The general aim of this work was to evaluate the outcome of specialised stroke rehabilitation and to examine the relation between both subjectively perceived and objectively assessed balance and impairments and some activity limitations. A further, integrated aim was to establish some psychometric properties and the usability of a newly developed Falls-Efficacy Scale, Swedish version (FES(S)) in stroke rehabilitation. Seventy-three patients younger than 70 years of age with a first stroke and reduced walking ability were randomised into an intervention group (walking on a treadmill with body weight support) and a control group (walking on the ground). Time points of assessment were: on admission for rehabilitation, at discharge and 10 months after stroke. Walking training on a treadmill with body weight support and walking training on the ground were found to be equally effective in the early rehabilitation. The patients in both groups improved their walking velocity, motor function, balance, self-efficacy and ADL performance. In a geriatric sample of 37 stroke patients examined at similar time points, significant improvements in self-efficacy, motor function, balance, ambulation and ADL occurred from admission to discharge independently of age. In comparison with observer-based balance measures, FES(S) at discharge was the most powerful predictor of ADL performance 10 months after onset of stroke. In 30 patients with stable stroke, the overall test-retest reliability of FES(S) was found to be adequate. The internal consistency confirmed that FES(S) has an adequate homogeneity. In a subsample of 62 patients from the original sample and in the geriatric sample, FES(S) correlated significantly with Berg’s balance scale, the Fugl-Meyer balance scale, with motor function and with gait performance. In the relatively younger group ADL (measured by the Functional Independence Measurement) correlated significantly with FES(S) on admission and at 10 months follow-up, while at discharge none of the FES(S) measures correlated significantly with ADL. In this subsample effect size statistics for detecting changes in FES(S) demonstrated very acceptable responsiveness of this scale during the early treatment period and during the total observation period In the light of these findings assessment and treatment of self-efficacy seems relevant in stroke rehabilitation.

Stroke is the third leading cause of morbidity and mortality in the industrialized world. Subarachnoid hemorrhage (SAH), the least common form of stroke, is one of the most demanding diseases treated in neurointensive care units. Cerebral ischemia may develop rapidly, and has a major influence on outcome.To be able to save parts of the brain that are at risk for ischemic brain damage, there is a need for reliable monitoring techniques. Understanding the pathophysiology of cerebral ischemia is a prerequisite both for the correct treatment of these diseases and for the development of new monitoring techniques and treatment modalities. The main aim of this thesis was to gain insight into the mechanisms of cerebral ischemia by studying early hemodynamic and metabolic changes with positron emission tomography and neurochemical changes with microdialysis. A secondary aim was to evaluate the potential of these techniques for detecting ischemia and predicting the degree of reversibility of ischemic changes. Early changes in cerebral blood flow (CBF) and metabolism (CMRO2) were studied with repeated positron emission tomography in an experimental model (MCAO) of transient focal ischemia, and in SAH patients. CMRO2 was superior to CBF in discriminating between tissue with irreversible damage and tissue with the potential for survival in the experimental model. A metabolic threshold of ischemia was found. Neurochemical changes in the ischemic regions were studied simultaneously with microdialysis. Extracellular concentrations of glucose, lactate, hypoxanthine, glutamate and glycerol were measured, and the lactate/pyruvate (LP) and lactate/glucose ratios were calculated. Changes in all the microdialysis parameters were related to the degree of ischemia (severe ischemia or penumbra). Especially the LP ratio and glycerol were found to be robust and specific markers of ischemia. In the patients, hemodynamic and metabolic changes were common, but diverse in the acute phase of SAH, and it was suggested that these changes may contribute to an increased vulnerability for secondary events and the development of secondary ischemic brain damage.

The subjects were 130 male prisoners in Swedish jails were examined by SCID and the diagnoses given in terms of DSM-IV. The most common mental disorder was drug abuse. On Axis II several personality disorders were diagnosed. Personality assessments were made by KSP. High scores were mainly found for e.g. impulsiveness, sensation seeking, aggression and low scores in socialisation. MAO assays were performed in 99 male criminal offenders and in 60 non-criminal volunteers. Offenders had lower MAO activity than controls also with the confounding factor smoking under control. It is proposed that platelet MAO is linked to personality traits, which can predispose for criminality. For testing the existence of combinations of vulnerability factors, a configuration frequency analysis (CFA) was used. The criteria which formed the basis for the subgrouping were; MAO activity below or above –0.5 SD of the mean (L and H), the presence or absence of an Axis I disorder (= drug abuse) (Y/N), the presence or absence of an Axis II disorder (Y/N), or the presence or absence of an Axis I and II disorder (Y/N). In this way eight subgroups were formed. Two significant "types" were found among the criminals: One was characterised by low platelet MAO activity, Cluster B personality diagnosis as well as Drug Abuse Disorder diagnosis (LYY); and the other by a pattern of normal platelet MAO activity, no Cluster B personality disorder, and no Drug Disorder diagnosis (HNN). Also two "antitypes", occurring less frequent than expected, were identified; LYN and LNY. Thus, the aggregation of certain risk factors in the same individual has been shown to contribute to the development of criminal behaviour. The subgroups HNN, LYN, LNY and LYY were then analysed for a variety of criminological factors. There was a difference in mean age between the subgroups, the HNN being lowest. Economical crimes were more common at an early criminal debut and crimes involving violence at an adult debut. The HNN subgroup had a lower number of crimes and times spent in jail than the other subgroups. More than 50% of the clients in all groups had previously been sentenced to Reformatory.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive disorder characterized by degeneration of motor neurons in the cortex, brainstem and spinal cord. The patients usually die within 3-5 years after onset. The full etiology of ALS is unknown and many hypotheses have been proposed to explain the neurodegeneration. However, basic mechanisms of cellular function such as transmethylation and polyamine metabolism have not been extensively studied in ALS. Transmethylation reactions are very important in the synthesis of substrates such as proteins, neurotransmitters, DNA and RNA. The polyamines, putrescine, spermidine and spermine, are involved in essential functions such as cellular growth, proliferation and differentiation. An initial study in this thesis concerned the process of neuronal death (apoptosis) in ALS spinal cord. The results showed increased levels of an apoptosis-stimulating protein and increased levels of DNA fragmentation indicative of an apoptotic process in the tissue. A comparative study of MAT-enzyme activity in spinal cord from different mammalian species was undertaken to provide a background for future studies on transmethylation and neurodegeneration. Transmethylation reactions were found altered in erythrocytes from males with ALS but not in spinal cord from ALS patients as compared to controls. An adaptation of previously described polyamine assays was made for the study of polyamines in ALS spinal cord. The method was validated and applied for polyamine analysis in human materials of different characteristics. Determination of polyamines in control and ALS spinal cords showed no major differences. However, in female ALS patients, significantly increased spermidine and spermine levels were observed in ventral horn regions. These gender-related alterations in transmethylation and polyamine metabolism are of interest since there is a male preponderance for the disease. The lack of major differences in polyamine levels between ALS and control spinal cord suggests a maintained regulation of polyamines at the end stage of this neurodegenerative disease.

After the acute spell of poliomyelitis, patients commonly suffers from sequelae of weakness. Some of these patients experience new weakness after a time period of stable symptoms. The aim of this thesis was to evaluate the possible mechanisms for persistent weakness and development of new weakness in prior polio patients. The usefulness of neurophysiologic methods to study prior polio was evaluated. Also two follow up investigations were performed in the attempt to investigate a possible relationship between development of weakness over time and possible failure in neuromuscular function and relation to muscular activity. In another investigation an evaluation of the exceptional finding of a history of paralytic poliomyelitis without neurophysiologic signs of anterior horn cell death was made. The last investigation dealt with reflex pattern in prior polio and it’s relation to weakness and anterior horn cell loss. The weakness in prior polio is mainly due to loss of motor neurons with incomplete compensatory mechanisms of reinnervation. The new weakness is mainly due to exaggerated physiological age dependent loss of whole motor neurons, but also fragmentation of the motor unit is likely when these have reached an upper size. Defective neuromuscular transmission and failure in the central drive contribute to a lesser degree to weakness. Neurophysiologic method of choice for the assessment of motor unit size and the micro-physiology of the motor unit is Macro EMG. Muscular overuse may accelerate motor unit loss over time in prior polio. Extremely large motor units measured with Macro EMG predict new weakness and Macro EMG can be used for prognostication of development of new weakness in prior polio.

Stem cells have the capacity for both self renewal, and to form all cell types in the body. Interestingly, so called neural stem cells (NSCs) are found in the adult human brain, which is of significance both out of a developmental perspective and from a clinical point of view. At the present moment, the regulation of neural stem cell (NSC) proliferation and fate determination is not completely understood. The overall aim of this thesis was to study the mechanisms that regulate NSC proliferation and fate determination in vitro and in vivo. In particular, the roles of the female sex hormone estrogen and the testosterone analogue nandrolone, as well as the melanocortin α-melanocyte stimulating hormone (α-MSH), were analyzed in this context. Also, the breast cancer susceptibility gene one (BRCA-1), was studied in the brain with emphasis on regions containing NSCs. Our findings show that estrogen and nandrolone have similar effects on NSCs; both decreased NSC proliferation and increased neurogenesis. Estrogen's ability to reduce proliferation was due to increased levels of p21, an inhibitor of cyclin dependent kinases. In contrast, no change in p21 was observed in the case of nandrolone, indicating differential regulation. Adult rats subjected to nandrolone injections had 30% reduced NSC proliferation in the dentate gyrus, indicating profound effects on NSCs in vivo. The melanocortin α-MSH acted as a mitogen by increasing levels of cyclinD1 and retinoblastoma protein; as a result NSC proliferation was doubled. Finally, BRCA-1 is expressed while NSCs proliferate, but is drastically down regulated upon differentiation, indicating that BRCA-1 could be used as a possible NSC marker. In summary, in this thesis estrogen and nandrolone were identified as NSC regulators which decrease proliferation and positively influence neurogenesis. Also, we have identified the hormone α-MSH as a NSC mitogen, and BRCA-1 as a possible NSC marker.

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of upper and lower motor neurons, resulting in muscle weakness and death from respiratory failure within 3-5 years after onset. The incidence is 1.5-2.7/100,000 inhabitants. 5-10% of all cases are hereditary. The aetiology of sporadic ALS is still unknown. The only neuroprotective drug approved for the treatment of ALS is riluzole, a glutamate-antagonist, which has shown to improve survival. We evaluated if riluzole sales statistics can be used as a method for estimating the prevalence of ALS/motor neuron disease in Sweden. We found that this method, which is less time consuming than conventional methods, could be used as a crude marker for the prevalence. In a longitudinal study of overall Quality of Life (QoL) in ALS we found that QoL changes only slightly over time despite disease progression. ALS does not necessarily result in a low QoL. Growth factors are important for the survival of neurons. In ALS we found increased or normal levels of GDNF mRNA and BDNF mRNA in muscle biopsies, VEGF in serum and spinal cord and FGF-2 in serum and cerebrospinal fluid. There is thus no deficit of these growth factors although there may be a relative lack because of high demands of the motor neurons. Polyamines are small aliphatic molecules that are important for the function of cells. The level of the polyamines spermidine and spermine were increased in red blood cells in both patients with ALS and patients with Parkinson’s disease, suggesting that polyamines may have a role for the neurodegenerative process. Polyamines in spinal cord were of the same level in the patients with ALS and in controls, indicating a maintained regulation of polyamines at the end-stage of the disease.

Human skeletal muscles possess thixotropic, i.e. history-dependent mechanical properties. This means that the degree of passive muscle stiffness and resting tension is dependent on the immediately preceding history of contractions and length changes. Athletes, for instance, reduce passive muscle stiffness by various types of ‘limbering-up’ procedures, whereas muscle stiffness gradually increases during inactivity. Passive resistance of antagonistic muscles may significantly add to the total load during voluntary muscle contractions. This resistance may vary from one moment to another, depending on immediately preceding events. This research was conducted to determine whether history-dependent variations in passive muscular forces influence motor control of voluntary joint movements and steady maintenance of joint positions in healthy subjects. In study I, the EMG signal revealed motor compensations for history-dependent variations in passive stiffness of the antagonists during slow voluntary wrist joint movements. Studies II and III demonstrated that the voluntary muscle activity required to maintain a certain wrist joint position was highly influenced by previous changes in forearm muscle length and contractions. Study IV showed that rapid voluntary movements varied in speed and onset time depending on the prevailing degree of muscle resistance, and in addition that the central nervous reaction time required to execute rapid movements was highly influenced by immediately preceding muscle-conditioning procedures. History-dependent variations in passive muscular forces seem to be effectively compensated by the motor control system. Presumably, voluntary motor commands to the muscles are automatically adjusted in strength to history-dependent changes in passive muscular forces. Such adjustments occur within the central nervous system, which receives information about the mechanical state of the muscles. Several issues in connection with muscle thixotropy remain unaddressed. For instance, do alterations in the normal thixotropic mechanical behaviour of the muscles impose a particular problem in patients with certain neuromuscular diseases?

Headache is the most frequently reported pain in children and is associated with missed schooldays, anxiety, depressive symptoms and various physical symptoms. A secular trend of increasing headache prevalence has been suggested. Few studies have focused on tension-type headache among children from the general population. The aims of this thesis were to describe the prevalence, incidence and prognosis of tension-type headache, migraine and overall headache in schoolchildren, to identify medical, psychological and social factors associated with these headache types, and to determine whether the prevalence of headache has increased over the last decades. In 1997, 1850 schoolchildren aged 7-15 years from the city of Uppsala participated in a questionnaire study and 1371 (74.1%) responded. Out of these, a randomly selected, stratified sample of 131 children and their parents were interviewed. Three years later, 122 children from the interview sample replied to an identical headache questionnaire. Compared with a similar study in 1955, a significantly lower proportion of schoolchildren reported no headache. The prevalence of tension-type headache increased with age and was significantly higher in girls than boys after the age of twelve. Similar age and gender differences were obtained for migraine. A higher proportion of girls reported frequent headache than boys. Children with headache, especially those with migraine, as well as their first-degree relatives suffered from other pains and physical symptoms more frequently than headache-free children and their first-degree relatives. Although the likelihood of experiencing the same headache diagnosis and symptoms at follow-up was high, about one fifth of children with migraine developed tension-type headache and vice versa. Female gender was a predictor of migraine and frequent headache a predictor of overall headache at follow-up. The estimated annual incidence for tension-type headache, migraine and overall headache was 81, 65 and 131 per 1000 children, respectively. In conclusion, the results indicate that headache has become increasingly common among schoolchildren over the last decades. Prevention and treatment of headache is particularly important for girls since they have high prevalence of headache, frequent headache episodes and a poor outcome. In children with headache, diagnoses and treatment should be reassessed regularly and other pains should be asked about and treated as well.

Impulses coming from peripheries are modified in the spinal cord and transmitted to the brain. Several neurotransmitters have been involved in the processing of impulses in the spinal dorsal horn. Acetylcholine (ACh) is one of many neurotransmitters involved in the regulation of nociception in the spinal cord. In this study we investigated the role of nicotinic, muscarinic, serotonergic and GABA receptors in the regulation of spinal ACh release since these receptors are reported to be involved in spinal nociceptive processes. Different receptor ligands were infused intraspinally via microdialysis and the spinal ACh release was measured by on-line HPLC. Receptor-ligand binding studies were performed with spinal cord homogenates as well as receptors expressed in cells. In the first study, we found that nicotine and some of the nicotinic antagonists used increased ACh release suggesting that spinal ACh release is regulated by different nAChRs. Nicotine and nicotinic agonists may act on different types of receptors with different affinity to produce the observed net effect of increased ACh release. We propose the possibility of an involvement of three different nicotinic receptor subtypes in the regulation of spinal ACh release. The effect of epibatidine, which is regarded as a nicotinic agonist, on muscarinic receptors was investigated in the second study. We propose that epibatidine, in μM concentrations, is a partial muscarinic receptor agonist that may interact with spinal muscarinic receptors to increase ACh release. The dual action on both nAChRs and mAChRs may explain the potent analgesic effect observed after intra-spinal epibatidine administration. In the third study, we investigated the role of serotonin receptor involvement in ACh release control. The results suggest that only 5-HT1A and 5-HT2A receptors are involved in spinal ACh release. Considering current knowledge, the most probable location of 5-HT2A receptors is on cholinergic neurones. On activation of the 5-HT2A receptors the cellular excitability of cholinergic neurones is increased which results in an increasing ACh release. The 5-HT1A receptors might be located on cell bodies of GABA neurones which inhibit the firing rate of the GABA neurones when activated by serotonin. In the fourth study, we investigated the GABA receptor involvement in the regulation in spinal ACh release. We found that GABAA receptors are tonically inhibiting spinal ACh release. The results further suggest that GABAB receptors also are involved in the regulation of spinal ACh release. However, unlike GABAA antagonists, GABAB antagonists do not increase ACh release. This suggests that GABAB receptors are not tonically regulating the spinal ACh release.