This dissertation focused on the neural and behavioral mechanisms underlying adolescent learning and mental health in the context of peers and friends. The neuroimaging findings revealed that... Show moreThis dissertation focused on the neural and behavioral mechanisms underlying adolescent learning and mental health in the context of peers and friends. The neuroimaging findings revealed that reward processing for self and peers rely on common reward-related brain regions, whereas a social brain region (TPJ) showed social specificity to observed outcomes for unfamiliar peers compared to friends. Moreover, typically developing adolescents and adolescents with ADHD show neural sensitivity in reward and salience brain regions towards rewards for themselves, friends and peers compared to losses. There were no group differences in neural processing of (vicarious) outcomes between adolescents with and without ADHD, yet a symptom-level approach showed more neural sensitivity for own compared to friends’ losses in individuals with more inattention symptoms. The behavioral findings indicated that adolescents’ learning performance benefitted from observing the choices and outcomes of peers irrespective of the relationship with this peer. The results did not show effects of friendship (quality) and social status on observational and academic learning, but there was a protective effect of friendship quality on internalizing problems. Taken together, these findings highlight adolescence as a period of observational learning opportunities from different types of peers. Adolescence can also serve as a window of opportunity to improve mental health by fostering high-quality friendships. Show less
Despite decades of research from psychology, anthropology, biology and economics, how social preferences arise and vary across contexts remains an open question. In three empirical chapters, this... Show moreDespite decades of research from psychology, anthropology, biology and economics, how social preferences arise and vary across contexts remains an open question. In three empirical chapters, this dissertation addresses this gap using a variety of economic games and neuroimaging techniques that allow for a tractable modeling of cooperation and competition. Overall, findings suggest that while social preferences are linked to neural structure, they can also adapt to environmental factors as well as beliefs about interaction partners. This doctoral thesis shows that interacting with ingroup or outgroup members, taking decisions publicly or privately, and knowing whether we may interact with others again affect our cooperative behavior. These results highlight the importance of understanding how prosociality may be altered and lay the foundations for policy makers to further those social environments that encourage prosocial behavior. Show less
Why do some children easily find their way in social situations and are satisfied with their social lives, while others experience more difficulties? One key component that may explain this is... Show moreWhy do some children easily find their way in social situations and are satisfied with their social lives, while others experience more difficulties? One key component that may explain this is social competence: the ability to fulfill both own and other’s social goals. This thesis focused on individual differences in social competence from childhood to adolescence by examining contextual, developmental and neurobiological influences on aggressive and prosocial responses to social evaluation. Findings showed robust neural processes related to social feedback and subsequent aggression already in middle childhood. Additionally, this thesis revealed that the period between childhood and adolescence is important for the behavioral and neural development of inhibition of aggression following negative, neutral and positive social feedback. Aggression following social feedback decreased towards adolescence, but aggression following positive feedback decreased earlier in childhood than following negative feedback. Moreover, the involvement of the dorsolateral prefrontal cortex, known for its role in executive functioning, decreased over time. Finally, results indicated that the co-occurrence of aggression following rejection and prosocial behavior following observed rejection may possibly protect against externalizing behaviors and promote wellbeing. This thesis highlights the importance of examining the interplay of developmental processes across social contexts to understand mental health outcomes. Show less
The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this... Show moreThe characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pul-satility is crucial for normal emotional response in man. In this study, we investigate the anatomical tran-scriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling - the ANXA1 gene and retrograde endocannabinoid signaling - show most significant differential expression (q = 3.99e- 10) and enrichment (fold enrichment = 5.56, q = 9.09e-4). Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies. Show less
Meer, A.F. van; Steenbergen, H. van; Dillen, L.F. van 2023
Distracted eating can cause overconsumption. Whereas previous work has shown that cognitive load suppresses perceived taste intensity and increases subsequent consumption, the mechanism behind... Show moreDistracted eating can cause overconsumption. Whereas previous work has shown that cognitive load suppresses perceived taste intensity and increases subsequent consumption, the mechanism behind distraction-induced overconsumption remains unclear. To elucidate this, we performed two event-related fMRI experiments that examined how cognitive load affects neural responses and perceived intensity and preferred intensity, respectively, to solutions varying in sweetness. In Experiment 1 (N = 24), participants tasted weak sweet and strong sweet glucose solutions and rated their intensity while we concurrently varied cognitive load using a digit-span task. In Experiment 2 (N = 22), participants tasted five different glucose concentrations under varying cognitive load and then indicated whether they wanted to keep, decrease or increase its sweetness. Participants in Experiment 1 rated strong sweet solutions as less sweet under high compared to low cognitive load, which was accompanied by attenuated activation the right middle insula and bilateral DLPFC. Psychophysiological interaction analyses showed that cognitive load moreover altered connectivity between the middle insula and nucleus accumbens and DLPFC and middle insula while tasting strong sweet solutions. In Experiment 2, cognitive load did not affect participants’ preferred sweetness intensity. fMRI results revealed that cognitive load attenuated DLPFC activation for the strongest sweet solutions in the study. In conclusion, our behavioral and neuroimaging results suggest that cognitive load dampens the sensory processing of strong sweet solutions in particular, which may indicate higher competition for attentional resources for strong sweet than weak sweet solutions under high cognitive load. Implications for future research are discussed. Show less
Background: This study aimed to investigate whether people with borderline personality disorder (BPD) can benefit from reliving positive autobiographical memories in terms of mood and state self... Show moreBackground: This study aimed to investigate whether people with borderline personality disorder (BPD) can benefit from reliving positive autobiographical memories in terms of mood and state self-esteem and elucidate the neural processes supporting optimal memory reliving. Particularly the role of vividness and brain areas involved in autonoetic consciousness were studied, as key factors involved in improving mood and state self-esteem by positive memory reliving. Methods: Women with BPD (N = 25), Healthy Controls (HC, N = 33) and controls with Low Self-Esteem (LSE, N = 22) relived four neutral and four positive autobiographical memories in an MRI scanner. After reliving each memory mood and vividness was rated. State self-esteem was assessed before and after the Reliving Autobio-graphical Memories (RAM) task. Results: Overall, mood and state self-esteem were lower in participants with BPD compared to HC and LSE, but both the BPD and LSE group improved significantly after positive memory reliving. Moreover, participants with BPD indicated that they relived their memories with less vividness than HC but not LSE, regardless of valence. When reliving (vs reading) memories, participants with BPD showed increased precuneus and lingual gyrus activation compared to HC but not LSE, which was inversely related to vividness. Discussion: Women with BPD seem to experience more challenges in reliving neutral and positive autobio-graphical memories with lower vividness and less deactivated precuneus potentially indicating altered autono-etic consciousness. Nevertheless, participants with BPD do benefit in mood and self-esteem from reliving positive memories. These findings underline the potential of positive autobiographical memory reliving and suggest that interventions may be further shaped to improve mood and strengthen self-views in people with BPD. Show less
Gool, J.K.; Fronczek, R.; Bosma, P.; Meer, J.N. van der; Werf, Y.D. van der; Lammers, G.J. 2022
The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment... Show moreThe brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual's ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting. Show less
Jepma, M.; Roy, M.; Ramlakhan, K.; Velzen, M. van; Dahan, A. 2022
Both unexpected pain and unexpected pain absence can drive avoidance learning, but whether they do so via shared or separate neural and neurochemical systems is largely unknown. To address this... Show moreBoth unexpected pain and unexpected pain absence can drive avoidance learning, but whether they do so via shared or separate neural and neurochemical systems is largely unknown. To address this issue, we combined an instrumental pain-avoidance learning task with computational modeling, functional magnetic resonance imaging (fMRI), and pharmacological manipulations of the dopaminergic (100 mg levodopa) and opioidergic (50 mg naltrexone) systems (N = 83). Computational modeling provided evidence that untreated participants learned more from received than avoided pain. Our dopamine and opioid manipulations negated this learning asymmetry by selectively increasing learning rates for avoided pain. Furthermore, our fMRI analyses revealed that pain prediction errors were encoded in subcortical and limbic brain regions, whereas no-pain prediction errors were encoded in frontal and parietal cortical regions. However, we found no effects of our pharmacological manipulations on the neural encoding of prediction errors. Together, our results suggest that human pain-avoidance learning is supported by separate threat- and safety-learning systems, and that dopamine and endogenous opioids specifically regulate learning from successfully avoided pain. Show less
The overarching goal of this thesis was to examine the behavioral, computational, and neural mechanisms underlying social learning in adolescence. The first aim was to examine developmental... Show moreThe overarching goal of this thesis was to examine the behavioral, computational, and neural mechanisms underlying social learning in adolescence. The first aim was to examine developmental patterns across adolescence of two forms of social learning: (1) learning about other people, specifically, whether they are (un)cooperative and (un)trustworthy, and (2) learning for other people (prosocial learning) to know what actions may benefit or help others. I made use of multiple experimental paradigms based on well-known economic games and/or probabilistic reinforcement learning paradigms to assess these forms of social learning. Secondly, I aimed to examine underlying mechanisms and factors that account for age-related and individual differences in social learning. Applying computational modeling and functional neuroimaging as additional tools contributed to a better understanding of the underlying mechanisms and how these develop across adolescence. The findings in this thesis converge to early-to-mid adolescence as a key developmental period for developing well-adjusted social behaviors, and especially in the cooperative domain there are pronounced improvements. These studies make an important contribution to the literature on social development and learning, and may eventually contribute to interventions targeted at promoting well-adjusted behavior in typically developing adolescents, as well as youth with maladaptive social tendencies. Show less
In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory... Show moreIn modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible light-emitting diode devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that blood oxygen level-dependent (BOLD) functional MRI signals in the SCN were suppressed by light. The suppressions were observed not only in response to narrowband blue light (lambda max: 470 nm) but remarkably, also in response to green (lambda max: 515 nm) and orange (lambda max: 590 nm), but not to violet light (lambda max: 405 nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive. Show less
Neuroimaging studies suggest that intranasal oxytocin (IN-OXT) may modulate emotional and social processes by altering neural activity patterns. The extent of brain penetration after IN-OXT is... Show moreNeuroimaging studies suggest that intranasal oxytocin (IN-OXT) may modulate emotional and social processes by altering neural activity patterns. The extent of brain penetration after IN-OXT is unclear, and it is currently unknown whether IN-OXT can directly bind central oxytocin receptors (OXTRs). We investigated oxytocin pathway gene expression in regions affected by IN-OXT on task-based fMRI. We found that OXTR is more highly expressed in affected than unaffected subcortical regions; this effect did not vary by task type or sex. Cortical results revealed higher OXTR expression in regions affected by IN-OXT in emotional processing tasks and in male-only data. No significant differences were found in expression of the closely related vasopressin receptors. Our findings suggest that the mechanism by which IN-OXT may alter brain functionality involves direct activation of central OXTRs. Show less
Chappell, M.A.; McConnell, F.A.K.; Golay, X.; Gunther, M.; Hernandez-Tamames, J.A.; Osch, M.J. van; Asllani, I. 2021
The mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE),... Show moreThe mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE), which in turn confounds the estimation of perfusion into a specific tissue of interest such as gray or white matter. This confound occurs because the image voxels contain a mixture of tissues with disparate perfusion properties, leading to estimated perfusion values that reflect primarily the volume proportions of tissues in the voxel rather than the perfusion of any particular tissue of interest within that volume. It is already recognized that PVE influences studies of brain perfusion, and that its effect might be even more evident in studies where changes in perfusion are co-incident with alterations in brain structure, such as studies involving a comparison between an atrophic patient population vs control subjects, or studies comparing subjects over a wide range of ages. However, the application of PVE correction (PVEc) is currently limited and the employed methodologies remain inconsistent. In this article, we outline the influence of PVE in ASL measurements of perfusion, explain the main principles of PVEc, and provide a critique of the current state of the art for the use of such methods. Furthermore, we examine the current use of PVEc in perfusion studies and whether there is evidence to support its wider adoption. We conclude that there is sound theoretical motivation for the use of PVEc alongside conventional, 'uncorrected', images, and encourage such combined reporting. Methods for PVEc are now available within standard neuroimaging toolboxes, which makes our recommendation straightforward to implement. However, there is still more work to be done to establish the value of PVEc as well as the efficacy and robustness of existing PVEc methods. Show less
This thesis consists of three empirical chapters that investigate elements of human social behavior, adherence to and violations of social norms, and the computational and neurological... Show moreThis thesis consists of three empirical chapters that investigate elements of human social behavior, adherence to and violations of social norms, and the computational and neurological underpinnings thereof. I focus on three behavioral paradigms in particular – the attacker-defender contest, the trust game, and the ultimatum game – which model asymmetrical conflicts, generosity and reciprocity, and norms of fairness, respectively. Ultimately, each chapter acts as a building block contributing a different perspective to the study of human sociality. Using economic games, computational models based on the principle of utility, and model-based neuroimaging, my research contributes to the scientific endeavor working to crack the “elaborate and secret code that is written nowhere, known by none, and understood by all” (Sapir, 1927, p.137) Show less
Bas-Hoogendam, J.M.; Steenbergen, H. van; Tissier, R.L.M.; Wee, N.J.A. van der; Westenberg, P.M. 2020
BACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial... Show moreBACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial prefrontal cortex activation in response to unintentional social norm (SN) transgressions, accompanied by increased embarrassment ratings for such SN violations. Here, we used data from the multiplex, multigenerational LFLSAD (Leiden Family Lab study on Social Anxiety Disorder), which involved two generations of families genetically enriched for SAD, and investigated whether these neurobiological and behavioral correlates of unintentional SN processing are SAD endophenotypes. Of four endophenotype criteria, we examined two: first, the cosegregation of these characteristics with social anxiety (SA) within families of SAD probands (criterion 4), and second, the heritability of the candidate endophenotypes (criterion 3).METHODS: Participants (n = 110, age range 9.0-61.5 years, eight families) performed the revised Social Norm Processing Task; functional magnetic resonance imaging data and behavioral ratings related to this paradigm were used to examine whether brain activation in response to processing unintentional SN violations and ratings of embarrassment were associated with SA levels. Next, heritability of these measurements was estimated.RESULTS: As expected, voxelwise functional magnetic resonance imaging analyses revealed positive associations between SA levels and brain activation in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, and these brain activation levels displayed moderate to moderately high heritability. Furthermore, although SA levels correlated positively with behavioral ratings of embarrassment for SN transgressions, these behavioral characteristics were not heritable.CONCLUSIONS: These results show, for the first time, that brain responses in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, related to processing unintentional SN violations, provide a neurobiological candidate endophenotype of SAD. Show less
Ai, H.; Opmeer, E.M.; Marsman, J.B.C.; Veltman, D.J.; Wee, N.J.A. van der; Aleman, A.; Tol, M.J. van 2020
Background The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are... Show moreBackground The importance of the hippocampus and amygdala for disrupted emotional memory formation in depression is well-recognized, but it remains unclear whether functional abnormalities are state-dependent and whether they are affected by the persistence of depressive symptoms. Methods Thirty-nine patients with major depressive disorder and 28 healthy controls were included from the longitudinal functional magnetic resonance imaging (fMRI) sub-study of the Netherlands Study of Depression and Anxiety. Participants performed an emotional word-encoding and -recognition task during fMRI at baseline and 2-year follow-up measurement. At baseline, all patients were in a depressed state. We investigated state-dependency by relating changes in brain activation over time to changes in symptom severity. Furthermore, the effect of time spent with depressive symptoms in the 2-year interval was investigated. Results Symptom change was linearly associated with higher activation over time of the left anterior hippocampus extending to the amygdala during positive and negative word-encoding. Especially during positive word encoding, this effect was driven by symptomatic improvement. There was no effect of time spent with depression in the 2-year interval on change in brain activation. Results were independent of medication- and psychotherapy-use. Conclusion Using a longitudinal within-subjects design, we showed that hippocampal-amygdalar activation during emotional memory formation is related to depressive symptom severity but not persistence (i.e. time spent with depression or 'load'), suggesting functional activation patterns in depression are not subject to functional 'scarring' although this hypothesis awaits future replication. Show less
Neurolinguistic approaches to morphology include the main theories of morphological representation and processing in the human mind, such as full-listing, full-parsing, and hybrid dual-route models... Show moreNeurolinguistic approaches to morphology include the main theories of morphological representation and processing in the human mind, such as full-listing, full-parsing, and hybrid dual-route models, and how the experimental evidence that has been acquired tosupport these theories uses different neurolinguistic paradigms (visual and auditory prim ing, violation, long-lag priming, picture-word interference, etc.) and methods (electroen cephalography [EEG]/event-related brain potential [ERP], functional magnetic resonance imaging [fMRI], neuropsychology, and so forth). Show less
Background: The combination of EEG and ultra-high-field (7T and above) fMRI holds the promise to relate electrophysiology and hemodynamics with greater signal to noise level and at higher spatial... Show moreBackground: The combination of EEG and ultra-high-field (7T and above) fMRI holds the promise to relate electrophysiology and hemodynamics with greater signal to noise level and at higher spatial resolutions than conventional field strengths. Technical and safety restrictions have so far resulted in compromises in terms of MRI coil selection, resulting in reduced, signal quality, spatial coverage and resolution in EEG-fMRI studies at 7 T.New method: We adapted a 64-channel MRI-compatible EEG cap so that it could be used with a closed 32-channel MRI head coil thus avoiding several of these compromises. We compare functional and anatomical as well as the EEG quality recorded with this adapted setup with those recorded with a setup that uses an open-ended 8-channel head-coil.Results: Our set-up with the adapted EEG cap inside the closed 32 channel coil resulted in the recording of good quality EEG and (f)MRI data. Both functional and anatomical MRI images show no major effects of the adapted EEG cap on MR signal quality. We demonstrate the ability to compute ERPs and changes in alpha and gamma oscillations from the recorded EEG data.Comparison with existing methods: Compared to MRI recordings with an 8-channel open-ended head-coil, the loss in signal quality of the MRI images related to the adapted EEG cap is considerably reduced.Conclusions: The adaptation of the EEG cap permits the simultaneous recording of good quality whole brain (f) MRI data using a 32 channel receiver coil, while maintaining the quality of the EEG data. Show less
People diagnosed with Borderline Personality Disorder (BPD) continuously struggle with knowing who they are and maintaining relationships. Fortunately, psychotherapies for BPD have proven effective... Show morePeople diagnosed with Borderline Personality Disorder (BPD) continuously struggle with knowing who they are and maintaining relationships. Fortunately, psychotherapies for BPD have proven effective. However, not everyone benefits from treatment with particular challenges remaining in social relations and finding meaning in life. Therefore, it is important to understand how we can better support people with BPD.We know that identity disturbances relate to interpersonal difficulties but we do not really understand how. Therefore, we investigated how interactions with others are influenced by how people see themselves, in the general population and in people diagnosed with BPD. To this end, we studied brain activation and the role of childhood trauma and low self-esteem. In addition, we investigated whether self-views can be strengthened using positive memories.We found that the way people respond to critiques and compliments relates to how positive or negative they see themselves. Moreover, vivid positive memories can benefit mood and self-esteem. However, people with BPD seem to not sufficiently distance themselves from critiques nor engage in positive memories and compliments. Finding the right balance between distance from critiques and engagement with a positive self-image may break the cycle of negative self-knowledge and contribute to better social interactions. Show less
This thesis describes a cross-sectional behavioral and neuroimaging study in a sample of n=85 adolescents with a history of childhood sexual abuse related PTSD (CSA-related PTSD), anxiety and/or... Show moreThis thesis describes a cross-sectional behavioral and neuroimaging study in a sample of n=85 adolescents with a history of childhood sexual abuse related PTSD (CSA-related PTSD), anxiety and/or depressive disorders or no psychiatric symptoms. We assessed attachment representation as well as psychopathological symptoms, attentional bias and emotional face processing among diagnostic groups. We also correlated unresolved-disorganized attachment representation (Ud) and psychopathology using a general psychopathology factor (GPF) to grey matter (volume), white matter (tracts) and resting state functional connectivity (RSFC) of the brain in the entire sample. We found that clinical groups did not significantly differ in psychopathology. The unresolved-disorganized cannot classify category (Ud/CC) was overrepresented in the CSA-related PTSD group. Coherence of mind also differentiated the clinical groups, but Ud did not. The CSA-related PTSD group had a negative attention bias for neutral and fearful faces, the anxiety/depressive disorders group only for fearful faces. No differences were found for emotional face processing among diagnostic groups. We found a differential relationship of Ud and a GPF to grey matter volume, white matter integrity of white matter tracts and RSFC for Ud. Ud was associated with lateralization of the brain to the left with regard to amygdala RSFC and hippocampal volume. Show less
In neuroscience, clustering subjects based on brain dysfunctions is a promising avenue to subtype mental disorders as it may enhance the development of a brain-based categorization system for... Show moreIn neuroscience, clustering subjects based on brain dysfunctions is a promising avenue to subtype mental disorders as it may enhance the development of a brain-based categorization system for mental disorders that transcends and is biologically more valid than current symptom-based categorization systems. As changes in functional connectivity (FC) patterns have been demonstrated to be associated with various mental disorders, one appealing approach in this regard is to cluster patients based on similarities and differences in FC patterns. To this end, researchers collect three-way fMRI data measuring neural activation over time for different patients at several brain locations and apply Independent Component Analysis (ICA) to extract FC patterns from the data. However, due to the three-way nature and huge size of fMRI data, classical (two-way) clustering methods are inadequate to cluster patients based on these FC patterns. Therefore, a two-step procedure is proposed where, first, ICA is applied to each patient’s fMRI data and, next, a clustering algorithm is used to cluster the patients into homogeneous groups in terms of FC patterns. As some clustering methods used operate on similarity data, the modified RV-coefficient is adopted to compute the similarity between patient specific FC patterns. An extensive simulation study demonstrated that performing ICA before clustering enhances the cluster recovery and that hierarchical clustering using Ward’s method outperforms complete linkage hierarchical clustering, Affinity Propagation and Partitioning Around Medoids. Moreover, the proposed two-step procedure appears to recover the underlying clustering better than (1) a two-step procedure that combines PCA with clustering and (2) Clusterwise SCA-ECP, which performs PCA and clustering in a simultaneous fashion. Additionally, the good performance of the proposed two-step procedure using ICA and Ward’s hierarchical clustering is illustrated in an empirical fMRI data set regarding dementia patients. Show less
