https://deepblue.lib.umich.edu/bitstream/handle/2027.42/90300/j.ejpain.2004.11.001.pdf?sequence=1

Human brain mechanisms of pain perception and regulation in health and disease.

http://www.unicog.org/publications/DehaeneChangeux_ReviewConsciousness_Neuron2011.pdf

Experimental and Theoretical Approaches to Conscious Processing

background Despite the known benefit of levodopa in reducing the symptoms of Parkinson’s disease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson’s disease. methods In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson’s disease who were assigned to receive carbidopa–levodopa at a daily dose of 37.5 and 150 mg, 75 and 300 mg, or 150 and 600 mg, respectively, or a matching placebo for a period of 40 weeks, and then to undergo withdrawal of treatment for 2 weeks. The primary outcome was a change in scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) between baseline and 42 weeks. Neuroimaging studies of 142 subjects were performed at baseline and at week 40 to assess striatal dopamine-transporter density with the use of iodine-123–labeled 2- b -carboxymethoxy3- b -(4-iodophenyl)tropane ([ 123 I] b -CIT) uptake. results The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and i1.4 in those receiving 600 mg daily (P<0.001). In contrast, in a substudy of 116 patients the mean percent decline in the [ 123 I] b -CIT uptake was significantly greater with levodopa than placebo (–6 percent among those receiving levodopa at 150 mg daily, –4 percent in those receiving it at 300 mg daily, and –7.2 percent among those receiving it at 600 mg daily, as compared with –1.4 percent among those receiving placebo; 19 patients with no dopaminergic deficits on the baseline scans were excluded from the analysis) (P=0.036). The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo. conclusions The clinical data suggest that levodopa either slows the progression of Parkinson’s disease or has a prolonged effect on the symptoms of the disease. In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter. The potential long-term effects of levodopa on Parkinson’s disease remain uncertain.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa033447

Levodopa and the progression of Parkinson's disease.

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques-which are frequently surrounded by dystrophic neurites-and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis.

/pdf/epidemiology-of-alzheimer-disease-4jbouco1i1.pdf

Epidemiology of Alzheimer disease

ronmentalinfluences,adjustingforage,werederivedfrom the twin data. Results: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantlygreaterindizygoticthaninmonozygoticpairs,suggesting genetic influences on timing of the disease. Conclusions: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset. Arch Gen Psychiatry. 2006;63:168-174

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209307/YOA40625.pdf

Role of Genes and Environments for Explaining Alzheimer Disease

OBJECTIVE: Patients who had suffered traumatic brain injury were evaluated to determine the occurrence of psychiatric disorders during a 30-year follow-up. METHOD: Sixty patients were assessed on average 30 years after traumatic brain injury. DSM-IV axis I disorders were diagnosed on a clinical basis with the aid of the Schedules for Clinical Assessment in Neuropsychiatry (version 2.1), and axis II disorders were diagnosed with the Structured Clinical Interview for DSM-III-R Personality Disorders. Cognitive impairment was measured with a neuropsychological test battery and the Mini-Mental State Examination. RESULTS: Of the 60 patients, 29 (48.3%) had had an axis I disorder that began after traumatic brain injury, and 37 (61.7%) had had an axis I disorder during their lifetimes. The most common novel disorders after traumatic brain injury were major depression (26.7%), alcohol abuse or dependence (11.7%), panic disorder (8.3%), specific phobia (8.3%), and psychotic disorders (6.7%). Fourteen patients (23.3...

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.159.8.1315

Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.

Background: Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography. Methods: 15 O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2 O( SN), (3) propofol alone, and (4) propofol plus 70% N2 O( PN). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level. Results: The mean SD end-tidal concentration of sevoflurane was 1.5 0.3% during sevoflurane alone and 1.2 0.3% during S N( P < 0.001). The measured propofol concentration was 3.7 0.7 g/ml during propofol alone and 3.5 0.7 g/ml during PN (not significant). Sevoflurane alone decreased rCBF in some (to 73‐ 80% of baseline, P < 0.01), and propofol in all brain structures (to 53‐70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83‐ 86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56 ‐70% and 50 ‐ 68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during SN, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone. Conclusions: Propofol reduced rCBF and rCMRO2 comparably. Sevoflurane reduced rCBF less than propofol but rCMRO2 to an extent similar to propofol. These reductions in flow and metabolism were partly attenuated by adjunct N2O. SN especially reduced the oxygen extraction fraction, suggesting disturbed flow‐activity coupling in humans at a moderate depth of anesthesia. KNOWLEDGE about the effects of different anesthetics and anesthetic regimens on cerebral circulation and brain metabolism is of vital clinical importance. Improper use of anesthetic techniques may have deleterious effects on the compromised brain. The current understanding of the effects of general anesthetics on cerebral blood flow (CBF) and metabolism is largely based on laboratory data using a variety of different animal species and methods. In spite of partly

Effects of sevoflurane, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans

Our preliminary observations on a small group of burning mouth syndrome (BMS) patients indicated a change in the non-nociceptive, tactile sensory function in BMS and provided evidence for the hypothesis of a neuropathic etiology of BMS. In the present clinical study on a group of 52 BMS patients, we used quantitative sensory tests (QST) in addition to the blink reflex (BR) recordings in order to gain further insight into the neural mechanisms of BMS pain. Based on electrophysiologic findings, the BMS patients could be grouped into four different categories: (1) The results of the BR were suggestive of brainstem pathology or peripheral trigeminal neuropathy in ten (19%) patients. In most of the cases, the abnormalities in the BR seemed to represent subclinical changes of the trigeminal system. (2) Increased excitability of the BR was found in the form of deficient habituation of the R2 component of the BR in 11 (21%) of the patients. Two of these patients also showed signs of warm allodynia in QST. (3) One or more of the sensory thresholds were abnormal indicating thin fiber dysfunction in altogether 35 patients (76%) out of the 46 tested with QST. Thirty-three of these patients showed signs of hypoesthesia. (4) There were only five patients with normal findings in both tests. The present findings with strong evidence for neuropathic background in BMS will hopefully provide insights for new therapeutic strategies.

Sensory dysfunction in burning mouth syndrome.

Background The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis. Methods Using H(2)(15)O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC(50), or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 microg/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation. Results Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36-53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7-16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62-70%, with minor further effects. In the SPM analysis of the "awake to 1 MAC/EC(50)" step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices. Conclusions Both anesthetic agents caused a global reduction of rCBF (propofol > sevoflurane) at the 1 MAC/EC(50) level. The effect was maintained at higher propofol concentrations, whereas 2 MAC sevoflurane caused noticeable flow redistribution. Despite the marked global changes, SPM analysis enabled detailed localization of regions with the greatest relative decreases.

Effects of Surgical Levels of Propofol and Sevoflurane Anesthesia on Cerebral Blood Flow in Healthy Subjects Studied with Positron Emission Tomography

BackgroundAnimal experiments have demonstrated neuroprotection by ketamine. However, because of its propensity to increase cerebral blood flow, metabolism, and intracranial pressure, its use in neurosurgery or trauma patients has been questioned.Methods15O-labeled water, oxygen, and carbon monoxide

Susanna Hinkka

Papers

Axis I and II psychiatric disorders after traumatic brain injury: a 30-year follow-up study.

Effects of sevoflurane, propofol, and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans

Sensory dysfunction in burning mouth syndrome.

Effects of Surgical Levels of Propofol and Sevoflurane Anesthesia on Cerebral Blood Flow in Healthy Subjects Studied with Positron Emission Tomography

Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans.