Development of MRI methods to map cerebral metabolic oxygen consumption in humans

The quantification of brain activity has been one of the main goals of neuroimaging since the earliest applications. In functional magnetic resonance imaging (fMRI) such an aim has been pursued indirectly by studying changes of the blood oxygenation dependent signal triggered by alterations in blood flow following changes in energy metabolism. Such approach is limited because of the complex relationship between the vascular and neural systems in brain tissue. Therefore methods have been proposed to assess oxygen metabolism, which directly underlies energy supply to brain tissue and therefore brain activity. Investigating existing and novel MRI methods, the thesis aims to improve the assessment of oxygen metabolism for a fully quantitative measurement of this biomarker. A simulation study has been carried out to optimise one of the mathematical (fMRI calibration) models used to relate the measured signal to the underlying physiology. As a result we are able to define a new model, less complex and more accurate for estimation of oxygen extraction fraction. Following this, an estimation approach recently developed in our centre is applied to carbon dioxide and oxygen calibrated fMRI data in an experimental setting firstly for a repeatability study and then for a drug study looking at the acute effects of caffeine on brain metabolism and haemodynamics. The precision of the novel approach shows values consistent with previous methods, but with much higher spatial resolution. Exploiting this, acute caffeine effects are characterized with a voxel-wise level of detail, showing results consistent with literature electrophysiological findings. Finally, an innovative method for estimating oxygen extraction fraction, based on velocity spectral imaging and estimation of transverse relaxation time, is introduced and tested at a proof-of-concept level. The performance and limits are examined through simulation and experimentation, suggesting that it might be a viable alternative to the calibration techniques previously introduced

Effects of exposure to colored light on cerebral and systemic physiology in humans

Humans in industrialized societies have become independent of the natural day and night cycle due to the invention and use of artificial light. Colored light is an element of everyday life, which affects various human functions. The main aim of this PhD thesis is to comprehensively investigate the effects of exposure to colored light on cerebral and human physiology. To achieve this goal, 201 healthy right-handed adults were recruited for 20 different colored light conditions. By using systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS) neuroimaging, each subject was measured 2-4 times on different days resulting in 676 single measurements. The SPA-fNIRS approach combines the measurement of brain activity and systemic physiological changes. fNIRS is a non-invasive neuroimaging technique employed to measure changes in cerebral hemodynamics and oxygenation. There is an interaction between these and changes in systemic physiology: consequently, the SPA-fNIRS generally enables us to identify and understand these interactions. We simultaneously assessed the effects of colored light exposure (CLE) in the visual cortex (VC), prefrontal cortex (PFC) and systemic physiology. Such a comprehensive study has not been carried out yet, and an integrative view of how the color of light affects the brain and systemic physiology is lacking. In general, CLE has relatively long-lasting effects on cerebral and systemic physiology in humans, and yellow light leads to higher brain activation in the PFC than the other colored lights. Yellow CLE is associated with more active and positive emotions, including happiness, joy, hope, and cheerfulness. We also show that long-term colored light exposures induce wavelength-dependent modulations of brain responses in the VC. Violet and blue lights elicit higher changes in cerebral parameters compared to the other colored lights during the CLE and recovery phase. Our results show that CLE affects individual humans differently. In particular, blue light leads to eight different hemodynamic response patterns, while the typical hemodynamic response pattern (increase in oxygenated ([O2Hb]) and decrease in deoxygenated ([HHb]) hemoglobin) is still observed and valid at the group-level analysis. The SPA-fNIRS approach is able to show that systemic and cerebral physiology interact. Experimental findings in most parts of this research display that inter-subject variability of hemodynamic responses is partially explained by systemic physiological changes. The finding of this research that blue light has an activating effect in the VC should be taken into consideration when assessing the impact of modern light sources such as screens and light-emitting diodes (LEDs) on the human body. Our findings that yellow light leads to higher PFC activation be tested as a potentially beneficial tool in chromotherapy, i.e., a complementary medicine method, to balance “energy” lacking in physical, emotional, and mental levels. Although yellow light, i.e., CLE in general term, influences humans in several positive ways, it should be noted that each individual reacts differently to the CLE, implying that colored light therapy has to be also adjusted to each individual. Therefore, further research should clarify which color in CLE benefits whom. In a civilization that is rapidly exposed to new and increasing lighting, the findings of this research are relevant for the scientific community, medical professionals, and society

Functional neuroimaging in subjects at high genetic risk of schizophrenia

Schizophrenia is an incapacitating psychiatric disorder characterized by hallucinations and delusions with a lifetime risk of around 1% worldwide. It is a highly heritable disorder which generally becomes manifest in early adult life. The established condition has been associated with structural and functional brain abnormalities, principally in prefrontal and temporal lobes, but it is unclear whether such abnormalities are related to inherited vulnerability, medication effects, or the presence of symptoms. Furthermore, the mechanisms by which the pre-morbid state switches into florid psychosis are unknown. The Edinburgh High Risk Study is designed to address these issues. The first phase (1994-1999) employed repeated clinical, neuropsychological assessments and structural imaging. In the current phase (1999-2004) functional magnetic resonance imaging (fMRI) has been added to the tests used previously.As part of the Edinburgh High Risk Study, this study used a covert verbal initiation fMRI task (the Hayling Sentence Completion Test) known to elicit frontal and temporal activation, to examine a large number of young participants at high risk of developing schizophrenia for genetic reasons, in comparison with a matched group of healthy controls. Subjects were scanned at baseline, and after approximately one year. At the time of the baseline scan none of the participants met criteria for any psychiatric disorder, however, a number of subjects reported isolated psychotic symptoms on direct questioning. Over the course of the entire study (1994-2004), 21 individuals developed schizophrenia according to standard diagnostic criteria. Four of these subjects made the transition over the course of the current study (1999-2004), i.e. subsequent to the baseline functional scanThere were three main aims of the current study (i) to use fMRI to identify the neural correlates of state and trait effects in high risk individuals, (ii) to determine ifit is possible to distinguish those who subsequently become ill from those who remain well using functional imaging, and (iii) to determine if patterns of brain activity change with the transition to illness, or vary with changes in symptomatic status of these individuals.Regarding the first aim, group differences of apparent genetic origin were found in prefrontal, thalamic, cerebellar regions, and differences in activation in those with symptoms were found in the parietal lobe. Functional connectivity analysis examining interactions between these regions also indicated similar abnormalities. These results may therefore reflect inherited deficits, and the earliest changes associated with the psychotic state, respectively. Although only a small number of subjects became ill over the course of the current study («=4), initial findings suggested abnormalities in medial prefrontal and medial temporal regions (with an indication of parietal lobe dysfunction) were able to distinguish those who later became ill versus those that remained well. Finally, there were also indications of changes in activation patterns over time in a subgroup of subjects with varying symptomatic status.To conclude, these results are consistent with previous findings in the Edinburgh High Risk Study - what is inherited by the high risk individuals is a state of heightened vulnerability manifesting, in the case of functional imaging, as abnormalities in activation and/or connectivity in preffontal-thalamiccerebellar and prefrontal-parietal regions. These finding also suggest that there are additional differences seen in those with psychotic symptoms, and to some extent in those who subsequently go on to develop the disorder. These results are not confounded by anti-psychotic medication since all subjects were anti-psychotic naive at the time of assessment. The lack of findings traditionally associated with the established illness (dorsolateral prefrontal cortex and lateral temporal lobe) indicate these may be specifically associated with the established state, or when performance differences become manifest. Overall therefore these findings reveal information regarding the pathophysiology of the state of vulnerability to the disorder and about the mechanisms involved in the development of schizophrenia or schizophrenic symptomatology

Guilt in the body and brain : a psychophysiological and neuroimaging investigation

Guilt has been described as a quintessential moral emotion with an important regulatory function for the individual and society. Few studies have, however, empirically investigated guilt, largely because of challenges associated with its real-time elicitation. I aimed to elucidate the physiological and neural correlates of guilt by developing two novel emotion elicitation paradigms

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches