these relationships on a broad scale using multiple tasks at a latent level contributing to better understanding of the nature of working memory capacity - fluid intelligence relationship and the influence of personality on higher-order cognition.Ph.D.Committee Chair: Engle, Randall, W

Esmase psühhoosiepisoodiga patsientide kognitiivne funktsionaalsus

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhootiliste häirete puhul on tegemist bioloogiliste põhjustega aju toimimise eripäradega. Enamlevinud krooniline psühhootiline häire on skisofreenia, mille puhul võivad ilmneda psühhopatoloogilised ilmingud tajumises, mõtlemises, tunde- ja tahteelus. Üha suuremat kliinilist ja teadusuuringute põhist tähelepanu pööratakse häire avaldumise esmasele episoodile ning haiguse tuumsümptomina käsitletakse kognitiivse funktsionaalsuse omapära. Uurimustöö eesmärgiks oli iseloomustada esmase psühhootilise episoodi ilmnemise järgselt patsientide kognitiivsete funktsioonide sooritussuutlikkuse eripärasid võrreldes tervete eakaaslastega. Lisaks, hinnata patsientide objektiivselt mõõdetud ja subjektiivselt hinnatud kognitiivset funktsionaalsust ajalises dünaamikas ning kirjeldada aju morfoloogiliste tunnuste (ajukoore paksuse ja pindala) seoseid aju funktsionaalse toimimisega. Uuritavate kognitiivseid funktsioone hinnati arvutipõhise neuropsühholoogilise testipatarei abil, mille patsiendid läbisid võimalusel kuuekuulise ajaintervalliga ka teistkordselt. Hinnatud kognitiivsete funktsioonide valdkonnad olid: visuaalne ja ruumiline äratundmismälu, õppimisvõime, tähelepanu ümberlülitumisvõime, tegevuse planeerimis- ja täidesaatmisvõimekus, töömälu maht, töömälus oleva infoga toimetamisvõimekus, strateegiate kasutus ning infotöötluskiirus. Lisaks andsid patsiendid tagasisidet subjektiivselt tajutud kognitiivsete funktsioonide sooritussuutlikkuse kohta. Magnetresonantstomograafilise ajukuvamisuuringu kasutamine võimaldas määratleda osalejate ajukoore paksust ja pindala iseloomustavaid väärtuseid. Tulemustest selgus, et esmase psühhoosiepisoodi järgselt ilmneb patsientide grupi tasandil laiaulatuslik kognitiivsete funktsioonide sooritussuutlikkuse langus võrreldes tervete eakaaslastega. Patsientidel avalduv kognitiivne düsfunktsionaalsus ei piirdu üksnes kvantitatiivsete muutustega, neil esinevad lisaks ka kvalitatiivsed ehk funktsionaalsuse struktuurilised erinevused. Lisaks selgitasime, et hinnatud kognitiivsete funktsioonide sooritussuutlikkuse muutused ajas võivad ilmneda määra, viisi ja suuna erinevustes. Ilmnes, et objektiivselt mõõdetud ja subjektiivselt hinnatud vaimse tegevuse sooritussuutlikkus on teineteisest eristuvad ja tõenäoliselt teineteist täiendavad konstruktid. Saamaks laiapõhjalisemat ülevaadet patsiendi igapäevasest vaimsest toimimisest tuleks kasutada samaaegselt mõlemat lähenemist. Osalejate ajukuvamisuuringute ja neuropsühholoogiliste testide tulemuste seosteanalüüsidele tuginedes näitasime, et eeskätt morfoloogilised muutused eesaju, oimu- ja kiirusagara ning vöökääru aladel korreleeruvad kognitiivse funktsionaalsuse eripäradega. Lisaks ilmnesid erinevused aju struktuuri ja funktsiooni korrelatsioonimustrites haigete ja kontrollgruppi kuulujate osas. Uurimustöö tulemused rõhutavad kognitiivse düsfunktsionaalsuse kui haigusspetsiifilise tunnuse olemasolu juba kroonilise psühhootilise häire varajases staadiumis.Schizophrenia is a severe psychiatric disorder that has a strong biological basis and is characterized by disturbances in perception, thought, emotion, and behaviour. In the field of psychiatric research, there is growing interest in the early stage of the chronic psychotic disorder and mounting evidence suggests that compromised cognitive function is a core feature of the illness. Aims of the research were to characterize cognitive functioning of the first-episode psychosis/schizophrenia patients, and to study its relationships with subjectively perceived cognitive functioning and brain morphological parameters. A comprehensive computer-based neuropsychological battery was used. The battery included tests designed to assess subjects’ pattern and spatial recognition memory capacity, learning and rapid visual information processing abilities, shifting and flexibility of attention, spatial planning and executive functioning, and to evaluate participants’ ability to retain spatial information and manipulate these remembered items in their working memory, and to use strategies. Objective and subjective mental functioning data were collected at baseline and follow-up measures were completed approximately six months later, in the patients’ group. We used magnet resonance imaging technique to evaluate brain morphological (i.e., cortical thickness and cortical area) parameters. The results indicated that patients exhibited widespread cognitive impairments, and that the structure of underlying cognitive abilities as measured by a selection of neuropsychological tests is not the same for healthy individuals and patients with first-episode psychosis. The findings suggested that there is variability in the type, direction, and size of the changes of different cognitive functions over time among patients with first psychotic episode. Objectively measured and sujectively perceived cognitive functioning are two distinct and probably complementary constructs, and should be measured separately in order to attain a more comprehensive assessment of each patient’s day-to-day functioning. Furthermore, we demonstrated that morphological changes in frontal, temporal, parietal, and cingulate cortices may be related to the altered cognitive functioning among patients and that the brain structure-function relationships may be dissimilar for patients with first psychotic episode and healthy subjects. Our findings support continued efforts to elucidate cognitive dysfunction as a characteristic feature of the early stage of chronic psychotic disorder

Tinnitus – psychiatric comorbidity and treatment using transcranial magnetic stimulation (TMS)

Tinnitus is the perception of sound in the absence of any external noise. It severely impairs the quality of life in 1-2% of people. Tinnitus is frequently associated with depression, anxiety, and insomnia. The exact pathophysiology of tinnitus is still unclear. No curative therapy exists for chronic tinnitus, and treatment focuses on symptomatic relief. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used for treating depression and neuropathic pain. The evidence of its efficacy for chronic tinnitus is still inconclusive, and the optimal treatment protocols are thus still obscure. This thesis aimed to further evaluate the use of rTMS for chronic tinnitus and investigate the psychiatric comorbidity of tinnitus patients. The first (open pilot) study utilized electric field (E-field) navigated rTMS for very severe chronic tinnitus with promising results. In the second (randomized placebo-controlled) study, the effects of 1-Hz E-field rTMS targeted according to the tinnitus pitch to the left auditory cortex were analyzed. Despite the significant improvements in tinnitus, active rTMS was not superior to the placebo, possibly due to large placebo-effect and wide inter-individual variation in treatment efficacy. The third study on parallel groups compared the effects of neuronavigated rTMS to nonnavigated rTMS (based on the 10-20 EEG localization system). Both groups benefitted from the treatment, but the method of coil localization was not a critical factor for treatment outcome. In the fourth study, current and lifetime DSM-IV diagnoses of Axis I (psychiatric disorders) and Axis II (personality disorders) were assessed in tinnitus patients using structured clinical interviews (SCID-I and -II). Tinnitus patients were prone to episodes of major depression, and they often had obsessive-compulsive personality features. Psychiatric disorders in this study seemed to be comorbid or predisposing conditions rather than the consequences of tinnitus.Tinnitus – psykiatrinen sairastavuus ja hoito transkraniaalisella magneettistimulaatiolla (TMS) Tinnituksen ääniaistimus syntyy ilman ulkoista äänilähdettä. Se heikentää vakavasti elämänlaatua 1-2%:lla ihmisistä. Tinnitus yhdistetään usein masennukseen, ahdistukseen ja unettomuuteen. Tinnituksen tarkka syntymekanismi on vielä epäselvä. Pitkäaikaiselle tinnitukselle ei ole parantavaa hoitoa, vaan hoidossa keskitytään oireiden lievittämiseen. Transkraniaalinen magneettistimulaatio sarjapulssein (rTMS) on kajoamaton aivojen toimintaa muokkaava menetelmä, jota käytetään masennuksen ja hermoperäisen kivun hoidossa. Sen teho pitkäaikaiseen tinnitukseen on vielä epävarmaa ja optimaaliset hoitoprotokollat ovat selvittämättä. Tämän väitöskirjan tavoitteena oli arvioida rTMS:n käyttöä pitkäaikaisen tinnituksen hoidossa ja lisäksi tutkia tinnituspotilaiden psykiatrista sairastavuutta. Ensimmäisessä osatyössä (avoin pilotti) käytettiin sähkökenttäohjattua (E-field) navigoivaa rTMS:a pitkäaikaiseen, erittäin vaikeaan tinnitukseen lupaavin tuloksin. Toisessa osatyössä (satunnaistettu lumekontrolloitu) arvioitiin tinnitusäänen korkeuden mukaan vasemmalle kuuloaivokuorelle suunnatun 1- Hz:n sähkökentän mukaan navigoidun rTMS:n vaikutuksia. Vaikka tinnitus helpottui merkittävästi, ei aktiivi-rTMS ollut lumehoitoa parempi, mahdollisesti johtuen suuresta lumevaikutuksesta ja laajasta yksilöiden välisestä vaihtelusta hoidon tehossa. Kolmannessa osatyössä verrattiin rinnakkaisryhmien välillä neuronavigoidun rTMS:n ja sokko rTMS:n (10-20 EEG-systeemiin perustuva paikannus) vaikutuksia. Molemmat ryhmät hyötyivät hoidosta, eikä kelan paikannusmenetelmä ollut ratkaiseva tekijä hoidon lopputuloksen kannalta. Neljännessä osatyössä nykyiset ja elämänaikaiset akselin I (psykiatriset häiriöt) ja akselin II (persoonallisuushäiriöt) DSM-IV diagnoosit määritettiin tinnituspotilailta käyttäen strukturoituja psykiatrisia haastatteluja (SCID-I ja -II). Tinnituspotilaat olivat alttiita vakaville masennusjaksoille ja heillä oli usein vaativan persoonallisuuden piirteitä. Psykiatriset häiriöt vaikuttivat olevan ennemmin samanaikaisia tai altistavia tiloja kuin tinnituksen seurauksena ilmaantuneita häiriöitä

The Objective Measurement of Sleep-Wake Disturbance in Parkinson's Disease

Parkinson’s disease (PD) is an increasingly prevalent neurodegenerative disease affecting older adults. Motor symptoms, including tremor, rigidity and tremor were classically predominant. However, troublesome non-motor symptomatology are known to impair quality of life for patients with PD and there carers. Sleep-wake disturbances are gaining attention in PD encompassing disturbances of the circadian, homeostatic and ultradian sleep systems. These symptoms have been linked to the troublesome problems of cognitive deficits, mood disturbance and visual hallucinations. Mechanisms exploring the interaction of sleep-wake disturbance and other non-motor symptoms in PD are not well understood. Bidirectional causality between sleep-wake disturbance and concomitant symptoms in PD provide insights into common chemical and neural mechanisms which prior to the development of therapy, must be understood. Furthermore, sleep-wake disorders in PD at present provide a maker of early diagnosis for which future disease modifying treatment can be targeted. However objective and reliable measurement techniques are yet to be devised in this field. This thesis aims to utilise the objective measurement of sleep-wake disturbances across the circadian, homeostatic and ultradian sleep systems in PD through four empiric experiments to help inform our understanding of these critical symptoms. While the usefulness of self-report data is not doubted as a means of engaging the patient and hearing their voice they cannot serve the same identification and measurement uses of objective data. Given our ageing population, the need for diagnostic, predictive and sensitive monitoring biomarkers in Parkinson’s disease has never been greater. Objective, accurate and reliable measurement techniques, as demonstrated in this thesis, underpins further research in this field