Structural and functional largescale brain network dynamics: Examples from mental disorders

Hjernen er organisert i ulike funksjonelle og strukturelle nettverk. Til tross for omfattende forskning, er fremdeles ikke funksjonen og dynamikken i slike nettverk godt forstått. En økt innsikt kan være avgjørende for å forstå symptomer, og mekanismene som kontrollerer disse, hos pasienter med psykiske lidelser som schizofreni. Avhandlingen omfatter tre studier som hver adresserer ulike delmål i forskningen. Den første studien undersøker endringer i strukturelle nettverk hos en gruppe pasienter med schizofreni. Studien viser på gruppenivå at det er dels utbredte strukturelle forskjeller i hvit substans hos pasienter med schizofreni som opplever hørselshallusinasjoner sammenlignet med pasienter som ikke opplever disse hallusinasjonen. For å undersøke mulig samsvarende funksjonelle endringer har det vært behov for først å utvikle en ny tilnærming for å måle forskjeller i dynamikken mellom hjernens nettverk i hvile (DMN) og i aktiv oppgaveløsing av krevende kognitive oppgaver (EMN) hos en gruppe friske frivillige deltakere. I korte trekk, ble tre ulike visuelle, kognitive oppgaver presentert for deltakerne gjennom et fMRI blokk design. Resultatene i studien viste en antikorrelasjon i tid i områder som er involvert i henholdsvis hvile (DMN) og aktiv tilstand (EMN). For å gjøre undersøkelser hos pasienter med psykiske lidelser mindre tidkrevende, beskrives i avhandlingen også en studie som undersøker om hvileområder i hjernen (DMN) som er aktivert nettopp som del av en fMRI blokk design studier overlapper med en tilleggsundersøkelse med femminutters kontinuerlig hvile («resting state»). Sammenligningen er også interessant fra et mer basalforskningsperspektiv fordi en rask endring mellom aktiv tilstand og hvile kanskje bedre reflekterer en realistisk hviletilstand enn den kontinuerlige undersøkelsen som i dag representerer «gullstandarden» i denne type forskning. Resultatene fra studien viste stor grad av overlapp mellom aktiverte områder og at den foreslåtte tilnærmingen dermed kan ha et stort potensial i videre undersøkelser. I sum beskriver forskningen i avhandlingen muligheter for å undersøke strukturelle og funksjonelle nettverk hos pasienter med psykiske lidelser. Avhandlingen viser første resultater hos pasienter med schizofreni som strukturelle forskjeller i hvit substans mellom pasientgrupper avhengig om de opplever hørselshallusinasjoner eller ikke. Slike undersøkelser kan og bør komplementeres med undersøkelser av funksjonelle nettverk slik som foreslått i de andre studiene i avhandlingen, og i sum bidra til et godt rammeverk for videre undersøkelser hos pasienter.The human brain is organized in various networks both functionally and structurally. However, despite the extensive research on brain connectivity, which was made possible due to the development of in vivo brain imaging techniques, the neuroscientific field is still far from fully comprehending networks function and dynamics. Detailed knowledge about the relationship between various brain networks is essential for understanding the function of the healthy brain. However, many studies on mental disorders such as schizophrenia suggest that it might be caused by abnormal brain network functioning and structural aberrations. Therefore, the knowledge of the brain network's dynamics and structure might be critical for revealing the underpinnings of mental disorders such as schizophrenia. The presented thesis had three main goals, resulting in three structural and functional imaging studies. Firstly, the brain's structural connectivity affected by schizophrenia has been investigated to determine the nature and extent of its changes. Hence, Diffusion Tensor Imaging (DTI) and tract-based spatial statistics (TBSS) were employed to explore white matter differences between subtypes of schizophrenia patients compared to healthy controls. This study revealed widespread FA-value reduction in the hallucinating schizophrenia subjects' white matter compared to non-hallucinating ones. Since widespread aberrations of the white matter should affect the function of the large-scale brain networks, the second goal was to explore the two main functional brain networks, Default Mode Network (DMN) and Extrinsic Mode Network (EMN). This is because dysfunction of DMN and EMN networks has been previously suggested to be significant for the generation of symptoms of schizophrenia disorder, such as Auditory Verbal Hallucinations (AVH). Since the concept of EMN is relatively new and not yet deeply explored, and additionally protocol used in that study has not been previously utilized to study EMN and DMN, it was first necessary to test the design in a group of healthy participants. This study used the novel protocol based on the classic block design fMRI experiment with three different visual tasks: mental rotation, working memory, and mental arithmetic. The results of study II proved the existence of the EMN that is anti-correlated with the DMN and is domain-general. Lastly, the neuroimaging studies of the participants suffering from mental disorders such as schizophrenia require relatively short and effective examination protocols. Therefore, the last project investigated both similarities and differences in DMN activity between two experimental designs: block design and resign state. A classic block design experiment would be a good candidate for the investigation reflecting the fluctuating activity of the brain during typical daily activity. The results of Study III showed that the activity of the DMN was generally similar in the two experiments, though with some discrepancies. These differences were in the DMN architecture itself and concerning the relations of the DMN with other brain networks. These findings, in combination with the results of study number two suggest that the block design experiment could be the most effective for studying the function of the brain in schizophrenia. The studies incorporated in that thesis add to the current findings on the white matter alterations in schizophrenia disorder and contribute to a better understanding of the function and dynamics of the large-scale brain networks: EMN and DMN. Last but not least, the performed studies give a good background for future clinical studies on schizophrenia disorder.Doktorgradsavhandlin

Dynamic switching between intrinsic and extrinsic mode networks as demands change from passive to active processing

In this study we report on the relationship between default and extrinsic mode networks across alternating brief periods of rest and active task processing. Three different visual tasks were used in a classic fMRI ON–OFF block design where task (ON) blocks alternated with equal periods of rest (OFF) blocks: mental rotation, working memory and mental arithmetic. We showed the existence of a generalized task-positive network, labelled the extrinsic mode network (EMN) that is anti-correlated with the default mode network (DMN) as processing demands shifted from rest to active processing. We then identified two key regions of interest (ROIs) in the supplementary motor area (SMA) and precuneus/posterior cingulate cortex (PCC) regions as hubs for the extrinsic and intrinsic networks, and extracted the time-course from these ROIs. The results showed a close to perfect anti-correlation for the SMA and Precuneus/PCC time-courses for ON- and OFF-blocks. We suggest the existence of two large-scale networks, an extrinsic mode network and an intrinsic mode network, which are up- and down-regulated as environmental demands change from active to passive processing.publishedVersio

Similarities and differences between intermittent and continuous resting-state fMRI

Introduction: Functional Magnetic Resonance Imaging (fMRI) block-design experiments typically include active ON-blocks with presentation of cognitive tasks which are contrasted with OFF- blocks with no tasks presented. OFF-blocks in between ON-blocks can however, also be seen as a proxy for intermittent periods of resting, inducing temporary resting-states. We still do not know if brain activity during such intermittent periods reflects the same kind of resting-state activity as that obtained during a continuous period, as is typically the case in studies of the classic Default Mode Network (DMN). The purpose of the current study was therefore to investigate both similarities and differences in brain activity between intermittent and continuous resting conditions. Methods: There were 47 healthy participants in the 3T fMRI experiment. Data for the intermittent resting-state condition were acquired from resting-periods in between active task-processing periods in a standard ON-OFF block design, with three different cognitive tasks presented during ON-blocks. Data for the continuous resting-state condition were acquired during a 5 min resting period after the task-design had been presented. Results and discussion: The results showed that activity was overall similar in the two conditions, but with some differences. These differences were within the DMN network, and for the interaction of DMN with other brain networks. DMN maps showed weak overlap between conditions in the medial prefrontal cortex (MPFC), and in particular for the intermittent compared to the continuous resting-state condition. Moreover, DMN showed strong connectivity with the salience network (SN) in the intermittent resting-state condition, particularly in the anterior insula and the supramarginal gyrus. The observed differences may reflect a “carry-over” effect from task-processing to the next resting-state period, not present in the continuous resting-state condition, causing interference from the ON-blocks. Further research is needed to fully understand the extent of differences between intermittent and continuous resting-state conditions.publishedVersio

White matter microstructural differences between hallucinating and non-hallucinating schizophrenia spectrum patients

The relation between auditory verbal hallucinations (AVH) and white matter has been studied, but results are still inconsistent. This inconsistency may be related to having only a single time-point of AVH assessment in many studies, not capturing that AVH severity fluctuates over time. In the current study, AVH fluctuations were captured by utilizing a longitudinal design and using repeated (Positive and Negative Symptoms Scale) PANSS questionnaire interviews over a 12 month period. We used a Magnetic Resonance Diffusion Tensor Imaging (MR DTI) sequence and tract-based spatial statistics (TBSS) to explore white matter differences between two subtypes of schizophrenia patients; 44 hallucinating (AVH+) and 13 non-hallucinating (AVH-), compared to 13 AVH- matched controls and 44 AVH+ matched controls. Additionally, we tested for hemispheric fractional anisotropy (FA) asymmetry between the groups. Significant widespread FA-value reduction was found in the AVH+ group in comparison to the AVH- group. Although not significant, the extracted FA-values for the control group were in between the two patient groups, for all clusters. We also found a significant difference in FA-asymmetry between the AVH+ and AVH- groups in two clusters, with significantly higher leftward asymmetry in the AVH- group. The current findings suggest a possible qualitative difference in white matter integrity between AVH+ and AVH- patients. Strengths and limitations of the study are discussed.publishedVersio

Simultaneous Measurement of the BOLD Effect and Metabolic Changes in Response to Visual Stimulation Using the MEGA-PRESS Sequence at 3 T

The blood oxygen level dependent (BOLD) effect that provides the contrast in functional magnetic resonance imaging (fMRI) has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy (MRS) and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate (measured as Glx) and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex (OCC) of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods.publishedVersio

Dynamic switching between intrinsic and extrinsic mode networks as demands change from passive to active processing

In this study we report on the relationship between default and extrinsic mode networks across alternating brief periods of rest and active task processing. Three different visual tasks were used in a classic fMRI ON–OFF block design where task (ON) blocks alternated with equal periods of rest (OFF) blocks: mental rotation, working memory and mental arithmetic. We showed the existence of a generalized task-positive network, labelled the extrinsic mode network (EMN) that is anti-correlated with the default mode network (DMN) as processing demands shifted from rest to active processing. We then identified two key regions of interest (ROIs) in the supplementary motor area (SMA) and precuneus/posterior cingulate cortex (PCC) regions as hubs for the extrinsic and intrinsic networks, and extracted the time-course from these ROIs. The results showed a close to perfect anti-correlation for the SMA and Precuneus/PCC time-courses for ON- and OFF-blocks. We suggest the existence of two large-scale networks, an extrinsic mode network and an intrinsic mode network, which are up- and down-regulated as environmental demands change from active to passive processing

Dynamic up- and down-regulation of thedefault (DMN) and extrinsic (EMN) modenetworks during alternating task-on and task-offperiods

Using fMRI, Hugdahl et al. (2015) reported the existence of a general-domain cortical network during active task-processing which was non-specific to the cognitive task being processed. They labelled this network the extrinsic mode network (EMN). The EMN would be predicted to be negatively, or anti-correlated with the classic default mode network (DMN), typically observed during periods of rest, such that while the EMN should be down-regulated and the DMN up-regulated in the absence of demands for task-processing, the reverse should occur when demands change from resting to task-processing. This would require alternating periods of task-processing and resting and analyzing data continuously when demands change from active to passive periods and vice versa. We were particularly interested in how the networks interact in the critical transition points between conditions. For this purpose, we used an auditory task with multiple cognitive demands in a standard fMRI block-design. Task-present (ON) blocks were alternated with an equal number of task-absent, or rest (OFF) blocks to capture network dynamics across time and changing environmental demands. To achieve this, we specified the onset of each block, and used a finite-impulse response function (FIR) as basis function for estimation of the fMRI-BOLD response. During active (ON) blocks, the results showed an initial rapid onset of activity in the EMN network, which remained throughout the period, and faded away during the first scan of the OFF-block. During OFF blocks, activity in the DMN network showed an initial time-lag where neither the EMN nor the DMN was active, after which the DMN was up-regulated. Studying network dynamics in alternating passive and active periods may provide new insights into brain network interaction and regulation

White matter microstructural differences between hallucinating and non-hallucinating schizophrenia spectrum patients

The relation between auditory verbal hallucinations (AVH) and white matter has been studied, but results are still inconsistent. This inconsistency may be related to having only a single time-point of AVH assessment in many studies, not capturing that AVH severity fluctuates over time. In the current study, AVH fluctuations were captured by utilizing a longitudinal design and using repeated (Positive and Negative Symptoms Scale) PANSS questionnaire interviews over a 12 month period. We used a Magnetic Resonance Diffusion Tensor Imaging (MR DTI) sequence and tract-based spatial statistics (TBSS) to explore white matter differences between two subtypes of schizophrenia patients; 44 hallucinating (AVH+) and 13 non-hallucinating (AVH-), compared to 13 AVH- matched controls and 44 AVH+ matched controls. Additionally, we tested for hemispheric fractional anisotropy (FA) asymmetry between the groups. Significant widespread FA-value reduction was found in the AVH+ group in comparison to the AVH- group. Although not significant, the extracted FA-values for the control group were in between the two patient groups, for all clusters. We also found a significant difference in FA-asymmetry between the AVH+ and AVH- groups in two clusters, with significantly higher leftward asymmetry in the AVH- group. The current findings suggest a possible qualitative difference in white matter integrity between AVH+ and AVH- patients. Strengths and limitations of the study are discussed

Simultaneous Measurement of the BOLD Effect and Metabolic Changes in Response to Visual Stimulation Using the MEGA-PRESS Sequence at 3 T

The blood oxygen level dependent (BOLD) effect that provides the contrast in functional magnetic resonance imaging (fMRI) has been demonstrated to affect the linewidth of spectral peaks as measured with magnetic resonance spectroscopy (MRS) and through this, may be used as an indirect measure of cerebral blood flow related to neural activity. By acquiring MR-spectra interleaved with frames without water suppression, it may be possible to image the BOLD effect and associated metabolic changes simultaneously through changes in the linewidth of the unsuppressed water peak. The purpose of this study was to implement this approach with the MEGA-PRESS sequence, widely considered to be the standard sequence for quantitative measurement of GABA at field strengths of 3 T and lower, to observe how changes in both glutamate (measured as Glx) and GABA levels may relate to changes due to the BOLD effect. MR-spectra and fMRI were acquired from the occipital cortex (OCC) of 20 healthy participants whilst undergoing intrascanner visual stimulation in the form of a red and black radial checkerboard, alternating at 8 Hz, in 90 s blocks comprising 30 s of visual stimulation followed by 60 s of rest. Results show very strong agreement between the changes in the linewidth of the unsuppressed water signal and the canonical haemodynamic response function as well as a strong, negative, but not statistically significant, correlation with the Glx signal as measured from the OFF spectra in MEGA-PRESS pairs. Findings from this experiment suggest that the unsuppressed water signal provides a reliable measure of the BOLD effect and that correlations with associated changes in GABA and Glx levels may also be measured. However, discrepancies between metabolite levels as measured from the difference and OFF spectra raise questions regarding the reliability of the respective methods