44 research outputs found
Optical imaging and spectroscopy for the study of the human brain: status report.
This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions
Optical imaging and spectroscopy for the study of the human brain: status report
This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions
Optical imaging and spectroscopy for the study of the human brain: status report
This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.
Keywords: DCS; NIRS; diffuse optics; functional neuroscience; optical imaging; optical spectroscop
Imaging Pain And Brain Plasticity: A Longitudinal Structural Imaging Study
Chronic musculoskeletal pain is a leading cause of disability worldwide yet the mechanisms of chronification and neural responses to effective treatment remain elusive. Non-invasive imaging techniques are useful for investigating brain alterations associated with health and disease. Thus the overall goal of this dissertation was to investigate the white (WM) and grey matter (GM) structural differences in patients with musculoskeletal pain before and after psychotherapeutic intervention: cognitive behavioral therapy (CBT). To aid in the interpretation of clinical findings, we used a novel porcine model of low back pain-like pathophysiology and developed a post-mortem, in situ, neuroimaging approach to facilitate translational investigation.
The first objective of this dissertation (Chapter 2) was to identify structural brain alterations in chronic pain patients compared to healthy controls. To achieve this, we examined GM volume and diffusivity as well as WM metrics of complexity, density, and connectivity. Consistent with the literature, we observed robust differences in GM volume across a number of brain regions in chronic pain patients, however, findings of increased GM volume in several regions are in contrast to previous reports. We also identified WM changes, with pain patients exhibiting reduced WM density in tracts that project to descending pain modulatory regions as well as increased connectivity to default mode network structures, and bidirectional alterations in complexity. These findings may reflect network level dysfunction in patients with chronic pain.
The second aim (Chapter 3) was to investigate reversibility or neuroplasticity of structural alterations in the chronic pain brain following CBT compared to an active control group. Longitudinal evaluation was carried out at baseline, following 11-week intervention, and a four-month follow-up. Similarly, we conducted structural brain assessments including GM morphometry and WM complexity and connectivity. We did not observe GM volumetric or WM connectivity changes, but we did discover differences in WM complexity after therapy and at follow-up visits.
To facilitate mechanistic investigation of pain related brain changes, we used a novel porcine model of low back pain-like pathophysiology (Chapter 6). This model replicates hallmarks of chronic pain, such as soft tissue injury and movement alteration. We also developed a novel protocol to perform translational post-mortem, in situ, neuroimaging in our porcine model to reproduce WM and GM findings observed in humans, followed by a unique perfusion and immersion fixation protocol to enable histological assessment (Chapter 4).
In conclusion, our clinical data suggest robust structural brain alterations in patients with chronic pain as compared to healthy individuals and in response to therapeutic intervention. However, the mechanism of these brain changes remains unknown. Therefore, we propose to use a porcine model of musculoskeletal pain with a novel neuroimaging protocol to promote mechanistic investigation and expand our interpretation of clinical findings
THE NEUROPHYSIOLOGICAL EFFECTS OF BLAST EXPOSURE AND MILD TRAUMATIC BRAIN INJURY IN SPECIAL OPERATIONS FORCES SOLDIERS
Introduction: Special Operations Forces (SOF) Soldiers sustain frequent low-level occupational blast and mild traumatic brain injury (mTBI). The cumulative impact of blast exposure and mTBI on long-term neurological health is poorly understood. Tracking changes in physiological outcomes that quantify brain tissue damage may elucidate early neurophysiological alterations linking neurotraumatic exposures to chronic neurodegenerative sequalae. The purpose of this study was to investigate the effect of occupational blast exposure and the interaction effect of mTBI on changes to regional brain volumes, structural connectivity, and blood biomarkers UCH-L1, NSE, t-tau, NfL and GFAP in SOF Soldiers. Methods: Soldiers (n=88) underwent neuroimaging assessments including T1, T2, and diffusion weighted magnetic resonance imaging at two timepoints. Time between visits varied between participants from 13 to 131 months. Cortical reconstruction, volumetric segmentation, and structural connectivity matrix construction was performed. A subset (n=16) had biomarker serum concentrations quantified. Months of blast exposure between visits was used to predict change in neuroimaging and blood biomarker outcomes between visits using general linear models. Post-hoc subgroup analyses and interactions were assessed. Results: Greater occupational blast exposure predicted increased lateral ventricular volume (F1,86= 5.45; p=0.022), left frontal lobe gray matter volume (F1,86=4.06; p=0.047), right parietal lobe gray matter volume (F1,86=4.15; p=0.045), decreased cerebellum gray matter volume (F1,86=5.70; p=0.019), and decreased serum t-tau (F1,14=6.42; p=0.02; B=-3.85 pg/mL; R2=0.31) Although mTBI did not moderate these relationships, trends suggest that brain volume changes attributed to blast exposure might be exacerbated by mTBI. Conclusion: Specific neurostructural changes and biomarker decreases are associated with chronic exposure to occupational blast. Sustained mTBI may intensify blast-related structural changes. Increasing lateral ventricle volume and decreasing t-tau both implicate glymphatic dysfunction as a possible blast exposure consequence and a target for future research. Biomarker concentrations in this SOF samples exceeded civilian brain injury levels, rendering current clinical cut-offs unusable. Replication is a needed in a larger sample. The observed cerebellum cortex loss should be investigated further with clinical and performance measures for coordination and balance. These findings may guide prevention, treatment, and inform neurodegenerative consequence risk prediction, ultimately leading to improved long-term neurological health outcomes for SOF Soldiers.Doctor of Philosoph
Ain't no rest for the brain: Neuroimaging and neuroethics in dialogue for patients with disorders of consciousness
The sheer amount of different opinions about what consciousness is
highlights its multifaceted character. The clinical study of consciousness in
coma survivors provides unique opportunities, not only to better
comprehend normal conscious functions, but also to confront clinical and
medico-ethical challenges. For example, pain in vegetative
state/unresponsive wakefulness syndrome patients (VS/UWS; i.e. awaken,
but unconscious) and patients in minimally conscious states (MCS; awaken,
with fluctuating signs of awareness) cannot be communicated and needs to
be inferred. Behaviorally, we developed the Nociception Coma Scale, a
clinical tool which measures patients’ motor, verbal, visual, and facial
responsiveness to noxious stimulation. Importantly, the absence of proof of
a behavioral response cannot be taken as proof of absence of pain.
Functional neuroimaging studies show that patients in VS/UWS exhibit no
evidence of control-like brain activity, when painfully stimulated, in
contrast to patients in MCS. Similarly, the majority of clinicians ascribe
pain perception in MCS patients. Interestingly, their opinions appear less
congruent with regards to pain perception in VS/UWS patients, due to
personal and cultural differences. The imminent bias in clinical practice due
to personal beliefs becomes more ethically salient in complex clinical
scenarios, such as end-of-life decisions. Surveys among clinicians show
that the majority agrees with treatment withdrawal for VS/UWS, but fewer
respondents would do so for MCS patients. For the issue of pain in patients
with disorders of consciousness, the more the respondents ascribed pain
perception in these states the less they supported treatment withdraw from
these patients. Such medico-ethical controversies require an objective and
valid assessment of pain (and eventually of consciousness) in noncommunicating
patients.
Functional neuroimaging during “resting state” (eyes closed, no task
performance) is an ideal paradigm to investigate residual cognition in noncommunicating
patients, because it does not require sophisticated technical
support or subjective input on patients’ behalf. With the ultimate intention
to use this paradigm in patients, we first aimed to validate it in controls. We
initially found that, in controls, fMRI “resting state” activity correlated with
subjective reports of “external” (perception of the environment through the
senses) or “internal” awareness (self-related mental processes). Then, using
hypnosis, we showed that there was reduced fMRI connectivity in the
“external network”, reflecting decreased sensory awareness. When more
cerebral networks were tested, increased functional connectivity was
observed for most of the studied networks (except the visual). These results
indicate that resign state fMRI activity reflects, at least partially, ongoing
conscious cognition, which changes under different conditions. Using the
resting state paradigm in patients with disorders of consciousness, we
vi
showed intra- and inter-network connectivity breakdown in sensorysensorimotor
and “higher-order” networks, possibly accounting for
patients’ limited capacities for conscious cognition. We have further
observed positive correlation between the Nociception Coma Scale scores
and the pain-related (salience) network connectivity, potentially reflecting
nociception-related processes in these patients, measured in the absence of
an external stimulus.
These results highlight the utility of resting state analyses in clinical
settings, where short and simple setups are preferable to activation
protocols with somatosensory, visual, and auditory stimulation devices.
Especially for neuroimaging studies, it should be stressed that such
experimental investigations tackle the necessary conditions supporting
conscious processing. The sufficiency of the identified neural correlates
accounting for conscious awareness remains to be identified via dynamic
and causal information flow investigations. Importantly, the quest of
subjectivity in non-communicating patients can be better understood by
adopting an interdisciplinary biopsychosocial approach, combining basic
neuroscience (bio), psychological-cognitive-emotional processing (psycho),
and the influence of different socioeconomic, cultural, and technological
factors (social)
Ain't no rest for the brain: Neuroimaging and neuroethics in dialogue for patients with disorders of consciousness
The sheer amount of different opinions about what consciousness is
highlights its multifaceted character. The clinical study of consciousness in
coma survivors provides unique opportunities, not only to better
comprehend normal conscious functions, but also to confront clinical and
medico-ethical challenges. For example, pain in vegetative
state/unresponsive wakefulness syndrome patients (VS/UWS; i.e. awaken,
but unconscious) and patients in minimally conscious states (MCS; awaken,
with fluctuating signs of awareness) cannot be communicated and needs to
be inferred. Behaviorally, we developed the Nociception Coma Scale, a
clinical tool which measures patients’ motor, verbal, visual, and facial
responsiveness to noxious stimulation. Importantly, the absence of proof of
a behavioral response cannot be taken as proof of absence of pain.
Functional neuroimaging studies show that patients in VS/UWS exhibit no
evidence of control-like brain activity, when painfully stimulated, in
contrast to patients in MCS. Similarly, the majority of clinicians ascribe
pain perception in MCS patients. Interestingly, their opinions appear less
congruent with regards to pain perception in VS/UWS patients, due to
personal and cultural differences. The imminent bias in clinical practice due
to personal beliefs becomes more ethically salient in complex clinical
scenarios, such as end-of-life decisions. Surveys among clinicians show
that the majority agrees with treatment withdrawal for VS/UWS, but fewer
respondents would do so for MCS patients. For the issue of pain in patients
with disorders of consciousness, the more the respondents ascribed pain
perception in these states the less they supported treatment withdraw from
these patients. Such medico-ethical controversies require an objective and
valid assessment of pain (and eventually of consciousness) in noncommunicating
patients.
Functional neuroimaging during “resting state” (eyes closed, no task
performance) is an ideal paradigm to investigate residual cognition in noncommunicating
patients, because it does not require sophisticated technical
support or subjective input on patients’ behalf. With the ultimate intention
to use this paradigm in patients, we first aimed to validate it in controls. We
initially found that, in controls, fMRI “resting state” activity correlated with
subjective reports of “external” (perception of the environment through the
senses) or “internal” awareness (self-related mental processes). Then, using
hypnosis, we showed that there was reduced fMRI connectivity in the
“external network”, reflecting decreased sensory awareness. When more
cerebral networks were tested, increased functional connectivity was
observed for most of the studied networks (except the visual). These results
indicate that resign state fMRI activity reflects, at least partially, ongoing
conscious cognition, which changes under different conditions. Using the
resting state paradigm in patients with disorders of consciousness, we
vi
showed intra- and inter-network connectivity breakdown in sensorysensorimotor
and “higher-order” networks, possibly accounting for
patients’ limited capacities for conscious cognition. We have further
observed positive correlation between the Nociception Coma Scale scores
and the pain-related (salience) network connectivity, potentially reflecting
nociception-related processes in these patients, measured in the absence of
an external stimulus.
These results highlight the utility of resting state analyses in clinical
settings, where short and simple setups are preferable to activation
protocols with somatosensory, visual, and auditory stimulation devices.
Especially for neuroimaging studies, it should be stressed that such
experimental investigations tackle the necessary conditions supporting
conscious processing. The sufficiency of the identified neural correlates
accounting for conscious awareness remains to be identified via dynamic
and causal information flow investigations. Importantly, the quest of
subjectivity in non-communicating patients can be better understood by
adopting an interdisciplinary biopsychosocial approach, combining basic
neuroscience (bio), psychological-cognitive-emotional processing (psycho),
and the influence of different socioeconomic, cultural, and technological
factors (social)
Fatigue and cognition - hormonal perspectives
Fatigue is a common complaint and considered a very challenging symptom to cope with in many
different medical diseases. The assessment of fatigue is bound up with the problems of both
conceptualization and definition. In addition, few studies have investigated suitable
neuropsychological tests to examine fatigue and its consequences.
This thesis evaluates whether neuropsychological tests can elicit cognitive fatigue. It also investigates
whether specific hormones and hormone replacement therapy influence fatigue as well as cognitive
performance.
Study I examined and compared neuropsychological measures of cognitive fatigue with self-rated
fatigue in patients with mild traumatic brain injury (mTBI). These patients scored significantly higher
than controls on both self-rated and on test-derived measures of cognitive fatigue. Cognitive fatigue
was best captured with a score derived from the WAIS Digit Symbol. From our findings we concluded
that cognitive fatigue was independent of depression and sleep disorder. Self-rated fatigue, on the
other hand, was highly correlated to depression.
Study II compared the effect of combined testosterone and estrogen replacement with estrogen
treatment alone on subjective and objective measures of memory in oophorectomized women.
Treatment with testosterone undecanoate 40 mg and estradiol 2 mg was associated with lower
performance on immediate verbal memory compared to treatment with estrogen plus placebo. All
other memory functions were unaffected.
Study III explored cognitive fatigue in oophorectomized women, and whether hormonal treatment
regimens, as described in study II, were related to self perceived well-being, estrogen or testosterone
serum levels. We found that cognitive fatigue was frequent in oophorectomized women and negatively
associated to self-perceived health and positively associated to BMI. However, treatment with
testosterone + estrogen or estrogen alone had no significant effect on cognitive fatigue.
Study IV investigated fatigue and cognitive performance in patients with Graves’ disease (GD). As
compared to controls, patients with GD scored significantly higher on self-rated fatigue and had a
higher frequency on the cognitive fatigue. They also demonstrated lower performance on learning,
memory, and various tests of executive functioning. Depression was associated with self-rated fatigue
but not with the cognitive fatigue measure. High-free triiodothyronine (T3) levels were positively
associated to better cognitive functions but negatively to self-rated everyday consequences of fatigue
among the patients.
In conclusion: Cognitive fatigue measure, derived from Digit Symbol, could be a useful instrument to
capture fatigue. It enables us to calculate an index of cognitive fatigue where neither depression nor
sleep disturbance interfere with the result. Cognitive fatigue seems to be related to BMI and self-rated
health but not directly related to hormonal levels. A curvilinear relation to sex hormones and the
estrogen/testosterone ratio seem more likely. Indirect hormonal imbalances could influence subtle
neuronal mechanisms leading to discrete neuropsychological dysfunctions
Computer aided assessment of CT scans of traumatic brain injury patients
A thesis submitted in partial fulfilment for the degree of Doctor of PhilosophyOne of the serious public health problems is the Traumatic Brain Injury, also known as silent epidemic, affecting millions every year. Management of these patients essentially involves neuroimaging and noncontrast CT scans are the
first choice amongst doctors. Significant anatomical changes identified on the neuroimages and volumetric assessment of haemorrhages and haematomas are of
critical importance for assessing the patients’ condition for targeted therapeutic and/or surgical interventions.
Manual demarcation and annotation by experts is still considered gold standard, however, the interpretation of neuroimages is fraught with inter-observer variability
and is considered ’Achilles heel’ amongst radiologists. Errors and variability can be attributed to factors such as poor perception, inaccurate deduction, incomplete
knowledge or the quality of the image and only a third of doctors confidently report the findings. The applicability of computer aided dianosis in segmenting the apposite regions and giving ’second opinion’ has been positively appraised to
assist the radiologists, however, results of the approaches vary due to parameters of algorithms and manual intervention required from doctors and this presents a gap for automated segmentation and estimation of measurements of noncontrast brain CT scans.
The Pattern Driven, Content Aware Active Contours (PDCAAC) Framework developed in this thesis provides robust and efficient segmentation of significant anatomical landmarks, estimations of their sizes and correlation to CT rating to assist the radiologists in establishing the diagnosis and prognosis more confidently. The integration of clinical profile of the patient into image segmentation algorithms
has significantly improved their performance by highlighting characteristics of the region of interest. The modified active contour method in the PDCAAC framework achieves Jaccard Similarity Index (JI) of 0.87, which is a significant improvement over the existing methods of active contours achieving JI of 0.807 with Simple Linear Iterative Clustering and Distance Regularized Level Set Evolution. The
Intraclass Correlation Coefficient of intracranial measurements is >0.97 compared with radiologists. Automatic seeding of the initial seed curve within the region of interest is incorporated into the method which is a novel approach and alleviates limitation of existing methods.
The proposed PDCAAC framework can be construed as a contribution towards research to formulate correlations between image features and clinical variables encompassing normal development, ageing, pathological and traumatic cases propitious to improve management of such patients. Establishing prognosis usually entails survival but the focus can also be extended to functional outcomes, residual
disability and quality of life issues
Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts
Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD