The role of GABA in fear and its relationship to emotion processing brain networks

The aim of the project described in this thesis was to explore the relationship between the inhibitiory neurotransmitter gamma-aminobutyric acid (GABA) and fear-related brain activation, measured with functional magnetic resonance imaging. The first part of the thesis deals with the question of how repeatable measures of fearrelated brain activation can be obtained. Two paradigms were evaluated, a frequently used task using fearful and neutral faces and a newly developed paradigm using pictures of spiders, negative images from the international affective picture system, and carefully matched control stimuli. In the main study latter paradigm was used to assess fear-related BOLD responses in two groups of participants, recruited for high vs. low levels of fearfulness. In the same participants, GABA concentration was measured using MRS in two brain regions relevant for emotion processing (left insula and left dorsolateral prefrontal cortex). Additionally, physiological parameters were recorded throughout the task, and a breath-hold task (to estimate vascular reactivity) as well as an arterial spin labeling aquisition (to estimate baseline cerebral blood ow) were included in the scanning session. The main experimental chapters of the thesis deal with the questions whether fearfulness,GABA concentration and fear-related BOLD responses are associated, and how potential confounding factors - such as physiological task responses, vascular reactivity and baseline cerebral blood ow - might mediate this relationship. The last part of the main experimental part explores the relationship between fearfulness, GABA concentration and resting state functional connectivity in emotion processing networks. In the general discussion, power of the study is estimated post-hoc, and limitations are outlined. Two chapters in the Appendix assess repeatability of the GABA MRS measures and vascular reactivity estimates

Aivovamman vaikutus aivokuoren rytmiseen toimintaan

Mild traumatic brain injuries (mTBI) are common, and while most patients recover well, there is a minority of patients suffering from prolonged symptoms lasting over three months. Pathological processes provoke low-frequency (0.5 - 7 Hz) oscillatory brain activity, measurable with electroencephalography (EEG) and magnetoencephalography (MEG). After mTBI, low frequency activity (LFA) is hypothesized to arise from cortical neurons suffering from de-afferentation after traumatic axonal injury. The natural evolution and prognostic value of low-frequency activity (LFA) measured with MEG, however, is not yet firmly established and reliable biomarkers for cognitive complaints after mTBI are lacking. The aim of this thesis was to examine the occurrence and natural evolution of low frequency activity (LFA) after mild traumatic brain injury (mTBI), and to assess its prognostic value in predicting those with prolonged symptoms. Additionally, we wanted to examine the effect of mTBI to brain oscillatory activity during cognitive tasks and find indicators for altered processing. The existence of LFA in healthy subjects might, however, hamper its’ diagnostic value. Therefore, in Study I we created a reference database of resting-state oscillatory brain activity and observed LFA in only 1,4% of healthy subjects’ MEG recordings. The Study II assessed the occurrence and evolution of LFA in resting-state MEG recordings of mTBI patients. At a single-subject level, 7/26 patients presented aberrant 4–7 Hz (theta) band activity; 3/7 patients with abnormal theta activity were without any detectable lesions in MRI. Of the twelve patients with follow-up measurements, five showed abnormal theta activity in the first recording, but only two in the second measurement, implying the importance of early measurements in clinical settings. The presence of LFA was not, however, correlated with the prevalence of self-reported symptoms. The Study III concentrated on the modulation of oscillatory activity during cognitive tasks, Paced Auditory Serial Addition Test (PASAT) and a vigilance test. Attenuation of cortical activity at alpha band (8 – 14 Hz) during PASAT compared with rest was stronger in patients than in controls (p≤0.05, corrected). Furthermore, the patients presented significant attenuation of oscillatory activity also in the left superior frontal gyrus and right prefrontal cortices which was not detected in controls. Spectral peak amplitudes of areal mean oscillatory activity at the alpha band were negatively correlated with the patients’ neuropsychological performance (p<0.01, uncorrected). Areal alpha frequency modulation during PASAT compared with rest was altered in patients: While the alpha peak frequency increased occipitally and remained stable parietally in controls, it was stable occipitally and decreased parietally in mTBI patients (p=0.012). According to our studies, LFA, especially theta-band oscillatory activity can provide an early objective sign of brain dysfunction after mTBI, and cortical oscillatory activity during a demanding cognitive task (PASAT) is altered after mTBI. Our observations suggest that both aberrant theta-band activity and the altered alpha activity during cognitive tasks may offer clinically relevant indicators of changes in neural processing after mTBI.Aivovamma on aivojen rakenteellinen tai toiminnallinen vaurio, joka syntyy kun päähän kohdistuu voimakas ulkoinen energia, tai äkillinen kiihtyvyys-hidastuvuusvoima (kuten äkkipysäyksissä). Aivovamma aiheuttaa tajunnanhäiriön tai muun neurologisen oireiston, joka voi olla ohimenevä tai pysyvä. Lievät aivovammat ovat yleisiä, ja vaikka suurin osa loukkaantuneista toipuu hyvin, kärsii pieni vähemmistö pitkäaikaisista jälkioireista. Lievä aivovamma ei aina aiheuta todennettavia diagnostisia muutoksia, eikä siitä toipumista ennustavia tekijöitä juuri tunneta. Aivosairaudet, myös aivovammat, muuttavat aivojen sähköistä toimintaa ja aiheuttavat matalataajuista rytmistä toimintaa (0.5 – 7 Hz), joka voidaan tunnistaa aivosähkökäyrän (EEG) tai magnetoenkefalografian (MEG) avulla. Aivovamman jälkeisen hidasaaltotoiminnan ajatellaan johtuvan hermosolujen viejähaarakkeiden vaurion aiheuttamasta hermosolujen poikkeavasta sähköisestä toiminnasta. Koska lievän- keskivaikean aivovamman todentaminen voi olla vaikeaa, tutkimme MEG:n mahdollisuuksia diagnostiikan apuvälineenä. Hidasaaltotoiminnan esiintyminen terveillä henkilöillä voisi vähentää löydöksen diagnostista merkitystä vamman jälkeen. Sen vuoksi selvitimme poikkeavan hidasaaltotoiminnan esiintyvyyttä 139:llä terveellä koehenkilöllä ja havaitsimme poikkeavia hidasaaltoja vain kahdella (1.4%). Lievän aivovamman saaneista 26:sta potilaasta hidasaaltotoimintaa (4-7 Hz) esiintyi 7:llä (27%). Kolmella heistä ei pystytty havaitsemaan poikkeavia muutoksia aivojen rakenteellisessa magneettikuvauksessa. Seurantamittaus kuuden kuukauden kuluttua saatiin tehtyä 12 potilaalle. Heistä viidellä (42%) havaittiin hidasaaltotoimintaa ensimmäisessä mittauksessa, mutta seurantamittauksessa vain kahdella. Aikainen mittausajankohta vamman jälkeen vaikuttaa siten parantavan tutkimuksen herkkyyttä. Alkuvaiheen hidasaaltotoiminta ei vaikuttanut ennustavan mahdollisen jälkioireiston kehittymistä, mutta pieni otoskoko vaikeuttaa löydöksen arvioimista. Tarkkaavaisuuden ja muistin häiriöt ovat tavallisimpia oireita aivovamman jälkeen. Tästä syystä tarkastelimme myös muisti- ja tarkkaavaisuustehtävien vaikutusta potilaiden aivojen rytmiseen toimintaan ja mahdollisten muutosten yhteyttä havaittuihin oireisiin. Havaitsimme haastavan muistitehtävän aikana potilaiden rytmisen toiminnan vaimentuvan lepotilanteeseen verrattuna voimakkaammin ja useammilla alueilla ns. alfa-taajuuskaistalla (8-14 Hz) kuin kontrollihenkilöiden. Rytmisen toiminnan voimakkaampi vaimentuminen potilailla oli yhteydessä parempaan neuropsykologiseen testisuoriutumiseen. Myös alueelliset huipputaajuudet käyttäytyivät eri tavoin kontrollihenkilöillä ja potilailla. Kontrollihenkilöillä tehtävän aikana takaraivolohkon alfa-taajuus nousi päälakilohkon taajuuden pysyessä vakaana verrattuna lepotilaan. Potilailla tehtävän aikana alfataajuus käyttäytyi päinvastoin; takaraivolohkon alfa-taajuus säilyi ennallaan, mutta päälakilohkon huipputaajuus laski verrattuna lepotilaan. Tutkimuksemme perusteella pian vamman jälkeen todettava hidasaaltotoiminta voi osoittaa objektiivisesti aivotoiminnan häiriön. Potilailla aivojen rytminen toiminta vaativan kognitiivisen tehtävän aikana erosi kontrolleista. Havaintojemme perusteella sekä hidasaaltotoiminnan esiintyminen, että rytmisen toiminnan muuntuminen kognitiivisten tehtävien aikana voivat jatkossa tarjota kliinisesti merkityksellisiä välineitä arvioitaessa tiedonkäsittelyn tehottomuutta lievän aivovamman jälkeen. Lisätutkimukset laajemmalla aineistolla havaintojemme vahvistamiseksi ovat tarpeellisia aivovamman diagnostiikan kehittämiseksi

Ventral striatal fMRI in affective and psychotic disorders: a transdiagnostic approach using resting state and task functional resonance imaging, clinical and genetic data

The effective clinical management of psychotic and affective disorders still represents a major challenge in psychiatry. Due to the high prevalence of these disorders and the subjective suffering, they cause a massive burden for the health system and society, and improvement in diagnostic and treatment strategies is urgently sought. In consideration of the literature, there are two promising avenues for this endeavour: On the one hand, particularly regarding schizophrenia (SCZ), early detection of high risk states or disease manifestation is crucial for the eventual treatment success. On the other hand, the heterogeneity of psychotic and affective disorders as well as blurry boundaries between the associated clinical syndromes often leave the diagnosis, which is the foundation of an evidence based treatment selection, on shaky ground. At the neurobiological level, several lines of evidence underline the role of the ventral striatum, particularly the nucleus accumbens (NAcc), for the pathophysiology of psychosis and more generally reward processing. Disturbed reward processing in turn is related to anhedonia, a core symptom of major depressive disorder (MDD), bipolar disorder (BD) and also SCZ. Against this background, this thesis aimed to unravel the potential of ventral striatal brain circuits as a source of biomarkers of psychotic and affective disorders. For this purpose, two sub-studies were performed: Firstly, we studied the impact of a validated polygenic risk score (PGRS) for SCZ, childhood adversity (CA) as widespread environmental factor and their interaction on resting state (RS) fMRI measures and NAcc seed connectivity in 253 healthy controls (HC) and compared these patterns with fully expressed disease in 23 patients with SCZ. Consistent with previous reports, SCZ patients showed strong regional functional connectivity density (FCD) increases in subcortical nuclei, particularly in the NAcc, compared with HC. Furthermore, in the HC sample, a a positive association between the FCD of the NAcc and both the PGRS and the interaction between PGRS and CA was found. Fine-mapping exhibited increased connectivity between the NAcc and visual association cortices for high levels of both PGRS and the PGRS-by-CA interaction. Taken together, this study showed that in HC, high PGRS for SCZ affects both global and regionally specific connectivity of the NAcc in a similar pattern as observed in SCZ patients, and that this effect was already amplified even by a history of very mild CA. This latter observation strengthened the notion that environmental factors need consideration in imaging genetics studies. Secondly, we examined the neural underpinnings of reward anticipation (RA) in MDD, BD and SCZ as studied by fMRI. This study revealed that aberrantly low striatal activation during RA is typical of SCZ, whereas the response of this network appeared to be preserved in MDD and BD. Interestingly, two further large-scale brain networks involved in RA – the salience network and the default mode network showed both transdiagnostic and further disease-specific alterations: While the salience network was found to be impaired primarily in SCZ patients, all patient groups revealed deficits in the suppression of the default mode network. Among hub regions of all three networks that were further differentiated in an early and a late response period, levels of anhedonia were correlated with the extent of the (early) hippocampal deactivation failure across diagnostic boundaries. In sum, both investigations confirm the possibility to use fMRI to probe the functional status of the ventral striatum. The first study underlines the centrality of striatal regions in the pahophysiology of psychosis as these alterations already emerged in healthy individuals at high genetic risk for developing SCZ, particularly when including unspecific environmental risk to the model. Hyperconnectivity of this region in SCZ during the resting state matched with a blunted response during the RA task. The latter studyshowed that at least two further large-scale brain networks are impaired in both psychotic and affective disorders during RA, indicating a potential of reward processing as a source of imaging phenotypes or biomarkers to characterize patients of the respective disease spectrum

Dimensions of psychosis: Elucidating the subclinical spectrum using neuroimaging markers

Psychosis unifies a collective of disorders characterised by symptom dimensions (Gaebel & Zielasek, 2015). Purposefully delimited clinical descriptors of schizophrenia spectrum and psychotic disorders (American Psychiatric Association, 2013) impose challenges on the identification of aetiological and clinically meaningful predictors. The disassembly of psychiatric diagnoses into their elementary symptom dimensions has helped formulate psychosis phenotypes fitted on a psychosis continuum (Verdoux & van Os, 2002). Aetiological models of psychosis may be studied through schizotypy and transient psychotic experiences (Barrantes-Vidal et al., 2015; Nelson, Fusar-Poli, & Yung, 2012), collectively termed subclinical psychosis phenotypes. The dimensional psychometric structures of these phenotypes varying in temporal stability (Linscott & van Os, 2013; Mason et al., 1995; Stefanis et al., 2002), and their implications might be further consolidated when paired with neuroimaging parameters (Siever & Davis, 2004). Three neuroimaging studies aimed to examine the relationship between subclinical psychotic phenotypes and neurobiology. Surface and volume-based morphometric (VBM) methods were implemented to examine the variety of cortical and subcortical signatures of different phenotype dimensions. Study 1 investigated whether cortical surface gyrification -a maker of genetic and developmental influences on cortical morphology (Docherty et al., 2015; Haukvik et al., 2012)- is associated with dimensional psychosis prone phenomena (Konings, Bak, Hanssen, van Os, & Krabbendam, 2006; Stefanis et al., 2002). Early cortical organisation contributes to cognitive capacities in later life (Gautam et al., 2015; Gregory et al., 2016; Papini et al., 2020). Given that cognitive deficits are present in psychosis prone and clinical samples to varying extents (Hou et al., 2016; Siddi et al., 2017), Study 1 also explored the mediating role of cognition (both as a general measure and intelligence quotient) as a psychosis endophenotype in the relationship between regional gyrification and PLE distress. Study 2 and Study 3 used VBM to investigate structural brain correlates for psychotic-like experiences (PLE) and trait psychosis phenotypes (schizotypy). Different PLE facets (quantity and distress severity) (Hanssen, Bak, et al., 2005; Ising et al., 2012) were used to estimate whole-brain grey matter volume, followed by interaction models in subsequent prefrontal regions of interest (Study 2). The medial temporal lobe includes the hippocampal subfields, which are regions of interest in psychosis pathophysiology (Lieberman et al., 2018; Mathew et al., 2014; Schobel et al., 2013). Based on a previous study in schizoytypy (Sahakyan et al., 2020), Study 3 examined the relationship between schizotypal trait dimensions (Mason et al., 1995) and PLE, and their interactions, and hippocampal subfields and the amygdala. The results of Study 1 showed that psychometrically assessed PLE were associated with reduced gyrification in parietal and temporal regions, indicating that psychosis proneness correlates with neurodevelopmental factors (Fonville et al., 2019; Liu et al., 2016). A lack of mediating pathways between regional gyrification and PLE suggested that cognition effects may emerge in larger samples (Mollon et al., 2016) and/or increasingly psychosis pone phenotypes. Elaborating on the distinction between PLE quantity versus distress, Study 2 showed that PLE load, but not distress severity, were associated with volume increases in prefrontal and occipitotemporal regions. At increased distress severity for perceptual abnormalities, PLE were associated with regional volume reductions of the superior frontal gyrus. Study 3 showed differential relationships between schizotypy dimensions and volumes of the MTL that are involved in the pathophysiology of schizophrenia. PLE per se did not associate with amygdala or hippocampal subfield volumes, but a positive association between the hippocampal subiculum and PLE was moderated by positive schizotypy. Study 3 underscored the enhanced usefulness of schizotypy as an endophenotype in psychosis research when its multidimensional organisation (Grant, 2015; Vollema & van den Bosch, 1995) is respected. The results support the use of psychosis symptom dimensions, showing different (positive and negative) neuroanatomical associations. While case-control studies in schizophrenia show consistent volume reductions of the prefrontal and temporal cortices (Haijma et al., 2013; Honea, Crow, Passingham, & Mackay, 2005), these findings contribute to more heterogeneous volumetric relationships in nonclinical individuals. Reduced regional cortical gyrification proposes a continuous distribution of neurodevelopmental impacts. Distress severity and schizotypy occasioned modulatory effects in prefrontal and hippocampal subfield volumes, respectively. Collectively, these three cross-sectional studies extend previous research suggesting that dimensional phenotypes show neuroanatomical variation supportive of a psychosis continuum possibly characterised by an underlying non-linearity (Bartholomeusz et al., 2017; Binbay et al., 2012; Johns & van Os, 2001)