Resting State fMRI Study of the Olfactory Region in Autism

This thesis was conducted to further the investigation of the Olfactory system of a typically developing individual compared to an individual with Autism. The Olfactory system is unique in that it is the only sensory system that is not relayed through the thalamus in the brain. Autism Spectrum Disorder (ASD), also known as Autism, is a developmental disorder which impairs a person's social, behavioral, developmental, cognitive and psychological aspects. Autism Spectrum Disorder can present with symptoms such as difficulty communicating, difficulty with social interactions obsessive thoughts and compulsions and repetitive behaviors. Subjects with Autism Spectrum Disorder present with an inability to process olfactory processes accurately compared to the typically developing (control) subjects. The results of this study can be used to further the understanding of the brain of a person with ASD in conjunction with developing treatments to increase the quality of life and neurological development

Review

Functional ultrasound (fUS) is a hemodynamic-based functional neuroimaging technique, primarily used in animal models, that combines a high spatiotemporal resolution, a large field of view, and compatibility with behavior. These assets make fUS especially suited to interrogating brain activity at the systems level. In this review, we describe the technical capabilities offered by fUS and discuss how this technique can contribute to the field of functional connectomics. First, fUS can be used to study intrinsic functional connectivity, namely patterns of correlated activity between brain regions. In this area, fUS has made the most impact by following connectivity changes in disease models, across behavioral states, or dynamically. Second, fUS can also be used to map brain-wide pathways associated with an external event. For example, fUS has helped obtain finer descriptions of several sensory systems, and uncover new pathways implicated in specific behaviors. Additionally, combining fUS with direct circuit manipulations such as optogenetics is an attractive way to map the brain-wide connections of defined neuronal populations. Finally, technological improvements and the application of new analytical tools promise to boost fUS capabilities. As brain coverage and the range of behavioral contexts that can be addressed with fUS keep on increasing, we believe that fUS-guided connectomics will only expand in the future. In this regard, we consider the incorporation of fUS into multimodal studies combining diverse techniques and behavioral tasks to be the most promising research avenue

Ontogeny of perception of maternal and nosocomial stimuli in infants

Preterm born infants in neonatal units experience unusual sensory inputs that can shape and nurture their developing brains differently from full-term healthy newborn infants. To improve the care of preterm infants and their neurodevelopmental outcomes, we need to understand how the brain functions at different developmental stages and implement this knowledge into clinical care and follow-up programs. An infant’s cortical response to external stimuli can be measured with functional near-infrared spectroscopy (fNIRS). We aimed to analyze how maternal and nosocomial stimuli are processed in the developing cerebral cortex in infants. In paper I, the functional cortical processing of a known face (the infant’s mother) and an unknown face were assessed at six to ten months of age with fNIRS. We found that the infants exhibited an increased brain response when they saw their mother’s face, as compared to the unknown face. In paper II, we aimed to study the regional cortical responses to known and unknown faces, to compare them between infants born extremely preterm and infants born full-term and to correlate them to regional brain volumes. The infants were examined at six to ten months of corrected age using fNIRS. We also performed structural brain magnetic resonance imaging in the preterm group and correlated their regional cortical volumes to their fNIRS responses. The preterm infants had a smaller hemodynamic response in the right frontotemporal area while viewing a face they knew than the full-term born infants. There was a negative correlation between the hemodynamic response in the right frontotemporal cortex and regional grey matter volume in the face processing areas. In paper III, we examined the effects of alien odors on preterm and full-term newborn infants, exploring whether these odors elicit pain, and if oral glucose modulates this pain. We exposed the infants to odorous stimuli from the hospital environment and recorded pain behaviors and cortical activation with fNIRS. We repeated the exposure and measurements after oral glucose administration. Newborn infants exhibited brain responses to both olfactory and nociceptive processing areas from 31 weeks of postmenstrual age and also demonstrated pain behaviors. Oral glucose inhibited pain behaviors and cortical activation. In paper IV, we studied the cortical processing of maternal breast odors in preterm and fullterm newborn infants. Three groups of infants, very preterm, late preterm and full-term, were exposed to their mother’s breast odor and a control odor during fNIRS measurements. Fullterm infants demonstrated bilateral activation of their olfactory cortices following exposure to the maternal breast odor. Late preterm infants and very preterm boys exhibited unilateral cortical activation, unlike very preterm girls

Single Trial Decoding of Movement Intentions Using Functional Ultrasound Neuroimaging

Brain-machine interfaces (BMI) are powerful devices for restoring function to people living with paralysis. Leveraging significant advances in neurorecording technology, computational power, and understanding of the underlying neural signals, BMI have enabled severely paralyzed patients to control external devices, such as computers and robotic limbs. However, high-performance BMI currently require highly invasive recording techniques, and are thus only available to niche populations. Here, we show that a minimally invasive neuroimaging approach based on functional ultrasound (fUS) imaging can be used to detect and decode movement intention signals usable for BMI. We trained non-human primates to perform memory-guided movements while using epidural fUS imaging to record changes in cerebral blood volume from the posterior parietal cortex, a brain area important for spatial perception, multisensory integration, and movement planning. Using hemodynamic signals acquired during movement planning, we classified left-cued vs. right-cued movements, establishing the feasibility of ultrasonic BMI. These results demonstrate the ability of fUS-based neural interfaces to take advantage of the excellent spatiotemporal resolution, sensitivity, and field of view of ultrasound without breaching the dura or physically penetrating brain tissue

Rapid disruption of cortical activity and loss of cerebral blood flow in a mouse model of mild traumatic brain injury

Every year 2.8 million Americans suffer a traumatic brain injury (TBI). Despite the prevalence and debilitating consequences of TBI, effective treatment options are scarce due to the limited understanding of the neurobiological effects of injury, especially in acute phases when the cellular processes leading to neuropathology are first initiated. To identify changes in neural function and cerebral blood flow (CBF) that might account for TBI-induced cognitive and sensory deficits, we took a multidisciplinary approach, examining synaptic function, cortical activity patterns, and microvascular hemodynamics. we used a weight drop model in mice to induce mild TBI, the most common form in humans, and focused on responses within the first hours of injury where existing data are particularly limited. For synaptic function, we measured excitatory and inhibitory input onto pyramidal cells in the piriform cortex with whole-cell recordings in acute brain slices. Increased excitation appeared at one hour but excitatory-inhibitory balance was reestablished by 48 hours, highlighting the importance of studying rapid-onset injury responses. We also compared neural activity before and after TBI using in vivo two-photon calcium imaging of pyramidal cells in visual cortex. While neural activity substantially decreased in most cells one hour after injury, a minority of cells showed hyperactivation or prolonged increases in intracellular calcium, again indicating major physiological disturbances during immediate post-injury phases. Finally, we measured in vivo changes in CBF throughout the cortical microvasculature with laser speckle contrast imaging and optical coherence tomography, tracking injury effects up to three weeks after TBI. CBF and capillary flow were dramatically reduced within minutes and remained suppressed for over one hour. As neurons’ high energetic needs require a constant supply of glucose and oxygen from local vasculature, decreased CBF likely contributes to altered neural activity and loss of ion homeostasis and thus potentially cognitive and sensory deficits after TBI. Our results reveal that even mild injury creates rapid, pronounced, and heterogeneous alterations in neural activity and capillary flow. The transient nature of these effects suggests that the first two hours after injury may be a key window for delivering interventions, and that restoring CBF may reduce damage due to metabolic stress

Functional Ultrasound Imaging of Spinal Cord Hemodynamic Responses to Epidural Electrical Stimulation: A Feasibility Study

This study presents the first implementation of functional ultrasound (fUS) imaging of the spinal cord to monitor local hemodynamic response to epidural electrical spinal cord stimulation (SCS) on two small and large animal models. SCS has been successfully applied to control chronic refractory pain and recently was evolved to alleviate motor impairment in Parkinson's disease and after spinal cord injury. At present, however, the mechanisms underlying SCS remain unclear, and current methods for monitoring SCS are limited in their capacity to provide the required sensitivity and spatiotemporal resolutions to evaluate functional changes in response to SCS. fUS is an emerging technology that has recently shown promising results in monitoring a variety of neural activities associated with the brain. Here we demonstrated the feasibility of performing fUS on two animal models during SCS. We showed in vivo spinal cord hemodynamic responses measured by fUS evoked by different SCS parameters. We also demonstrated that fUS has a higher sensitivity in monitoring spinal cord response than electromyography. The high spatial and temporal resolutions of fUS were demonstrated by localized measurements of hemodynamic responses at different spinal cord segments, and by reliable tracking of spinal cord responses to patterned electrical stimulations, respectively. Finally, we proposed optimized fUS imaging and post-processing methods for spinal cord. These results support feasibility of fUS imaging of the spinal cord and could pave the way for future systematic studies to investigate spinal cord functional organization and the mechanisms of spinal cord neuromodulation in vivo

Robot-assisted fMRI assessment of early brain development

Preterm birth can interfere with the intra-uterine mechanisms driving cerebral development during the third trimester of gestation and often results in severe neuro-developmental impairments. Characterizing normal/abnormal patterns of early brain maturation could be fundamental in devising and guiding early therapeutic strategies aimed at improving clinical outcome by exploiting the enhanced early neuroplasticity. Over the last decade the morphology and structure of the developing human brain has been vastly characterized; however the concurrent maturation of brain function is still poorly understood. Task-dependent fMRI studies of the preterm brain can directly probe the emergence of fundamental neuroscientific notions and also provide clinicians with much needed early diagnostic and prognostic information. To date, task-fMRI studies of the preterm population have however been hampered by methodological challenges leading to inconsistent and contradictory results. In this thesis I present a modular and flexible system to provide clinicians and researchers with a simple and reliable solution to deliver computer-controlled stimulation patterns to preterm infants during task-fMRI experiments. The system is primarily aimed at studying the developing sensori-motor system as preterm infants are often affected by neuro-motor dysfunctions such as cerebral palsy. Wrist and ankle robotic stimulators were developed and firstly used to study the emerging somatosensory “homunculus”. The wrist robotic stimulator was then used to characterize the development of the sensori-motor system throughout the mid-to-late preterm period. An instrumented pacifier system was also developed to explore the potential sensorimotor modulation of early sucking activity; however, despite its clear potential to be employed in future fMRI studies, results have not yet been obtained on preterm infants. Functional difficulties associated with prematurity are likely to extend to multi-sensory integration, and the olfactory system currently remains under-investigated despite its clear developmental importance. A custom olfactometer was developed and used to assess its early functionality.Open Acces

Arenguline lähenemine emotsionaalse käitumisega seotud geenide Wfs1 ja Lsampʼi funktsiooni uurimisel

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhiaatriliste häirete kujunemises mängib olulist rolli aju areng. Geenid, mis osalevad emotsioonidega seotud ajupiirkondade arengus ja funktsioneerimises, on olulised psühhiaatriliste häirete seisukohalt. Wfs1 ja Lsamp geenid osalevad hirmu- ja ärevuskäitumise regulatsioonis. Wfs1 (Wolframi sündroom 1), nagu nimigi ütleb, on seotud samanimelise haruldase sündroomiga, mille sümptomid on diabetes insipidus, diabetes mellitus, nägemisnärvi kärbumine ja sensorineuraalne kurtus, sageli kaasnevad ka psühhiaatrilised häired. Wfs1 valk mängib olulist rolli insuliini sekretsioonis ja pankrease β-rakkude ellujäämise tagamises, selle funktsioonist ajus on vähem teada. Lsamp (limbilise süsteemiga seotud membraanivalk) osaleb neuriitide väljakasvu, aksonite sihtmärgini jõudmise ja sünaptogeneesi reguleerimises. Lsamp geenil on kaks evolutsiooniliselt konserveerunud alternatiivset esimest eksonit koos eraldi promootoritega, sellise struktuuri funktsionaalne tähtsus on teadmata. Nii Wfs1 kui Lsamp geeni puhul on näidatud kindlate alleelide seotust meeleolu- ja ärevushäirete, skisofreenia ja suitsidaalsusega. Enda doktoritöös uurisin Wfs1 ja Lsamp`i funktsiooni arengulisest vaatevinklist. Selgus, et Wfs1 ekspressioon on evolutsiooniliselt konserveerunud dopamiinergilist sisendit saavates ajupiirkondades, ning et Wfs1 suhtes puudulike hiirte hipokampuses on D1-tüüpi dopamiini retseptorite hulk suurenenud. Arengu käigus ekspresseerus Wfs1 ajutiselt paljudes ajupiirkondades; see laialdane ekspressioon polnud seotud arengulise endoplasmaatilise retiikulumi stressi vastuse regulatsiooniga, mis on üks Wfs1 põhilisi funktsioone täiskasvanud organismis. Lsamp`i puhul näitasime, et selle alternatiivsed promootorid on aktiivsed erinevate funktsioonidega ajupiirkondades: 1a-promootor on põhiline limbilises süsteemis, samas kui 1b-promootori aktiivsus piiritleb sensoorseid juhteteid. Lsamp`i promootorite aktiivsus hiirte hipokampuses, ventraalses striatumis ja temporaalsagaras korreleerus sotsiaalse- ja ärevusega seotud käitumise näitajatega. Saadud tulemused aitavad paremini mõista Wfs1 ja Lsamp`i rolli psühhiaatriliste häirete väljakujunemises ning näitavad suunda edasisteks uuringuteks.Genes that are involved in the development and functioning of the emotional circuits of the brain are highly susceptible targets in psychiatric diseases. Wfs1 and Lsamp, two genes studied in the present thesis, are both involved in the regulation of anxiety- and fear-related behaviour in the adult brain. Wfs1 (Wolfram syndrome 1) is a causative gene for Wolfram syndrome, a rare genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness. Often, the core symptoms are accompanied by psychiatric manifestations. Wfs1 is important for the survival and functioning of pancreatic β-cells, its roles in the nervous system are not well understood. Lsamp (Limbic system associated membrane protein) is involved in regulating neurite outgrowth, axon targeting and synaptogenesis in the limbic system. Lsamp has two alternative first exons with separate promoters, the role of this conserved gene structure is unknown. Allelic variants of both, Wfs1 and Lsamp, are associated with depression, anxiety disorders, bipolar disorder, schizophrenia and suicidality. We took advantage of the neurodevelopmental approach to study the functions of Wfs1 and Lsamp in the brain. Wfs1 showed evolutionarily conserved expression in the dopaminoceptive brain regions. Relating to this, Wfs1-deficient mice had increased number of D1-type dopamine receptor ligand binding sites in the hippocampi compared to wild-type mice. During the development, Wfs1 was transiently expressed in many brain regions. The widespread expression of Wfs1 in early postnatal mouse brain was not involved in the regulation of developmental endoplasmic reticulum stress, which has previously been shown to be one of the main functions of Wfs1 in the adult organism. The activity pattern of the two alternative promoters of Lsamp was complementary in the mouse brain: 1a promoter was prevailing in the limbic-related structures, while the activity of 1b promoter mainly delineated sensory pathways. The activity of Lsamp promoters in the hippocampus, ventral striatum and temporal lobe correlated with measures of anxiety and social behaviour of mice. The present results help to understand the role of Wfs1 and Lsamp in the context of psychiatric diseases and point direction for further research

3D ultrafast ultrasound imaging in vivo

Very high frame rate ultrasound imaging has recently allowed for the extension of the applications of echography to new fields of study such as the functional imaging of the brain, cardiac electrophysiology, and the quantitative imaging of the intrinsic mechanical properties of tumors, to name a few, non-invasively and in real time. In this study, we present the first implementation of Ultrafast Ultrasound Imaging in 3D based on the use of either diverging or plane waves emanating from a sparse virtual array located behind the probe. It achieves high contrast and resolution while maintaining imaging rates of thousands of volumes per second. A customized portable ultrasound system was developed to sample 1024 independent channels and to drive a 32 x 32 matrix-array probe. Its ability to track in 3D transient phenomena occurring in the millisecond range within a single ultrafast acquisition was demonstrated for 3D Shear-Wave Imaging, 3D Ultrafast Doppler Imaging, and, finally, 3D Ultrafast combined Tissue and Flow Doppler Imaging. The propagation of shear waves was tracked in a phantom and used to characterize its stiffness. 3D Ultrafast Doppler was used to obtain 3D maps of Pulsed Doppler, Color Doppler, and Power Doppler quantities in a single acquisition and revealed, at thousands of volumes per second, the complex 3D flow patterns occurring in the ventricles of the human heart during an entire cardiac cycle, as well as the 3D in vivo interaction of blood flow and wall motion during the pulse wave in the carotid at the bifurcation. This study demonstrates the potential of 3D Ultrafast Ultrasound Imaging for the 3D mapping of stiffness, tissue motion, and flow in humans in vivo and promises new clinical applications of ultrasound with reduced intra--and inter-observer variability