Brain Functional and Structural Networks Underpinning Musical Creativity

Musical improvisation is one of the most complex forms of creative behavior, which offers a realistic task paradigm for the investigation of real-time creativity. Despite previous studies on the topics of musical improvisation, brain activations, and creativity, the main questions about the neural mechanisms for musical improvisation in efforts to unlocking the mystery of human creativity remain unanswered. What are the brain regions that are activated during the improvised performances of music? How do these brain areas coordinate activity among themselves and others during such performances? Whether and how does the brain connectivity structure encapsulate such creative skills? In attempts to contribute to answering these questions, this dissertation examines the brain activity dynamics during musical improvisation, explores white matter fiber architecture in advanced jazz improvisers using functional and structural magnetic resonance imaging (MRI) techniques. A group of advanced jazz musicians underwent functional and structural magnetic resonance brain imaging. While the functional MRI (fMRI) of their brains were collected, these expert improvisers performed vocalization and imagery improvisation and pre-learned melody tasks. The activation and connectivity analysis of the fMRI data showed that musical improvisation is characterized by higher brain activity with less functional connectivity compared to pre-learned melody in the brain network consisting of the dorsolateral prefrontal cortex (dlPFC), supplementary motor area (SMA), lateral premotor cortex (lPMC), Cerebellum (Cb) and Broca’s Area (BCA). SMA received a dominant causal information flow from dlPFC during improvisation and prelearned melody tasks. The deterministic fiber tractography analysis also revealed that the underlying white matter structure and fiber pathways in advanced jazz improvisers were enhanced in advanced jazz improvisers compared to the control group of nonmusicians, specifically the dlPFC - SMA network. These results point to the notion that an expert\u27s performance under real-time constraints is an internally directed behavior controlled primarily by a specific brain network, that has enhanced task-supportive structural connectivity. Overall, these findings suggest that a creative act of an expert is functionally controlled by a specific cortical network as in any internally directed attention and is encapsulated by the long-timescale brain structural network changes in support of the related cognitive underpinnings

Correlations between Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (1H MRS) in schizophrenic patients and normal controls

<p>Abstract</p> <p>Background</p> <p>Evidence suggests that white matter integrity may play an underlying pathophysiological role in schizophrenia. N-acetylaspartate (NAA), as measured by Magnetic Resonance Spectroscopy (MRS), is a neuronal marker and is decreased in white matter lesions and regions of axonal loss. It has also been found to be reduced in the prefrontal and temporal regions in patients with schizophrenia. Diffusion Tensor Imaging (DTI) allows one to measure the orientations of axonal tracts as well as the coherence of axonal bundles. DTI is thus sensitive to demyelination and other structural abnormalities. DTI has also shown abnormalities in these regions.</p> <p>Methods</p> <p>MRS and DTI were obtained on 42 healthy subjects and 40 subjects with schizophrenia. The data was analyzed using regions of interests in the Dorso-Lateral Prefrontal white matter, Medial Temporal white matter and Occipital white matter using both imaging modalities.</p> <p>Results</p> <p>NAA was significantly reduced in the patient population in the Medial Temporal regions. DTI anisotropy indices were also reduced in the same Medial Temporal regions. NAA and DTI-anisotropy indices were also correlated in the left medial temporal region.</p> <p>Conclusion</p> <p>Our results implicate defects in the medial temporal white matter in patients with schizophrenia. Moreover, MRS and DTI are complementary modalities for the study of white matter disruptions in patients with schizophrenia.</p

Impact of arterial stiffness on white matter microstructure in the elderly

La rigidité artérielle fait référence à la perte d'élasticité principalement dans les grandes artères telles que l'aorte et les carotides. On sait que la rigidité artérielle chroniquement élevée contribue à des modifications vasculaires cérébrales telles que des lésions parenchymateuses de la substance blanche cérébrale via une modification du flux sanguin cérébral. En particulier, parmi les structures perfusées par les artérioles fournies par les artères cérébrales antérieure et moyenne, le corps calleux, la capsule interne, la corona radiata et le faisceau longitudinal supérieur sont les plus vulnérables à l’hypoperfusion. Des études antérieures ont montré que l'augmentation de la rigidité artérielle évaluée par la vitesse de l'onde de pouls carotide-fémorale (cfPWV) est associée à une diminution de l'anisotropie fractionnelle (FA) et à une augmentation de la diffusivité radiale (RD). On a émis l'hypothèse que les altérations au niveau des régions vulnérables de la substance blanche (par exemple, le corps calleux, la capsule interne) seraient probablement liées à la démyélinisation axonale. Cependant, bien que la RD a auparavant été corrélée avec la démyélinisation axonale, l'imagerie de diffusion est principalement aveugle à la myéline. En revanche, l'imagerie par transfert de magnétisation (MT) est une métrique adaptée pour estimer la fraction volumique de myéline. De plus, malgré leur sensibilité à l'organisation des fibres axonales, les métriques de tenseur de diffusion (DTI) telles que les FA et RD manquent de spécificité pour la microstructure tissulaire individuelle. Des modèles microstructuraux plus avancés tels que l’imagerie dispersion et de l'orientation des neurites (NODDI) fournissent des outils pour disséquer les changements microstructuraux derrière les mesures DTI. Dans l'article 1, nous avons utilisé les métriques de DTI et basé sur le MT pour examiner de plus près l'interaction entre la rigidité artérielle et la microstructure de la substance blanche chez les personnes âgées de plus de 65 ans. Nous avons constaté que la mesure de référence absolue de la rigidité artérielle, la mesure de la vitesse de l'onde de pouls entre l’artère fémorale et carotidienne (cfPWV) était associée à l'organisation axonale des fibres telle que reflétée par FA et RD plutôt qu'à la démyélinisation dans les régions de la substance blanche qui ont été précédemment désignées comme vulnérables à rigidité artérielle. Dans notre deuxième article, nous avons utilisé le modèle NODDI pour approfondir la relation entre le cfPWV et l'organisation axonale. Nos résultats ont montré que la cfPWV est positivement associée à la diffusion extracellulaire de l'eau (ISOVF), ce qui signifie que la rigidité artérielle peut entraîner une dispersion axonale, diminuant la contrainte de directionnalité de l'eau le long des axones. En outre, nous avons constaté que la rigidité artérielle est associée à une augmentation de la densité des fibres dans le corps calleux tel que mesuré par l’ICVF, ce qui pourrait suggérer que les personnes à risque plus élevé de déclin cognitif présentent des mécanismes compensatoires précoces avant l'apparition de signes cliniques de déclin cognitif. Compte tenu de la forte interaction entre la rigidité artérielle et le déclin à la fois de la structure du cerveau et des fonctions cérébrales, on peut envisager un avenir meilleur où la rigidité artérielle sera mesurée dans la pratique clinique de routine afin d'identifier les personnes à risque plus élevé d’altérations de la substance blanche et de déclin cognitif. Ces personnes pourraient bénéficier de programmes multi-interventionnels visant à préserver la structure et la fonction cérébrale. Un seuil de rigidité artérielle est donc nécessaire pour identifier ces individus. L'article 3 présente la première estimation d'une valeur seuil de cfPWV à laquelle la rigidité artérielle affecte la microstructure de la substance blanche chez les personnes âgées. Nos résultats suggèrent que le seuil actuel de 10 m / s de cfPWV adopté par la Société européenne d'hypertension n'est peut-être pas le seuil optimal pour diviser les individus en groupes à risque neurovasculaire élevé et faible. Au lieu de cela, nos résultats suggèrent que le seuil de cfPWV est plus susceptible d’être autour de 8,5 m / s. Bien que le cfPWV offre une excellente valeur pronostique chez les adultes, il reste malheureusement principalement utilisé dans la recherche en raison du besoin d'experts formés pour cette mesure. À l'inverse, la mesure de l'indice de rigidité artérielle (ASI) à l'aide de la pléthysmographie suscite un intérêt croissant ces dernières années en raison de son approche simple à utiliser. Dans l'article 4, nous avons étudié la relation entre l'ASI et la pression pulsée (PP) qui est une mesure indirecte de la rigidité artérielle, avec la FA et les lésions de la substance blanche chez les participants du UK Biobank. Nous avons constaté que la PP prédit mieux l'intégrité de la substance blanche que l'ASI chez les participants de moins de 75 ans. Cette constatation implique que l'ASI de la pléthysmographie ne semble pas être une mesure fiable de la rigidité artérielle chez les personnes âgées. Des études futures sont évidemment nécessaires pour valider nos résultats, en particulier notre seuil de cfPWV. Une fois ce seuil validé, nous envisageons un avenir radieux où la mesure du cfPWV sera non seulement utilisée pour aider à sélectionner les personnes qui bénéficieraient le plus d'un programme multi-interventionnel visant à préserver l'intégrité cérébrale, mais pourrait également être utilisée pour surveiller l’effet d’une telle intervention.Arterial stiffness refers to the loss of elasticity mainly in large arteries such as the aorta and carotids. Chronically elevated arterial stiffness contributes to cerebrovascular changes such as cerebral white matter parenchymal damage via an alteration of cerebral blood flow. In particular, among the areas perfused by arterioles supplied by the anterior and middle cerebral arteries, the corpus callosum, the internal capsule, the corona radiata, and the superior longitudinal fasciculus are more vulnerable to cerebral hypoperfusion. Previous studies have shown that increased arterial stiffness as assessed by carotid-femoral pulse wave velocity (cfPWV) is associated with a decrease in fractional anisotropy (FA) and increase in radial diffusivity (RD). It was hypothesized that alterations in vulnerable white matter tracts (e.g. corpus callosum, internal capsule) are likely to be related to axonal demyelination. However, while RD was previously correlated with axonal demyelination, diffusion imaging is mostly blind to myelin. In contrast magnetization transfer (MT) imaging is a tailored metric to estimate myelin volume fraction. Moreover, despite their sensitivity to axon fiber organization, diffusion tensor metrics (DTI) such as FA and RD lack specificity for individual tissue microstructure. More advanced microstructural model such as neurite orientation dispersion and density imaging (NODDI) give tools to disecate the microstructural changes behind DTI metrics. In Article 1 we used DTI and MT based metric to look more closely at the interplay between arterial stiffness and white matter microstructure in older adults > 65 years old. We found that the gold standard measure of arterial stiffness, the measure of carotid femoral pulse wave velocity (cfPWV) was associated with axonal fiber organization as reflected by FA and RD rather than demyelination in the white matter regions that have been previously denoted as vulnerable to arterial stiffness. In our second Article, we used the NODDI model to take a further look at the relationship between cfPWV and axonal organization. Our results showed that cfPWV is positively associated with the extracellular water diffusion (ISOVF) which means that arterial stiffness may result in axonal dispersion, lessening the constraint of water directionality along axons. In addition, we found that arterial stiffness is associated with increased fibers density in the corpus callosum as measured by ICVF which could suggest that individuals at higher risk for cognitive decline demonstrate early compensatory mechanisms before the appearance of clinical signs of cognitive decline. Considering the strong interplay between arterial stiffness and decline both in brain structure and function, one can envision a bright future where arterial stiffness would be measured in routine clinical practice in order to identify individuals at higher risk for white matter changes and cognitive decline. Such individuals could benefit from multi-interventions programs aiming to preserve brain structure and function. A cut-off arterial stiffness is thus needed to identify these individuals. Article 3 presents the first estimation of an cfPWV cut-off value at which arterial stiffness impacts the white matter microstructure in older adults. Our results suggested that the current 10 m/s cfPWV cut-off adopted by the European Society of Hypertension may not be the optimal threshold to split individuals into high and low neurovascular risk groups. Instead, our findings suggest that the cfPWV cut-off is more likely to fall around 8.5 m/s. While cfPWV provides excellent prognostic value in adults, it remains unfortunately mainly used in research due to the need of trained experts. Conversely, measure of arterial stiffness index (ASI) using plethysmography is getting increased interest in the last few years due to its simple-to-use approach. In article 4, we investigated the relationship between ASI and pulse pressure (PP), an indirect measure of arterial stiffness, with FA and white matter lesions in participants of the UK Biobank. We found that PP better predicts white matter integrity compared to ASI in participants younger than 75 years old. This finding implies that ASI from plethysmography may not be a reliable measure of arterial stiffness in older adults. Future studies are obviously needed to validate our results, in particular our cfPWV cut-off. Once such cut-off will be validated, the present author envision a bright future where measure of cfPWV will not only be used to help selecting individuals that would most benefit from a multi intervention program aiming to preserve brain integrity, but could also be used to monitor the effect of such intervention

Combining DTI and fMRI to investigate language lateralisation

Hemispheric lateralisation in the human brain has been a focus of interest in different fields of neurosciences since a long time (Galaburda, LeMay, Kemper, & Geschwind, 1978; Rubino, 1970). One of the most studied and earliest observed lateralised brain functions is language. Reported in the nineteenth by the French physician and anatomist Paul Broca (1861) and by the German anatomist and neuropathologist Carl Wernicke (1874), language was found to be more impaired following tumours or strokes in the left hemisphere. In recent years, a number of studies have employed diffusion tensor imaging (DTI) to characterize left hemisphere language-related white matter pathways (Barrick, Lawes, Mackay, & Clark, 2007; Bernal & Altman, 2010; Catani et al., 2007; Glasser & Rilling, 2008; Hagmann et al., 2006; Parker et al., 2005; Propper et al., 2010; Upadhyay, Hallock, Ducros, Kim, & Ronen, 2008; Vernooij et al., 2007). In addition, lesion and fMRI studies in healthy subjects have indicated that speech comprehension and production are lateralised to the left brain hemisphere (A. U. Turken & Dronkers, 2011). The main aim of the present doctoral work is to better delineate the relationship between anatomical and functional correlates of hemispheric dominance in the perisylvian language network. To this purpose a multi-modal neuroimaging approach including DTI and fMRI on a population of 23 healthy individuals was applied. In the first study, a virtual in vivo interactive dissection of the three subcomponents of the arcuate fasciculus was carried out and measures of perisylvian white matter integrity were derived from tract-specific dissection. Consistently with previous studies (Barrick, et al., 2007; Buchel et al., 2004; Catani, et al., 2007; Powell et al., 2006), a significant leftward asymmetry in the fractional anysotropy (FA) value of the long direct segment of the arcuate fasciculus (AF) has been found. In addition, I found another significant leftward lateralisation in the streamlines (SL) of the posterior segment and a rightward distribution of the SL index of the anterior segment of the AF. Finally, I found no evidence of a significant relationship between the leftward lateralisation indeces and any measures of language and verbal memory performance in my group. In the second study, I implemented functional connectivity analysis to test whether leftward lateralisation of connectivity indeces between perisylvian regions can be observed in individuals performing a language-related task. The main finding of the functional connectivity analysis is a significant rightward lateralisation (left, 0.347 ± 0.183; right, 0.493 ± 0.228; P = 0.037) in the anterior connection, between the the inferior frontal gyrus (IFG) and the inferior parietal lobe (IPG). In the third study, I combined DTI and fMRI data to examine whether a significant relationship is present between these measures of perisylvian connectivity and it significantly differs between hemispheres. The correlation analysis demonstrated significant negative relations between the mean FA values in the long segment of the AF and the strength of inter-regional coupling between the IFG and the middle temporal gyrus (MTG) in the left hemisphere, and between the mean FA values in the anterior segment of the AF and the strength of regional coupling between IFG and IPL in the right hemisphere. Finally, there were no significant correlations between laterality indices estimated on FA and functional connectivity values.

White Matter Correlates of Verbal Memory in Left Temporal Lobe Epilepsy: A Study of Structural Connectivity

Verbal memory deficits are among the most prominent cognitive sequelae in individuals with left temporal lobe epilepsy (LTLE). However, relationships between verbal memory function and white matter integrity (WMI) in the left temporal lobe remain unclear. Current study aims included determining fractional anisotropy (FA) and mean diffusivity (MD) differences as an index of WMI between participants with left temporal lobe epilepsy (LTLE), participants with right TLE (RTLE), and controls, establishing group differences based on verbal memory function between TLE groups, and describing relationships between WMI and verbal memory function within TLE groups. Probabilistic tractography defined the left fornix (FRX), left uncinate fasciculus (UF), left parahippocampal cingulum (PHC), and a control region, the left corticospinal tract (CST), in 26 LTLE, 29 RTLE, and 20 control participants. The LTLE group demonstrated significantly lower fractional anisotropy (FA) along the PHC compared with controls. LTLE and RTLE groups did not differ significantly on measures of verbal memory until analyses were restricted to participants with left-lateralized language functioning. PHC FA was negatively correlated with semantic memory function in LTLE, but positively associated with episodic memory functioning in RTLE. Overall, findings highlight the PHC as vulnerable in LTLE, and differentially related to verbal memory functioning based on TLE group. Both findings are likely secondary to left-lateralized white matter disruption in LTLE. The current study also highlighted the importance of identifying homogenous groups to more clearly identify brain-behavior relationships. Current findings further define left-lateralized white matter alternations and related verbal memory deficits in TLE. Implications for these findings are presented in context with previous TLE literature, and future directions for further study are discussed

White matter microstructure in early onset Obsessive-Compulsive Disorder and Tourette Syndrome. A diffusion tensor imaging study in a population of drug-naïve children and adolescents with long-term clinical follow-up

Background and Objective Early onset obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are frequently associated conditions. Beside the evidence of their high epidemiological cross-prevalence supported by a common genetic liability (Huisman-van Dijk et al., 2016; Yu et al., 2015), little is known on the nature of their close relationship on a pathophysiological level. By analyzing white matter (WM) microstructure through diffusion tensor imaging (DTI), the present study aimed to characterize and compare primary pathophysiological changes in drug-naïve children and adolescents with OCD, TS, and TS+OCD. Methods Fifty-one participants (mean age 10.2 2.0 years), including N=10 with OCD, N=16 with pure TS, N=14 with TS+OCD, and 11 age-matched controls were studied cross-sectionally through 3T MRI. We performed tractography and extracted DTI metrics in five WM tracts of interest, i.e., the cortico-spinal tract (CST), the anterior thalamic radiations (ATR), the inferior longitudinal fasciculus (ILF), the corpus callosum (CC), and the cingulum. Relationship between DTI changes and clinical severity was examined through correlational analyses. A clinical follow-up at mean 7.6 years after MRI examination was performed to evaluate clinical outcomes and association to neuroimaging findings. Results Significant between-group differences emerged in DTI metrics, specifically in fractional anisotropy (FA), an index of myelination and organization of axon fibers (Johansen-Berg &amp; Rushworth, 2009; Toga et al., 2006). All analyzed tracts of interest except for the cingulum revealed a differential microstructure at group comparisons. The OCD group showed decreased FA within CST, ATR, ILF, and CC in respect to controls. A negative correlation was found between obsessive-compulsive symptoms and FA values in OCD, indicating that more severe clinical phenotypes are likely underpinned by less organized WM. Compared to controls, TS and TS+OCD groups both displayed remarkably different correlates from OCD and opposite DTI changes, i.e., increased FA in CST, ATR, ILF, and CC. Moreover, TS and TS+OCD had comparable DTI changes within all the investigated WM tracts and FA showed negative correlation with tic severity, revealing a shared pattern of WM organization in TS/TS+OCD with inverse relationship to symptom expression. At follow-up, no significant associations were found between FA values at baseline and long-term outcomes. Substantial symptom remission was achieved in 58.3% of TS, 63.6% of TS+OCD, and 70% of OCD patients, although a significant proportion of patient developed additional psychiatric disorders such as anxiety or depression. Conclusion The study highlights differential white matter involvement in pediatric OCD as opposed to TS/TS+OCD. Compared to neurotypical population, children with TS/TS+OCD showed an early increase in axons, fiber density, and/or myelination in WM bundles linking the frontal, occipital, and temporal cortices with each other and with the thalamus. Conversely, children with OCD showed widespread reduced organization of callosal, temporo-occipital, and fronto-thalamic WM tracts. Correlational analysis suggests that DTI changes in TS may reflect a compensatory reorganization in response to the disease pathophysiology, while in OCD they may represent a marker of the overall disease severity deriving from delay or damage to white matter development. Confirmation of these possibilities awaits longitudinal studies. The observation of shared DTI correlates of TS and TS+OCD strengthens the concept that at least some forms of OCD are etiologically related to TS and might therefore be a variant expression of the same etiologic factors that are important for the expression of tics (i.e., TS+OCD as a peculiar subtype of TS). By characterizing and differentiating early-stage neural underpinnings of OCD and TS, future targeted and neuroimaging-informed interventions may be developed

Neuronal underpinnings of stuttering

Fluent speech production depends on robust connections between brain regions that are crucial for auditory processing, motor planning and execution. The ability of the speech apparatus to produce effortless, continuous and uninterrupted flow of speech is compromised in people who stutter (PWS). Stuttering is a multifactorial speech fluency disorder that results in unintended occurrences of sound syllable repetitions, prolongations, and blocks, particularly on the initial part of words and sentences. Decades of research on the topic have produced an extensive amount of data but the mechanism behind the symptoms associated with stuttering is not clear. The aim of the present study was to investigate the neuronal basis of stuttering by looking at the brains neurochemistry utilizing the proton magnetic resonance spectroscopy (1H - MRS) technique. In particular, we looked at the neurotransmitters N-acetyl Aspartate (NAA), an aggregate of Glutamate and Glutamine (Glx) and myo-inositol (mI) as potential candidates for understanding the biochemical manifestations of stuttering. We have also collected behavioral data from the PWS group and correlated it with their spectroscopy results. Finally, we combined the measurements of neuronal activity behind speech production, probed with functional magnetic resonance imaging (fMRI), with 1H-MRS measurements in order to achieve information on the interaction between neuronal activation and underlying neurochemical function. The inferior frontal gyrus (IFG) was chosen as a target region for this investigation, given its' involvement in speech motor control. Neurotransmitter mI showed the main group effect. The cerebral metabolite pattern of PWS is characterized by the pronounced reduction in myo-inositol level in the IFG. Myo- inositol is considered a glial marker and its concentration may reflect the condition of myelin in the brain. The myelination process is referred to as the maturation process of the fibers that facilitates rapid neural innervation of speech muscles underlying speech fluency. Hence, given the existing literature on the topic and our main findings we suggested that delayed or impaired myelination of the speech-related neuronal network in the postnatal period might be responsible for the later development of stuttering.Flytende tale er avhengig av solide forbindelser mellom hjerneområder involvert i auditorisk prosessering, motorisk planlegging og utførelse. Taleapparatets evne til uanstrengt å produsere flytende uforstyrret tale er forstyrret hos personer som stammer (PWS). Stamming er en sammensatt forstyrrelse av taleflyt som resulterer i ufrivillige gjentagelser av stavelser, utvidelser, og blokkeringer, spesielt i begynnelsen av ord og setninger. Gitt tiår med forskning på området er det ennå ikke klart hvilke mekanismer som ligger til grunn for stammingen. Hensikten med dette studiet har vært å utforske det nevrale grunnlaget til stamming ved å se på hjernens nevrokjemi ved å ta i bruk proton-magnetisk resonsansspektroskopi (1H-MRS) teknikk. Vi har sett på om nevrotransmitterene: N-acetyl Asparatate (NAA); glutamat og glutamin (Glx) og myo-inositol kan bidra til forståelsen av de biokjemiske manifestasjonene av stamming. Vi har også samlet inn atferdsdata fra PWS-gruppen og korrelert dette med spektroskopi-dataen. Til slutt kombinerte vi målingene av den nevral aktiviteten av taleproduksjon med 1H-MRS målingene for å se på interaksjon mellom nevral aktivering og underliggende nevrokjemisk funksjon. Inferior frontal gyrus (IFG) var målområdet for undersøkelsen, siden området er viktig for motorisk kontroll av tale. Nevrotransmitteren myo-inositol viste en hovedgruppeeffekt. Metabolittene i hjernen til personer som stammer var karakterisert av en tydelig reduksjon i nivå av myo-inositol i IFG. Myo-inositol er ansett som en glial markør, og dets konsentrasjon kan muligens fortelle om myelinets tilstand i hjernen. Myelineringsprosessen av nerveceller er en modningsprosess som fasiliterer rask signaloverføring fra hjernen til muskelfibrene involvert i tale. Vi foreslår derfor på bakgrunn av foreliggende litteratur på området og våre resultater at forsinket eller hemmet myelinering av tale-relaterte nevrale nettverk i spedbarnsperioden kan føre til senere utvikling av stamming.LOGO345MAPS-LOG0

The impact of aerobic exercise on brain's white matter integrity in the Alzheimer's disease and the aging population

The brain is the most complex organ in the body. Currently, its complicated functionality has not been fully understood. However, in the last decades an exponential growth on research publications emerged thanks to the use of in-vivo brain imaging techniques. One of these techniques pioneered for medical use in the early 1970s was known as nuclear magnetic resonance imaging based (now called magnetic resonance imaging [MRI]). Nowadays, the advances of MRI technology not only allowed us to characterize volumetric changes in specific brain structures but now we could identify different patterns of activation (e.g. functional MRI) or changes in structural brain connectivity (e.g. diffusion MRI). One of the benefits of using these techniques is that we could investigate changes that occur in disease-specific cohorts such as in the case of Alzheimer’s disease (AD), a neurodegenerative disease that affects mainly older populations. This disease has been known for over a century and even though great advances in technology and pharmacology have occurred, currently there is no cure for the disease. Hence, in this work I decided to investigate whether aerobic exercise, an emerging alternative method to pharmacological treatments, might provide neuroprotective effects to slow down the evident brain deterioration of AD using novel in-vivo diffusion imaging techniques. Previous reports in animal and human studies have supported these exercise-related neuro-protective mechanisms. Concurrently in AD participants, increased brain volumes have been positively associated with higher cardiorespiratory fitness levels, a direct marker of sustained physical activity and increased exercise. Thus, the goal of this work is to investigate further whether exercise influences the brain using structural connectivity analyses and novel diffusion imaging techniques that go beyond volumetric characterization. The approach I chose to present this work combined two important aspects of the investigation. First, I introduced important concepts based on the neuro-scientific work in relation to Alzheimer’s diseases, in-vivo imaging, and exercise physiology (Chapter 1). Secondly, I tried to describe in simple mathematics the physics of this novel diffusion imaging technique (Chapter 2) and supported a tract-specific diffusion imaging processing methodology (Chapter 3 and 4). Consequently, the later chapters combined both aspects of this investigation in a manuscript format (Chapter 5-8). Finally, I summarized my findings, include recommendations for similar studies, described future work, and stated a final conclusion of this work (Chapter 9)

Different patterns of white matter and immunological alterations in the various phases of bipolar disorder

Bipolar disorder (BD) is a prevalent recurrent and chronic mental disease, clinically characterized by the occurrence of active phases of illness, mania and depression, alternated to asymptomatic periods of euthymia. Considering the complex clinical presentation of BD, our work aimed to investigate the neurobiological underpinning of the various phases of BD separately in order to detect their specific abnormalities, thus helping clarifying the pathophysiology of this disorder. Firstly, we investigated potential abnormalities of brain white matter (WM) in BD by using the diffusion tensor imaging (DTI) technique. By using a tract-based spatial statistics (TBSS) voxel-wise approach, we found a widespread alteration in WM microstructure (as evidenced by a decrease in fractional anisotropy (FA) and increase in mean diffusivity (MD) and radial diffusivity (RD) parameters) in BD, showing distinct patterns of changes in the different phases of illness. In particular, such WM abnormalities were larger in the active phases of illness (i.e., depression and mania) with respect to euthymia. Then, by using a probabilistic tractography, we coherently detected a reduction in the structural connectivity of the cingulum in mania. Secondly, we explored potential factors associated with the observed pattern of WM alterations of BD, by conducting a combined immunological-DTI study on an independent BD sample. By using a TBSS approach, we found a widespread combined FA-RD alteration mainly in the manic phase, with relatively specific involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR). Then, by using flow cytometry, we detected peripheral immunological alterations in the manic phase, mainly characterized by an increase in CD4+ T cells as well as a decrease in total CD8+ T cells and their subpopulations effector memory (CD8+CD28-CD45RA-), terminal effector memory (CD8+CD28-CD45RA+) and CD8+IFN\u3b3+. Finally, an association between WM and immunological alterations was found in the whole cohort, and a correlation of FA-RD alterations in the BCC and SCR with reduced CD8+ terminal effector memory and CD8+IFN\u3b3+ T cells was detected in mania. Finally, we conducted a longitudinal study, collecting both DTI and bio-humoral follow-up data of our sample and investigating WM and immunological alterations in BD patients across their different phases of illness. The results preliminarily confirmed our previous findings in a longitudinal perspective, by showing increased FA/decreased RD in midline structures complemented by an increase in the circulating activated CD8+ T cell subsets, in BD patients passing from active phases to euthymia. Collectively, these findings suggest a new pathophysiological model of mania. Accordingly, an acute immune response may occur in mania, sustained by early generated CD4+ T cell compartment (likely with T helper function), leading to activation of CD8+ effector T cell subpopulations that leave the circulation to migrate into the brain, where exert their cytotoxic action, finally leading to WM damage. Our model thus supports a relationship between BD and immune-inflammatory neurological diseases such as multiple sclerosis. Moreover, our results suggest a prominent role of mania in BD and, interestingly, seem to be in accordance with the \u201cprimacy of mania\u201d hypothesis, where mania is described as the fire of BD and seen as the core of the pathophysiology of the illness. Finally, our data suggest a potential role for immunotherapy as an important future aid in the treatment of BD