Normal pressure hydrocephalus (NPH), a CSF circulation disorder, is important as a reversible cause of gait and cognitive disturbance in an aging population. The inconsistent response to CSF shunting is usually attributed to difficulties in differential diagnosis or co-morbidity. Improving outcome depends on an increased understanding of the pathophysiology of NPH. Specifically, this thesis examines the contribution of, and inter-relationship between, the brain parenchyma and CSF circulation in the pathophysiology of NPH. Of the four core studies of the thesis, the first quantifies the characteristics of the CSF circulation and parenchyma in NPH using CSF infusion studies to measure the resistance to CSF absorption and brain compliance. The second study assesses cerebral blood flow (CBF) was using O15-labelled positron emission tomography (PET) with MR co-registration. By performing CSF infusion studies in the PET scanner, CBF at baseline CSF pressure and at a higher equilibrium pressure is measured. Regional changes and autoregulatory capacity are assessed. The final study examines the microstructural integrity of the parenchyma using MR diffusion tensor imaging. These studies confirm the importance of the inter-relationship of the brain parenchyma and CSF circulation. NPH symptomatology and its relationship to the observed regional CBF reductions in the basal ganglia and thalamus are discussed. Regional CBF reductions with increased CSF pressure and the implications for autoregulatory capacity in NPH are considered. The reduction in CBF when CSF was increased was most striking in the periventricular regions. In addition, periventricular structures demonstrated increased diffusivity and decreased anisotropy. The relationship between these changes and mechanisms such as transependymal CSF passage are reviewed. The findings of this thesis support a role of both the CSF circulation and the brain parenchyma in the pathophysiology of NPH. The results have implications for the approach to the management of patients with NPH.

The hypothalamic paraventricular nucleus (PVN) is known to be a major integrative region within the forebrain. It is composed of functionally different subgroups of neurons, including the parvocellular neurons that project to important autonomic targets in the brainstem e.g. the rostral ventrolateral medulla (RVLM) and the intermediolateral cell column (IML) of the spinal cord, where the sympathetic preganglionic motor-neurons are located. These regions are critical in cardiovascular regulation; hence, these projections are likely to mediate the effects of the PVN on sympathetic nerve activity and hence may contribute to the cardiovascular changes induced by physiological stimuli such as elevations in body temperature. The neurotransmitter such as nitric oxide (NO) is important in cardiovascular regulation and it is now emerging as a major focus of investigation in thermoregulation. One of the most striking accumulations of NO containing-neurons is in the PVN where it appears to be playing an important role in cardiovascular regulation and body fluid homeostasis. The results of the work show; 1. That spinally-projecting and nitrergic neurons in the PVN may contribute to the central pathways activated by exposure to a hot environment. 2. Suggests that nitrergic neurons and spinally- projecting neurons in the brainstem may make a small contribution to the central pathways mediating the reflex responses initiated by hyperthermia. 3. The present study also illustrates that these PVN neurons projecting to the RVLM may make a smaller contribution than the spinal-projecting neurons in the PVN to the cardiovascular responses initiated by heat. 4. The results of my studies showed that the microinjection of muscimol to inhibit the neuronal activity in the PVN abolished the reflex decrease in renal blood flow following an elevation of core body temperature. In addition, this effect was specific to the PVN, since microinjections of muscimol into areas outside the PVN were not effective. These findings demonstrate that the PVN is critical for this reflex cardiovascular response initiated by hyperthermia. In conclusion, PVN is critical for the reflex decrease in renal blood flow during elevations in core body temperature. We hypothesise that projections from the PVN to the spinal cord and the RVLM contribute to the reflex cardiovascular responses. Additionally, nitrergic neurons in the PVN may contribute but the physiological role of those neurons in the reflex responses elicited by hyperthermia needs to be investigated.

<p>In the human body, turbulent flow is associated with many complications. Turbulence typically occurs downstream from stenoses and heart valve prostheses and at branch points of arteries. A proper way to study turbulence may enhance the understanding of the effects of stenoses and improve the functional assessment of damaged heart valves and heart valve prostheses.</p><p>The methods of today for studying turbulence in the human body lack in either precision or speed. This thesis exploits a magnetic resonance imaging (MRI) phenomenon referred to as signal loss in order to develop a method for estimating turbulence intensity in blood flow.</p><p>MRI measurements were carried out on an appropriate flow phantom. The turbulence intensity results obtained by means of the proposed method were compared with previously known turbulence intensity results. The comparison indicates that the proposed method has great potential for estimation of turbulence intensity.</p>

The overall aim of this thesis was to elucidate and investigate psychophysiological aspects and effects of acupuncture and needle stimulation. Within this framework emphasis was directed toward the effects of needle stimulation (acupuncture) on muscle blood flow in the tibialis anterior and trapezius muscles in healthy subjects and patients suffering from chronic muscle pain. This study also included evaluation of a new application of photoplethysmography in noninvasive monitoring of muscle blood flow. The evaluation was based on experiments known to provocate skin or muscle blood flow. The psychological aspects studied comprised the effects of manual acupuncture on pain in fibromyalgia patients and the effects of electro-acupuncture on psychological distress and vasomotor symptoms in postmenopausal women in the clinical context. The results showed that photoplethysmography have potential to noninvasively monitor muscle blood flow and to discriminate between blood flow in skin and muscle, although some considerations still have to be accounted for. It was further shown that muscle blood flow change in response to needle stimulation differed between healthy subjects and patients. Deep needle stimulation in the muscle of healthy subjects consistently increased muscle blood flow more than subcutaneous needle stimulation. In the painful trapezius muscle of FMS patients, however, subcutaneous needling was equal or even more effective in increasing muscle blood flow than deep intramuscular stimulation. Generally, needle stimuli had weak effect on blood flow in the trapezius muscle of the severely affected trapezius myalgia patients, possibly depending on older age and lesser number of patients included in the study. The different patterns of blood flow response to needle stimulation between healthy subjects and patients with chronic muscle pain might be a manifestation of altered somatosensory processing in the patients. The clinical studies showed that best pain relief of acupuncture in FMS patients was achieved in the neck-shoulder region, while the effect on the generalised symptoms was of short duration. Well-being and sleep was found to best predict treatment outcome. The results suggest that acupuncture treatment may be used for the alleviation of neck-shoulder pain, primarily, but it is not an alternative as the sole treatment. Electro-acupuncture, significantly decreased psychological distress and climacteric symptoms in postmenopausal women, but not better than a (near-) placebo control, implying pronounced non-specific effects. / Akupunktur ingår som en del i traditionell kinesisk medicin (TCM) och har använts i över 2000 år för att lindra sjukdom och symptom. I Sverige blev akupunktur godkänd som smärtlindringsmetod inom Hälso- och Sjukvården 1984. Sedan nästan 10 år är akupunktur jämställd med övrig behandling i sjukvården vilket innebär, att akupunktur kan användas även för behandling av annat än smärta. Förutsättningen är emellertid, att det finns tillräckligt med vetenskapliga belägg, s.k. evidens, för detta. I de allra flesta fall saknas det idag. För att säkerställa att evidens föreligger krävs omfattande forskning om effekter av akupunktur. Syftet med de olika studierna i avhandlingen var att belysa och studera psykologiska och fysiologiska aspekter och effekter av akupunktur och nålstimulering. Effekt på blodflöde i hud och muskel undersöktes på friska personer och på patienter med kronisk muskelsmärta. Normalt krävs ett mindre kirurgiskt ingrepp för att mäta blodflöde i muskel, men i dessa studier användes en mätmetod, som enkelt och utan ingrepp (icke-invasivt) i normala fall används för att mäta blodflöde i huden, s.k. fotopletysmografi (PPG, eng.). Med hjälp av ny teknik användes PPG i dessa studier för att mäta även muskelblodflöde. En studie för utvärdering av den nya PPG-tekniken ingick också i avhandlingen. Utvärderingen av mätmetoden visade goda möjligheter att mäta muskelblodflöde icke-invasivt med hjälp av PPG. Hos friska personer blev effekten på blodflödet störst vid djup stimulering i muskeln och där den s.k. DeQi-känslan framkallades (som vid klassisk akupunktur). Hos patienter med fibromyalgi var nålstimulering i huden lika, eller t.o.m. mer, effektiv att öka muskelblodflödet i skuldran än den djupa nålstimuleringen. De olika mönstren av blodflödesökning mellan de friska personerna och patienterna kan bero på ett förändrat reaktionssätt i nervsystemet som svar på smärtsam stimulering. I två kliniska studier studerades den smärtlindrande effekten av manuell akupunktur vid fibromyalgi och effekten av elektroakupunktur på stress och klimakteriebesvär hos kvinnor i övergångsåldern. Akupunktur vid fibromyalgi visade sig ha bäst smärtlindrande effekt i nack-skulderområdet, medan effekten på de generella symptomen var kortvarig. Patienter som mådde och sov relativt bra erhöll bäst effekt. Efter en behandlingsserie, bestående av elektroakupunktur, minskade stress och klimakteriebesvär påtagligt hos kvinnorna i övergångsåldern, men inte mer än hos en grupp kvinnor, som fick en kontrollbehandling bestående av mycket ytligt placerade nålar i huden. Detta tyder på att en betydlig del av behandlingsresultatet utgjordes av ospecifika effekter eller, s.k. eller placeboeffekter.

Background and aims: Laparoscopic technique was quickly adopted in general surgery because of less pain, quicker recovery and shorter hospital stay. In the 1990´s several reports on port site metastases restrained the enthusiasm to use laparoscopic surgery in malignant diseases. The numerous reports on port site metastases initiated a debate whether laparoscopic surgery would increase the risk of tumour spread and growth. Personal experience of two patients who devloped port site metastases from an incidental gall bladder cancer (GBC) after laparoscopic cholecystectomy (LC), encouraged us to study the incidence of wound metastases from GBC after laparoscopic and open cholecystectomy (OC). Experimentally we examined whether pneumoperitoneum would increase the risk of tumour development. Several studies had demonstrated that minimally invasive procedures exert a less negative influence on the immune system and may have beneficial effects for cancer patients. We wanted to compare the long term survival after OC and LC and if the occurence of port site metastases had any impact on survival. Material and methods: A questionnaire was sent out to all major hospitals in Sweden requesting information obout the number of port site metastases encountered 1991-94. Data on all pateints with verfied GBC were obtained from the Swedish Oncological Centres. Data on all patients with GBC registered with surgical codes for cholecystectomy were collected from the National Board of Health and Welfare (EpC). The patient files were scrutinized and long term survival data was achieved (EpC). In the first experiment on Wistar Fu rats, adenocarcinoma cells were injected intraperitoneally in animals insufflated with air, CO2 and not insufflated controls. In the following studies, rats were similarly insufflated with air,CO2 and compared to not insufflated controls. Laser Doppler blood flow in the abdominal wall was concomitantly measured. To study the effect of reduced blood flow, one rectus muscle was clamped and the other not and laser Doppler Blood flow was measured in both rectus muscles. Adenocarcinoma cells were injected into the rectus muscles in all animals at the induction of pneumoperitoneum/clamping. Results: 14 of 55 patients developed wound metastases from GBC after LC and 12 of 187 after OC. Gallbladder perforation was overrepresented in patients with wound metastases. Improved survival was noted after LC in patients with T3 tumours. Experimentally, air and CO2 equally increased intraperitoneal tumour development, Insufflation with air,CO2 and clamping decreased blood flow in the abdominal wall and increased tumour growth at the same site. Conclusion: Despite a high rate of wound metastases, LC does not seem to worsen the prognosis of GBC and may even have a positive effect on survival. Perforation of the malignant gallbladder seems to be associated with an increased risk of metastatic formation. In the experimental setting, pneumoperitoneum seems to increase tumour development. Other features of laparoscopic surgery such as decreased blood flow in the abdominal wall may contribute to increased risk of tumour progress.

Purpose: To determine the vascular reactivity (VR) capacity and visual function (VF) response to potent vasoconstrictor and vasodilatory provocations of retinal arterioles in healthy subjects. Methods: One hyperoxic hypocapnic and two graded hypoxic hypercapnic stimuli were administered. VR in response to gas provocation was assessed using the Canon Laser Blood Flowmeter. VF was assessed using high and low contrast ETDRS logMAR charts, Medmont C-100, and H.R.R. Pseudoisochromatic Plates. Results: Flow reduced by 23% (p=0.0001) during hyperoxic hypocapnia and increased by 18% (p=0.0129) during hypoxic hypercapnia. During hyperoxic hypocapnia, high contrast VA improved by -0.026 (p=0.0372). During hypoxic hypercapnia, high and low contrast VA were reduced (+0.033, p=0.0110; +0.025, p=0.0058, respectively). Colour vision was unaffected. Conclusions: The retinal arterioles demonstrated a greater capacity for vasoconstriction than vasodilation in response to the stimuli used in our study. Hyperoxic hypocapnia improved high contrast VA while hypoxic hypercapnia reduced high and low contrast VA.

The current work investigated the stimulation induced spatial response of the cerebral microvascular network by reconstruction of the 3D microvascular morphology from in vivo two photon fluorescence microscopy (2PFM) volumes using an automated, model based tracking algorithm. In vivo 2PFM imaging of the vasculature in the forelimb representation of the primary somatosensory cortex of alpha-chloralose anesthetized rats was achieved via implantation of a closed cranial window, and intravascular injection of fluorescent dextran. The dilatory and constrictory responses of the cerebral microvascular network to functional stimulation were heterogeneous and depended on resting vascular radius and response latency. Capillaries experienced large relative dilations and constrictions, but the larger vessel absolute volume changes dominated the overall network cerebral blood volume change.

This thesis investigated the role of CBF assessment in the management of stroke in children with sickle cell disease (SCD). It is divided into two parts. In the first part, a systematic review of CBF assessment using different imaging modalities in SCD children was designed. The prevalence of CBF abnormalities was found to be equal to or higher than those of structural MRI and transcranial Doppler (TCD) in SCD children who have not experienced stroke. Studies reviewed suggested CBF assessment in SCD could aid in addressing brain abnormalities at the tissue level. In the second part, the arterial spin labeling (ASL) technique was used to depict CBF abnormalities in SCD children. ASL demonstrated perfusion abnormalities that seem to remain invisible in TCD measurements; CBF interhemispheric asymmetries were associated with clinically silent infarctions with no corresponding flow velocity interhemispheric asymmetries assessed with TCD.

Purpose: To determine the vascular reactivity (VR) capacity and visual function (VF) response to potent vasoconstrictor and vasodilatory provocations of retinal arterioles in healthy subjects. Methods: One hyperoxic hypocapnic and two graded hypoxic hypercapnic stimuli were administered. VR in response to gas provocation was assessed using the Canon Laser Blood Flowmeter. VF was assessed using high and low contrast ETDRS logMAR charts, Medmont C-100, and H.R.R. Pseudoisochromatic Plates. Results: Flow reduced by 23% (p=0.0001) during hyperoxic hypocapnia and increased by 18% (p=0.0129) during hypoxic hypercapnia. During hyperoxic hypocapnia, high contrast VA improved by -0.026 (p=0.0372). During hypoxic hypercapnia, high and low contrast VA were reduced (+0.033, p=0.0110; +0.025, p=0.0058, respectively). Colour vision was unaffected. Conclusions: The retinal arterioles demonstrated a greater capacity for vasoconstriction than vasodilation in response to the stimuli used in our study. Hyperoxic hypocapnia improved high contrast VA while hypoxic hypercapnia reduced high and low contrast VA.

The current work investigated the stimulation induced spatial response of the cerebral microvascular network by reconstruction of the 3D microvascular morphology from in vivo two photon fluorescence microscopy (2PFM) volumes using an automated, model based tracking algorithm. In vivo 2PFM imaging of the vasculature in the forelimb representation of the primary somatosensory cortex of alpha-chloralose anesthetized rats was achieved via implantation of a closed cranial window, and intravascular injection of fluorescent dextran. The dilatory and constrictory responses of the cerebral microvascular network to functional stimulation were heterogeneous and depended on resting vascular radius and response latency. Capillaries experienced large relative dilations and constrictions, but the larger vessel absolute volume changes dominated the overall network cerebral blood volume change.