By Dr. D. C. Laycock, Ph.D. Med. Eng. MBES, MIPEM

All living cells within the body possess potentials between the inner and outer membrane of the cell, which, under normal healthy circumstances, are fixed. Different cells, e.g. Muscle cells and Nerve cells, have different potentials of about -70 mV respectively. When cells are damaged, these potentials change such that the balance across the membrane changes, causing the attraction of positive sodium ions into the cell and negative trace elements and proteins out of the cell. The net result is that liquid is attracted into the interstitial area and swelling or edema ensues. The application of pulsed magnetic fields has, through research findings, been shown to help the body to restore normal potentials at an accelerated rate, thus aiding the healing of most wounds and reducing swelling faster. The most effective frequencies found by researchers so far, are very low frequency pulses of a 50Hz base. These, if gradually increased to 25 pulses per second for time periods of 600 seconds (10 minutes), condition the damaged tissue to aid the natural healing process.

PAIN REDUCTION is another area in which pulsed electromagnetic therapy has been shown to be very effective. Pain signals are transmitted along nerve cells to pre-synaptic terminals. At these terminals, channels in the cell alter due to a movement of ions. The membrane potential changes, causing the release of a chemical transmitter from a synaptic vesicle contained within the membrane. The pain signal is chemically transferred across the synaptic gap to chemical receptors on the post synaptic nerve cell. This all happens in about 1/2000th of a second, as the synaptic gap is only 20 to 50 n.-meter wide. As the pain signal, in chemical form, approaches the post synaptic cell, the membrane changes and the signal is transferred. If we look at the voltages across the synaptic membrane then, under no pain conditions, the level is about -70 mV. When the pain signal approaches, the membrane potential increases to approximately +30 mV, allowing a sodium flow. This in turn triggers the synaptic vesicle to release the chemical transmitter and so transfer the pain signal across the synaptic gap or cleft. After the transmission, the voltage reduces back to its normal quiescent level until the next pain signal arrives.

The application of pulsed magnetism to painful sites causes the membrane to be lowered to a hyper-polarization level of about -90 mV. When a pain signal is detected, the voltage must now be raised to a relatively higher level in order to fire the synaptic vesicles.

Since the average change of potential required to reach the trigger voltage of nearly +30 mV is +100 mV, the required change is too great and only +10 mV is attained. This voltage is generally too low to cause the synaptic vesicle to release the chemical transmitter and hence the pain signal is blocked. The most effective frequencies that have been observed from research in order to cause the above changes to membrane potentials, are a base frequency of 200Hz and pulse rate settings of between 5 and 25Hz.

Source: Lecture abstract of 28-01-1995, Dr. D. C. Laycock, Ph.D. Med. Eng. MBES, MIPEM, B.Ed. (Hons Phys. Sc.). Consultant Clinical Engineer, Westville Associates and Consultants (UK).

--------------------------------------------------------------------------------

Beneficial Effects of Pulsed Electromagnetic Fields

Bassett CA.

Bioelectric Research Center, Columbia University, Riverdale, New York 10463.

Selective control of cell function by applying specifically configured, weak, time-varying magnetic fields has added a new, exciting dimension to biology and medicine. Field parameters for therapeutic, pulsed electromagnetic field (PEMFs) were designed to induce voltages similar to those produced, normally, during dynamic mechanical deformation of connective tissues. As a result, a wide variety of challenging musculoskeletal disorders have been treated successfully over the past two decades. More than a quarter million patients with chronically ununited fractures have benefitted, worldwide, from this surgically non-invasive method, without risk, discomfort, or the high costs of operative repair. Many of the athermal bioresponses, at the cellular and subcellular levels, have been identified and found appropriate to correct or modify the pathologic processes for which PEMFs have been used. Not only is efficacy supported by these basic studies but by a number of double-blind trials. As understanding of mechanisms expands, specific requirements for field energetics are being defined and the range of treatable ills broadened. These include nerve regeneration, wound healing, graft behavior, diabetes, and myocardial and cerebral ischemia (heart attack and stroke), among other conditions. Preliminary data even suggest possible benefits in controlling malignancy.

Source: J Cell Biochem 1993 Apr;51(4):387-93

Alzheimer's Disease

After applying external electromagnetic fields ranging 5 to 8 Hz, large improvements were detected in Alzheimer's patients. These included improved visual memory, drawing performance, spatial orientation, mood, short-term memory and social interactions. Ref R. Sandyk, "Alzheimer's Disease: Improvement of Visual Memory and Visuoconstructive Performance Treatment with Picotesla Range Magnetic Fields," International Journal of Neurosci.

Alzheimer's Disease

R. Sandyk et al.: 'Age-Related Disruption of Circadian Rhythms: Possible Relationship to Memory Impairment and Implications for Therapy with Magnetic Fields, 'International Journal of Neuroscience, 59 (4), August 1991, pp. 259-262. - The circadian rhythm seems to be causally related to memory loss in the elderly and possibly also to Alzheimer's disease. PEMF can probably improve memory performance in elderly patients by resetting the biological clock.

R. Sandyk: 'Alzheimer's Disease: Improvement of Visual Memory and Visuoconstructive Performance by Treatment with low intensity PEMF in Picotesla intensity ' International Journal of Neuroscience, 76 (3-4), June 1994, pp. 185ff. - Two Alzheimer's patients showed a definite improvement after treatment with PEMF, especially in the visual memory and their drawing abilities. There were also improvements in other cognitive functions, in the ability of these patients to orient themselves in space, their mental/emotional condition, their ability to make social contact and their short-term memory.

Neuropsychologia. 2003;41(8):952-67. Related Articles, Links

Spelling via semantics and phonology: exploring the effects of age, Alzheimer's disease, and primary semantic impairment.
Cortese MJ, Balota DA, Sergent-Marshall SD, Buckner RL.
Department of Psychology, Morehead State University, 601 Ginger Hall, Morehead, KY 40351, USA.
Spelling performance across a common set of stimuli was examined in young adults, healthy older adults, individuals with early stage dementia of the Alzheimer's type (DAT), and four individuals with a primary semantic impairment (PSI). The stimuli included homophones and low-frequency sound-to-spelling consistent (i.e. words with more predictable spellings) and inconsistent words (i.e. words with less predictable spellings). The results indicate that when spelling homophonic words (spelling/pleIn/ as plane versus plain), younger adults and to a greater extent individuals with PSI placed relatively more emphasis on phonological information (i.e. spell the word based on sound-to-spelling principles) whereas healthy older adults and individuals with DAT placed relatively more emphasis on semantic information (i.e. spell the word based on the dominant usage). For non-homophonic words, large consistency effects (spelling plaid as plad) were observed for both individuals with DAT and individuals with PSI. It is proposed that the decrease in accuracy for inconsistent words has different bases in DAT and PSI. We propose that deficits in attentional control (i.e. selection) underlie performance in DAT whereas disruption of semantic representations underlies performance in PSI.
PMID: 12667531 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

Hippocampus. 2003;13(1):67-80. Related Articles, Links

Encoding of novel picture pairs activates the perirhinal cortex: an fMRI study.
Pihlajamaki M, Tanila H, Hanninen T, Kononen M, Mikkonen M, Jalkanen V, Partanen K, Aronen HJ, Soininen H.
Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland.
It is well established in nonhuman primates that the medial temporal lobe (MTL) structures, the hippocampus and the entorhinal and perirhinal cortices, are necessary for declarative memory encoding. In humans, the neuropathological and neuropsychological changes in early Alzheimer's disease (AD) further support a role for the rhinal cortex in the consolidation of new events into long-term memory. Little is known, however, regarding the function of the rhinal cortex in humans in vivo. To examine the participation of the interconnected MTL structures as well as the whole-brain network of activated brain areas in visual associative long-term memory, functional magnetic resonance imaging (fMRI) was used to determine the brain regions that are activated during encoding and retrieval of paired pictures in 12 young control subjects. The most striking finding in the MTL activation pattern was the consistent activation of the perirhinal cortex in the encoding-baseline and encoding-retrieval comparisons with a strict statistical threshold (P < 0.00001). In contrast, no perirhinal cortex activation was detected in the retrieval-baseline or retrieval-encoding comparisons even with a low statistical threshold (P < 0.05). The location of the perirhinal activation area was in the transentorhinal part of the perirhinal cortex, in the medial bank of the collateral sulcus. The hippocampus and the more posterior parahippocampal gyrus were activated in both encoding and retrieval conditions. During the encoding processing, MTL activations were more consistent and the hippocampal activation area located more anteriorly than during retrieval. The frontal, parietal, temporal, and occipital association cortices were also activated in the encoding-baseline and retrieval-baseline comparisons. The data suggest that encoding, but not retrieval, of novel picture pairs activates the perirhinal cortex. To our knowledge, this is the first fMRI study reporting encoding activation in this transentorhinal part of the perirhinal cortex, the site of the very earliest neuropathological changes in AD.
PMID: 12625459 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

Methods Find Exp Clin Pharmacol. 2002;24 Suppl D:17-20. Related Articles, Links

Simultaneous ERP and event-related fMRI: focus on the time course of brain activity in target detection.
Mulert C, Jager L, Pogarell O, Bussfeld P, Schmitt R, Juckel G, Hegerl U.
Laboratory for Clinical Neurophysiology, Department of Psychiatry, LMU, Munich, Germany.
The event-related P300 potential has been widely used in neurophysiological research. It is usually evoked with an oddball paradigm. One main reason for its broad application in neurophysiological research is the fact that in several brain/mental diseases, such as Alzheimer's disease or schizophrenia, attenuations of the P300 amplitude and latency have been described. However, a precise correlation of the scalp data to the underlying brain regions was not possible, as the correct localization of the generators of scalp-measured electroencephalogram (EEG) data was limited, due to the low spatial resolution of EEG-data. With the availability of modern imaging technologies, functional Magnetic Resonance Imaging (fMRI) in particular, the underlying brain activations could be detected using an oddball task. Although the spatial resolution of fMRI is excellent, the time resolution is restricted. For a comprehensive understanding of the brain activity underlying the P300 paradigm, we have used a combination of EEG and fMRI to get a precise localization and a high-time resolution of the underlying brain activity.
PMID: 12575464 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

5: Ann Neurol. 2003 Jan;53(1):102-8. Related Articles, Links

Motor cortex excitability in Alzheimer's disease: A transcranial magnetic stimulation study.
Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM.
Department of Neurology, University Campus Biomedico.
Motor deficits affect patients with Alzheimer's disease only at later stages. Recent studies demonstrate that the primary motor cortex is affected by neuronal degeneration accompanied by the formation of amyloid plaques and neurofibrillary tangles. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries occurring along the natural course of the disease, thereby maintaining motor performances in daily living. Cortical motor output to upper limbs was tested via motor-evoked potentials from forearm and hand muscles elicited by transcranial magnetic stimulation of motor cortex in 16 patients with mild Alzheimer's disease without motor deficits. Motor cortex excitability was increased, and the center of gravity of motor cortical output, as represented by excitable scalp sites, showed a frontal and medial shift, without correlated changes in the site of maximal excitability (hot-spot). This may indicate functional reorganization, possibly after the neuronal loss in motor areas. Hyperexcitability might be caused by a dysregulation of the intracortical GABAergic inhibitory circuitries and selective alteration of glutamatergic neurotransmission. Such findings suggest that motor cortex hyperexcitability and reorganization allows prolonged preservation of motor function during the clinical course of Alzheimer's disease.
PMID: 12509853 [PubMed - in process]

------------------------------------------------------------------------

6: Brain Res Cogn Brain Res. 2002 Nov;14(3):347-56. Related Articles, Links

Functional magnetic resonance imaging of brain activity in the visual oddball task.
Ardekani BA, Choi SJ, Hossein-Zadeh GA, Porjesz B, Tanabe JL, Lim KO, Bilder R, Helpern JA, Begleiter H.
Center for Advanced Brain Imaging, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Abnormalities in the P300 ERP, elicited by the oddball task and measured using EEG, have been found in a number of central nervous system disorders including schizophrenia, Alzheimer's disease, and alcohol dependence. While electrophysiological studies provide high temporal resolution, localizing the P300 deficit has been particularly difficult because the measurements are collected from the scalp. Knowing which brain regions are involved in this process would elucidate the behavioral correlates of P300. The aim of this study was to determine the brain regions involved in a visual oddball task using fMRI. In this study, functional and high-resolution anatomical MR images were collected from seven normal volunteers. The data were analyzed using a randomization-based statistical method that accounts for multiple comparisons, requires no assumptions about the noise structure of the data, and does not require spatial or temporal smoothing. Activations were detected (P<0.01) bilaterally in the supramarginal gyrus (SMG; BA 40), superior parietal lobule (BA 7), the posterior cingulate gyrus, thalamus, inferior occipitotemporal cortex (BA 19/37), insula, dorsolateral prefrontal cortex (BA 9), anterior cingulate cortex (ACC), medial frontal gyrus (BA 6), premotor area, and cuneus (BA 17). Our results are consistent with previous studies that have observed activation in ACC and SMG. Activation of thalamus, insula, and the occipitotemporal cortex has been reported less consistently. The present study lends further support to the involvement of these structures in visual target detection.
PMID: 12421658 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

7: Neuroimage. 2002 Nov;17(3):1403-14. Related Articles, Links

Functional imaging of visuospatial processing in Alzheimer's disease.
Prvulovic D, Hubl D, Sack AT, Melillo L, Maurer K, Frolich L, Lanfermann H, Zanella FE, Goebel R, Linden DE, Dierks T.
Department of Psychiatry, University of Frankfurt, Frankfurt, Germany.
Alzheimer's disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.
PMID: 12414280 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

8: Hum Brain Mapp. 2002 Dec;17(4):230-6. Related Articles, Links

Novelty detection and repetition suppression in a passive picture viewing task: a possible approach for the evaluation of neuropsychiatric disorders.
Jessen F, Manka C, Scheef L, Granath DO, Schild HH, Heun R.
Department of Psychiatry, University of Bonn, Bonn, Germany.
The applicability of functional magnetic resonance imaging (fMRI) in patients with Alzheimer's disease (AD) or schizophrenia is frequently limited by cognitive impairment, which prevents the adequate execution of complex tasks. An experimental design that puts only minor demands on the patients' cognitive ability but engages disease-relevant brain structures would be of benefit. Novelty detection and repetition suppression are two basic components of memory that might be used to investigate specific brain areas under these conditions. Novelty detection has been related to hippocampal activation increases. Stimulus repetition related activation decreases (suppression) have been observed in the extrastriate cortex and have been related to perceptual priming. Both processes have been examined primarily in neuroimaging studies with complex cognitive tasks. We used event-related fMRI to investigate novelty- and repetition-related effects in an attended but passive picture-viewing task in healthy subjects. The differential activation, detected in the novel vs. repeated contrast, was located in the bilateral anterior hippocampus and in bilateral occipital and inferior-temporal areas. The hippocampal activation is of interest because medial temporal lobe lesions are key features in AD and schizophrenia. The repetition-related activation decreases in the extrastriate areas are of potential value in investigating the conflicting results regarding perceptual priming impairment in both disorders. Our results indicate that activation of disease-relevant brain regions under passive task conditions is possible. This might increase the utility of functional imaging in cognitively impaired patients. Copyright 2002 Wiley-Liss, Inc.
PMID: 12395390 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

9: Neurosci Lett. 2002 Sep 6;329(3):293-6. Related Articles, Links

Motor cortex excitability in Alzheimer disease: one year follow-up study.
Pennisi G, Alagona G, Ferri R, Greco S, Santonocito D, Pappalardo A, Bella R.
Department of Neurological Sciences, University of Catania, Azienda Policlinico dell' Universita, Via S. Sofia, 78, 95123 Catania, Italy.
Seventeen patients affected by Alzheimer disease (AD) underwent two transcranial magnetic stimulation (TMS) studies separated by an interval of 12 months, in order to monitor possible changes in motor cortex excitability. After the first examination, all patients were treated with cholinesterase inhibitor drugs. Motor threshold (MT), amplitude of motor evoked potentials and central motor conduction time were considered. After one year, the mean MT values showed a decrease significantly correlated with the severity of cognitive involvement, evaluated by means of the Mini Mental State Examination (MMSE). The difference in MT between the two recording sessions showed no significant correlation with the difference in MMSE score. One year of treatment with cholinesterase inhibitor drugs did not stop the progressive increase in motor cortex excitability. Serial analysis of TMS might represent a method to monitor the rate of change in motor cortex excitability in patients with AD.
PMID: 12183034 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

10: Neurology. 2002 Aug 13;59(3):392-7. Related Articles, Links

Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation.
Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, Profice P, Saturno E, Pilato F, Masullo C, Rothwell JC.
Institute of Neurology, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy.
BACKGROUND: A recently devised test of motor cortex excitability (short latency afferent inhibition) was shown to be sensitive to the blockade of muscarinic acetylcholine receptors in healthy subjects. The authors used this test to assess cholinergic transmission in the motor cortex of patients with AD. METHODS: The authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. RESULTS: Afferent inhibition was reduced in the patients (mean responses +/- SD reduced to 85.7% +/- 15.8% of the test size) compared with controls (mean responses +/- SD reduced to 45.3% +/- 16.2% of the test size; p < 0.001, unpaired t-test). Administration of a single oral dose of rivastigmine improved afferent inhibition in a subgroup of six patients. CONCLUSIONS: The findings suggest that this method can be used as a noninvasive test of cholinergic pathways in AD. Future studies are required to evaluate whether short latency afferent inhibition measurements have any consistent clinical correlates.
PMID: 12177373 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

11: J Neurosci. 2002 Aug 15;22(16):7218-24. Related Articles, Links

Compromised hemodynamic response in amyloid precursor protein transgenic mice.
Mueggler T, Sturchler-Pierrat C, Baumann D, Rausch M, Staufenbiel M, Rudin M.
Central Technologies, Novartis Pharma, AG, CH-4002 Basel, Switzerland.
APP23 transgenic mice overexpressing amyloid precursor protein (APP751) reproduce neuropathological changes associated with Alzheimer's disease such as high levels of amyloid plaques, cerebral amyloid angiopathy, and associated vascular pathologies. Functional magnetic resonance imaging (fMRI) was applied to characterize brain functionality in these mice through global pharmacological stimulation. The cerebral hemodynamic response to infusion of the GABA(A) antagonist bicuculline was significantly reduced in aged APP23 mice compared with age-matched wild-type littermates. This is in part attributable to a compromised cerebrovascular reactivity, as revealed by the reduced responsiveness to vasodilatory stimulation by acetazolamide. The study shows that fMRI is a sensitive tool to phenotype genetically engineered animals modeling neuropathologies.
PMID: 12177216 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

12: Ann Neurol. 2002 Apr;51(4):491-8. Related Articles, Links

Subjective memory complaints: objective neural markers in patients with Alzheimer's disease and major depressive disorder.
Gron G, Bittner D, Schmitz B, Wunderlich AP, Riepe MW.
Memory Clinic, University of Ulm, Germany.
Patients with probable Alzheimer's disease and depressive patients frequently present with subjective memory complaints. Objective distinction of underlying neuronal substrate malfunction and early cross-sectional differential diagnosis have been elusive thus far. We used repetitive learning and free recall of abstract geometric patterns during functional magnetic resonance imaging to assess episodic memory in older subjects (ages 56-64 years) who sought first-time medical attention with subjective memory complaints and were diagnosed with probable Alzheimer's disease (NINCDS-ADRDA criteria; ages 51-67 years) or major depressive disorder (DSM-IV; ages 50-65 years). Contrasting healthy seniors or depressive patients with Alzheimer's disease patients revealed superiority of hippocampal activation. Contrasting Alzheimer's disease patients with seniors showed bilateral prefrontal activity as a correlate of futile compensation of episodic memory failure. Contrasting patients who had major depressive disorder with seniors or patients who had Alzheimer's disease showed bilateral activation of the orbitofrontal cortex and the anterior cingulate. Subjective memory complaints may be classified objectively and very early with functional magnetic resonance imaging of episodic memory in groups of patients with Alzheimer's disease and depressive syndrome. This may facilitate drug trials with evaluation of specific treatments, but further studies will be needed to establish the differential diagnosis for the individual patient.
PMID: 11921055 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

13: Neurosci Lett. 2001 Nov 13;314(1-2):57-60. Related Articles, Links

Transcranial magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity.
Alagona G, Bella R, Ferri R, Carnemolla A, Pappalardo A, Costanzo E, Pennisi G.
Department of Neurological Sciences, University of, Catania, Italy
To study the possible changes of cortical excitability in the Alzheimer disease (AD) by transcranial magnetic stimulation (TMS) and to evaluate their eventual correlation with its stage twenty-one AD patients and 18 normal controls underwent TMS. Motor threshold, amplitudes of motor evoked potentials (MEPs), central motor conduction time (CMCT) and silent period (SP) were considered. The motor threshold in AD patients was lower than in normal subjects with a significant correlation between the stage of cognitive severity. The amplitude of MEPs was increased and the SP duration was reduced in AD patients. No significant differences were obtained for CMCT. These findings could suggest a correlation between increased motor cortical excitability and cognitive severity. Moreover, the increased cortical excitability could represent a key to understand the mechanism of AD and may have implication for novel treatment strategies.
PMID: 11698146 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

14: Neurology. 2001 Sep 11;57(5):812-6. Related Articles, Links

Dissociation of regional activation in mild AD during visual encoding: a functional MRI study.
Kato T, Knopman D, Liu H.
Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, USA.
OBJECTIVE: The authors studied mild patients with AD with a visual learning paradigm to determine whether activations of medial temporal regions on fMRI differ in AD compared to nondemented individuals. BACKGROUND: Changes in activation patterns of medial temporal lobe regions may serve as a biologic marker of altered brain function early in the course of AD. METHODS: The authors studied eight healthy young subjects, eight late middle-age nondemented volunteers, and seven patients with mild AD. All subjects underwent fMRI scanning in which they viewed a set of geometric designs for 45 seconds. Changes in blood flow were analyzed by comparing the prestimulus fMRI signal with that present during the stimulus presentation. RESULTS: Patients with AD, who had very poor recall of the geometric designs subsequently, showed increased blood flow (activation) during stimulus presentation only in a visual association area. Both the young and older nondemented subjects, all of whom had good recall of the designs, showed activations during stimulus presentation of the right entorhinal cortex, right supramarginal gyrus, right prefrontal regions, and left anterior-inferior temporal lobe. The younger and older nondemented subjects did not differ in fMRI activation patterns. CONCLUSIONS: Failure of activation in AD of either temporal lobe or prefrontal regions is consistent with established clinical-pathologic correlations in AD. fMRI may be useful in confirming a memory disorder diagnosis and also may be useful in detecting individuals with incipient dysfunction in learning as a result of disorders such as AD.
PMID: 11552009 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

15: J Cogn Neurosci. 2000;12 Suppl 2:24-34. Related Articles, Links

Functional brain imaging of young, nondemented, and demented older adults.
Buckner RL, Snyder AZ, Sanders AL, Raichle ME, Morris JC.
Howard Hughes Medical Institute and Department of Psychology, Washington University, St. Louis, MO 63130, USA.
Brain imaging based on functional MRI (fMRI) provides a powerful tool for characterizing age-related changes in functional anatomy. However, between-population comparisons confront potential differences in measurement properties. The present experiment explores the feasibility of conducting fMRI studies in nondemented and demented older adults by measuring hemodynamic response properties in an event-related design. A paradigm involving repeated presentation of sensory-motor response trials was administered to 41 participants (14 young adults, 14 nondemented older adults, and 13 demented older adults). For half of the trials a single sensory-motor event was presented in isolation and in the other half in pairs. Hemodynamic response characteristics to the isolated events allowed basic response properties (e.g., amplitude and variance) between subject groups to be contrasted. The paired events further allowed the summation properties of the hemodynamic response to be characterized. Robust and qualitatively similar activation maps were produced for all subject groups. Quantitative results showed that for certain regions, such as in the visual cortex, there were marked reductions in the amplitude of the hemodynamic response in older adults. In other regions, such as in the motor cortex, relatively intact response characteristics were observed. These results suggest caution should be exhibited in interpreting simple main effects in response amplitude between subject groups. However, across all regions examined, the summation of the hemodynamic response over trials was highly similar between groups. This latter finding suggests that, even if absolute measurement differences do exist between subject groups, relative activation change should be preserved. Designs that rely on group interactions between task conditions, parametric manipulations, or group interactions between regions should provide valuable data for making inferences about functional-anatomic changes between different populations.
PMID: 11506645 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

16: Clin Neurophysiol. 2001 Aug;112(8):1436-41. Related Articles, Links

Motor cortex disinhibition in Alzheimer's disease.
Liepert J, Bar KJ, Meske U, Weiller C.
Department of Neurology, Friedrich Schiller University, Jena, Germany.
OBJECTIVES: To explore subclinical disturbances in the motor cortex of patients with Alzheimer's disease (AD). METHODS: We used transcranial magnetic stimulation in a paired pulse technique to test intracortical inhibition (ICI) and intracortical facilitation in mildly to moderately demented AD patients with a normal neurological examination. Patients were studied before and during treatment with the cholinesterase inhibitor donepezil. RESULTS: AD patients had a reduced ICI compared to an age-matched control group. The amount of disinhibition correlated with the severity of dementia. Treatment with 10 mg donepezil daily was associated with an increase of ICI. CONCLUSIONS: The subclinical motor cortex disinhibition in AD patients indicates a functional disturbance, and is probably associated with a cholinergic deficit.
PMID: 11459683 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

17: Neuroscience. 2001;104(3):667-76. Related Articles, Links

Remembering familiar people: the posterior cingulate cortex and autobiographical memory retrieval.
Maddock RJ, Garrett AS, Buonocore MH.
Depaartment of Psychiatry, University of California Davis, Sacramento 65817, USA.
Most functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories differ from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was significantly activated in all eight subjects studied. Most subjects also showed significant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.Our findings are consistent with prior studies showing posterior cingulate cortex activation during autobiographical memory retrieval. This region is also consistently activated during retrieval of standardized memory stimuli when experimental designs emphasizing successful retrieval are employed. Our results support the hypothesis that the posterior cingulate cortex plays an important role in successful memory retrieval. The posterior cingulate cortex has strong reciprocal connections with entorhinal and parahippocampal cortices. Studies of early Alzheimer's disease, temporal lobectomy, and hypoxic amnesia show that hypometabolism of the posterior cingulate cortex is an early and prominent indicator of pathology in these patients. Our findings suggest that autobiographical memory retrieval tasks could be used to probe the functional status of the posterior cingulate cortex in patients with early Alzheimer's disease or at risk for that condition.
PMID: 11440800 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

18: Neuroreport. 2001 Jun 13;12(8):1649-52. Related Articles, Links

Preserved stimulus deviance detection in Alzheimer's disease.
Pekkonen E, Jaaskelainen LP, Erkinjuntti T, Hietanen M, Huotilainen M, Ilmoniemi RJ, Naatanen R.
Department of Neurology, University of Helsinki, and Medical Engineering Centre, Helsinki University Central Hospital, Finland.
Aging attenuates automatic auditory discrimination to duration change, whereas frequency change detection is relatively unimpaired in aging and in Alzheimer's disease (AD). Here we studied with a whole-head magnetometer whether cortical auditory discrimination to duration change as shown by magnetic mismatch negativity (MMNm) response is impaired in AD. Twenty AD patients with mild to moderate cognitive impairment and 18 age-matched healthy subjects were monaurally presented a sequence of frequent standard tones embedded with occasional deviants with shorter duration. MMNm was significantly delayed in the left hemisphere ipsilaterally to the ear stimulated in the patient group, whereas the MMNm amplitudes over both hemispheres were quite similar in both groups. This suggests that although MMNm is delayed in the left hemisphere, the automatic discrimination to duration change in the auditory cortex is not attenuated in the early stages of AD.
PMID: 11409733 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

19: Brain. 2001 Jun;124(Pt 6):1131-7. Related Articles, Links

Examination of motor output pathways in patients with corticobasal ganglionic degeneration using transcranial magnetic stimulation.
Valls-Sole J, Tolosa E, Marti MJ, Valldeoriola F, Revilla M, Pastor P, Blesa R.
Unitat d'EMG, Neurology Service, Hospital Clinic, Universitat de Barcelona, Villarroel, 170 Barcelona 08036, Spain.
The alien hand sign (AHS) is often encountered in patients with corticobasal ganglionic degeneration (CBGD), revealing a unilateral dysfunction of the motor system of unknown pathophysiology. We examined the possibility of an abnormal cortical representation of hand muscles in 10 patients with probable CBGD and a prominent AHS. Cortical maps were obtained from the responses to magnetic stimuli applied with a figure of eight coil at an intensity of 110% above motor threshold. For comparison, the same study was carried out in 10 normal volunteers, eight patients with Parkinson's disease and eight patients with Alzheimer's disease. AHS patients had a larger extension of the cortical map to stimulation of the hemisphere contralateral to the AHS in comparison with the ipsilateral hemisphere. Furthermore, in six patients, focal stimulation of the hemisphere ipsilateral to the AHS gave rise to ipsilateral responses, delayed by a mean of 7.7 +/- 2.2 ms with respect to those recorded in the same muscle to contralateral stimulation. None of the other patients or control subjects had ipsilateral responses. Our results indicate an enhanced excitability, or reduced inhibition, of the motor area of the hemisphere contralateral to the AHS. The delay of the ipsilateral responses is compatible with a disinhibited transcallosal input.
PMID: 11353729 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

20: Hum Brain Mapp. 2000 Aug;10(4):195-6. Related Articles, Links

Comment on:
* Hum Brain Mapp. 2000 Aug;10(4):197-203.

Perceptual priming and extrastriate cortex: consensus and controversy.
Nyberg L.
Department of Psychology, Umea University, Sweden.
Publication Types:
* Comment

PMID: 10949056 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

21: AJNR Am J Neuroradiol. 2000 Mar;21(3):524-31. Related Articles, Links

Functional MR imaging using a visually guided saccade paradigm for comparing activation patterns in patients with probable Alzheimer's disease and in cognitively able elderly volunteers.
Thulborn KR, Martin C, Voyvodic JT.
Department of Radiology, MR Research Center, University of Pittsburgh Medical Center, PA, USA.
BACKGROUND AND PURPOSE: Alzheimer's disease is associated with progressive visuospatial dysfunction. This study used functional MR (fMR) imaging with an eye movement paradigm to investigate differences in visuospatial cognition between patients with probable Alzheimer's disease (pAD) and cognitively able elderly volunteers. METHODS: Using established, although imperfect, clinical criteria, patients with pAD (n = 18) and cognitively able elderly volunteers (n = 10) were selected for study. All patients underwent echo-planar fMR imaging at 1.5 T. The visually guided saccade paradigm consisted of alternating periods (30 s) of central fixation and visually guided saccades to a target appearing randomly along the horizontal meridian. Activation maps were derived using a voxelwise t test, comparing the signal intensities between the two steady-state conditions. The activation patterns were characterized by Talairach coordinates, activation volumes, and laterality ratios (LRs). RESULTS: Statistically significant differences existed between the activation patterns of the patients with pAD and those of the volunteers. In contrast to the control group, a left-dominant parietal activation pattern and enhanced prefrontal cortical activation were observed in most patients with pAD. CONCLUSION: Within the limitations of the imperfect clinical standard of reference, the reduction in right parietal activation producing the left-dominant LR for the intraparietal sulcus may reflect the progressive dysfunction in spatial attention associated with Alzheimer's disease, considering the known parietal lobe involvement in this function and the disease. The high specificity of a positive intraparietal sulcal LR measured by fMR imaging may have a role in detecting and monitoring Alzheimer's disease.
PMID: 10730646 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

22: Dtsch Med Wochenschr. 1999 Dec 23;124(51-52):1577-81. Related Articles, Links

[Neurology. Therapeutic advances through systems research and molecular biology]
[Article in German]
Hohlfeld R, Brandt T.
Institut fur Klinische Neuroimmunologie, Klinikum Grosshadern, Ludwig Maximilians Universitat, Munchen.
PMID: 10664661 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

23: Brain Res. 1999 Dec 11;850(1-2):179-88. Related Articles, Links

Regulation of GTPase and adenylate cyclase activity by amyloid beta-peptide and its fragments in rat brain tissue.
Soomets U, Mahlapuu R, Tehranian R, Jarvet J, Karelson E, Zilmer M, Iverfeldt K, Zorko M, Graslund A, Langel U.
Department of Neurochemistry and Neurotoxicology, Arrhenius Laboratories, Stockholm University, Sweden.
Modulation of GTPase and adenylate cyclase (ATP pyrophosphate-lyase, EC 4.6.1.1) activity by Alzheimer's disease related amyloid beta-peptide, A beta (1-42), and its shorter fragments, A beta (12-28), A beta (25-35), were studied in isolated membranes from rat ventral hippocampus and frontal cortex. In both tissues, the activity of GTPase and adenylate cyclase was upregulated by A beta (25-35), whereas A beta (12-28) did not have any significant effect on the GTPase activity and only weakly influenced adenylate cyclase. A beta (1-42), similar to A beta (25-35), stimulated the GTPase activity in both tissues and adenylate cyclase activity in ventral hippocampal membranes. Surprisingly, A beta (1-42) did not have a significant effect on adenylate cyclase activity in the cortical membranes. At high concentrations of A beta (25-35) and A beta (1-42), decreased or no activation of adenylate cyclase was observed. The activation of GTPase at high concentrations of A beta (25-35) was pertussis toxin sensitive, suggesting that this effect is mediated by Gi/G(o) proteins. Addition of glutathione and N-acetyl-L-cysteine, two well-known antioxidants, at 1.5 and 0.5 mM, respectively, decreased A beta (25-35) stimulated adenylate cyclase activity in both tissues. Lys-A beta (16-20), a hexapeptide shown previously to bind to the same sequence in A beta-peptide, and prevent fibril formation, decreased stimulation of adenylate cyclase activity by A beta (25-35), however, NMR diffusion measurements with the two peptides showed that this effect was not due to interactions between the two and that A beta (25-35) was active in a monomeric form. Our data strongly suggest that A beta and its fragments may affect G-protein coupled signal transduction systems, although the mechanism of this interaction is not fully understood.
PMID: 10629763 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

24: J Neurol Sci. 1999 Nov 30;170(2):119-23. Related Articles, Links

Motor cortex inhibition is not impaired in patients with Alzheimer's disease: evidence from paired transcranial magnetic stimulation.
Pepin JL, Bogacz D, de Pasqua V, Delwaide PJ.
University Department of Neurology, CHR Citadelle, Bd du XIIeme de Ligne, 1, 4000, Liege, Belgium.
Motor cortex excitability was studied by transcranial magnetic stimulation (TMS) in 17 patients with Alzheimer's disease (AD). Resting and active thresholds for TMS were significantly reduced in AD patients compared to young and aged healthy subjects. The maximum amplitude of the motor response evoked by TMS was also significantly increased in AD patients. We have tested if these changes are related to a modification of the short-lasting intracortical inhibition of the motor cortex by paired conditioning-test TMS. We found no significant differences between AD patients and aged healthy subjects even if there is a slight but significant difference between aged and young normal subjects. We conclude that the modification of excitability of the motor cortex does not result from an impaired intracortical inhibition.
PMID: 10561527 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

25: J Int Neuropsychol Soc. 1999 Jul;5(5):377-92. Related Articles, Links

Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: patterns of functional MRI activation.
Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, O'Jile JR, Riordan HJ, Santulli RB, Smith CA, Weaver JB.
Department of Psychiatry, Dartmouth Medical School, Lebanon, NH 03756, USA.
Impairment in semantic processing occurs early in Alzheimer's disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.
PMID: 10439584 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

26: J Neurol. 1997 May;244(5):304-7. Related Articles, Links

Magnetic stimulation in Alzheimer's disease.
de Carvalho M, de Mendonca A, Miranda PC, Garcia C, Luis ML.
Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal.
Alzheimer's disease (AD) is a common cause of dementia in which some clinical motor abnormalities have been described. We used transcranial magnetic stimulation in order to test the hypothesis that the change in the motor cortex might cause modifications in motor excitability. Fourteen mildly to moderately affected AD patients were compared with 11 controls matched for age, height and sex. The motor evoked potential threshold value for the relaxed abductor digiti minimi was lower in the AD patients than in the control group for both left and right hemispheres (P < 0.05). No statistically significant difference was found comparing the left and the right hemispheres thresholds in each population. The mean interside threshold differences were small and not significantly different between patients and controls. The spinal motor neuron excitability, as evaluated by F/M and H/M waves amplitude ratios, showed no difference between the groups, reinforcing the motor cortex increased excitability hypothesis to explain this difference. Degeneration of inhibitory gabaergic terminals might be the basis for the increased cortical excitability in the motor cortex of the Alzheimer patients; postsynaptic changes in the GABAA receptors might also affect inhibitory gabaergic transmission. The increased excitability found by transcranial magnetic stimulation in the motor cortex is important for understanding the emergence of seizures and myoclonus in this disease.
PMID: 9178155 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

27: Neuroreport. 1996 May 31;7(8):1365-8. Related Articles, Links

Alzheimer's disease affects parallel processing between the auditory cortices.
Pekkonen E, Huotilainen M, Virtanen J, Naatanen R, Ilmoniemi RJ, Erkinjuntti T.
Department of Psychology, University of Helsinki, Finland.
Auditory evoked magnetic fields (AEFs) were recorded from 11 patients with Alzheimer's disease (AD) and 11 age-matched controls using the 122-channel whole-head magnetometer. Auditory stimuli were monaurally presented with interstimulus intervals (ISI) of 0.5 and 2.5 s in different blocks. The peak latencies of P50m and N100m responses were significantly longer in AD patients than in controls over the ipsilateral but not over the contralateral auditory cortex with respect to the ear stimulated. This finding suggests that parallel auditory processing is impaired between the auditory cortices in AD patients. The present MEG measurement might provide an objective index to evaluate auditory dysfunction in AD.
PMID: 8856676 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

28: J Neurol Sci. 1996 Jan;135(1):31-7. Related Articles, Links

Evaluation of the motor cortex by magnetic stimulation in patients with Alzheimer disease.
Perretti A, Grossi D, Fragassi N, Lanzillo B, Nolano M, Pisacreta AI, Caruso G, Santoro L.
Department of Clinical Neurophysiology, University of Naples, Italy.
Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles elicited by transcranial magnetic stimulation of the motor cortex were studied in 15 patients with Alzheimer disease (AD). An abnormally higher MEP threshold in APB, frequently associated with absence of the MEP in relaxed TA muscles, was found in 40% of patients, almost all of them in the more severe stage of the disease. The MEP amplitude and averaged MEP/MAP ratio were reduced respectively by 20% and 26% in the APB muscle, and by 46.7% and 53.3% in the TA muscle. The less frequent prolongation of the central conduction time (CCT) (20%) might reflect preservation of the impulse propagation along the surviving pyramidal fibers. In 63.6% of the patients the central silent period (cSP) duration in the APB muscle was shortened; the mean value was significantly different between patients and controls. The results of this study suggest that loss and/or dysfunction of motor cortex neurones, including pyramidal cells and inhibitory interneurones may occur in AD patients before clinical signs become apparent.
PMID: 8926493 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

29: J Med Chem. 1995 Apr 28;38(9):1558-70. Related Articles, Links

In vitro muscarinic activity of spiromuscarones and related analogs.
Wu ES, Griffith RC, Loch JT 3rd, Kover A, Murray RJ, Mullen GB, Blosser JC, Machulskis AC, McCreedy SA.
Department of Chemistry and Biology, Fisons Pharmaceuticals, Rochester, New York 14623, USA.
The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa-2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a Ki value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.
PMID: 7739014 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

30: West J Med. 1994 Sep;161(3):273-8. Related Articles, Links

Mapping human brain activity in vivo.
Mazziotta JC.
Department of Neurology, Reed Neurological Research Center, Los Angeles, CA.
A wide range of structural and functional techniques now exists to map the human brain in health and disease. These approaches span the gamut from external tomographic imaging devices (positron-emission tomography, single photon-emission computed tomography, magnetic resonance imaging, computed tomography), to surface detectors (electroencephalography, magnetoencephalography, transcranial magnetic stimulation), to measurements made directly on the brain's surface or beneath it (intrinsic signal imaging, electrocorticography). The noninvasive methods have been combined to provide unique and previously unavailable insights into the macroscopic organization of the functional neuroanatomy of human vision, sensation, hearing, movement, language, learning, and memory. All methods have been applied to patients with neurologic, neurosurgical, and psychiatric disease and have provided a rapidly expanding knowledge of the pathophysiology of diseases such as epilepsy, cerebrovascular disease, neoplasms, neurodegenerative diseases, mental illness, and addiction states. In addition, these new methods have become a mainstay of preoperative surgical planning and the monitoring of pharmacologic or surgical (transplantation) interventions. Most recently, the ability to observe the reorganization of the human nervous system after acute injury, such as occurs with cerebral infarction or head trauma, or in the course of a progressive degenerative process such as Alzheimer's or Parkinson's disease, may provide new insights and methods in the rapidly expanding field of neurorehabilitation. Our newfound ability to generate maps and databases of human brain development, maturation, skill acquisition, aging, and disease states is both an exciting and formidable task.
Publication Types:
* Review
* Review, Tutorial

PMID: 7975566 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

31: J Med Chem. 1994 Aug 19;37(17):2774-82. Related Articles, Links

Design, synthesis, and neurochemical evaluation of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines and 2-amino-5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists.
Dunbar PG, Durant GJ, Rho T, Ojo B, Huzl JJ 3rd, Smith DA, el-Assadi AA, Sbeih S, Ngur DO, Periyasamy S, et al.
Department of Medicinal and Biological Chemistry, College of Pharmacy, University of Toledo, Ohio 43606.
Four regioisomers of 2-amino-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (2a-5a) were synthesized as the racemates to evaluate the utility of exocyclic amidines in the development of novel agonists for M1 muscarinic receptors. Of the four regioisomers, only racemic 2-amino-5-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (4a; CDD-0075-A) displayed high affinity (IC50 = 10 +/- 3.0 microM) and activity at muscarinic receptors coupled to PI metabolism in the rat cortex (260 +/- 4.5% stimulation above basal levels at 100 microM). A series of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines then was synthesized for further evaluation as M1 agonists. Only the propargyl derivative (4d) retained substantial agonist activity (120 +/- 14% at 100 microM) in this series. On the basis of the activity of the 5-(alkoxycarbonyl)-1,4,5,6- tetrahydropyrimidines (1a and 1d) and the 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines, the corresponding cyclic guanidine derivatives were synthesized and tested. 2-Amino-5-(methoxycarbonyl)-1,4,5,6-tetrahydropyrimidine (7a) displayed a modest affinity for muscarinic receptors in the CNS (22 +/- 5.3 microM) and an ability to stimulate PI turnover in rat cerebral cortex (81 +/- 16% at 100 microM). The propargyl derivative (7d) also had modest binding affinity (31 +/- 15 microM) and high activity (150 +/- 8.5% at 100 microM), as expected based on the activity of propargyl esters of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine. Computational chemical studies revealed five distinct minimum-energy conformations for 1a, (R)-4a, and 7a, and three for 1d, (R)-4d, and 7d, each with a unique orientation of the ester moiety. Each of the five conformations for 1a could be superimposed upon a unique conformer of (R)-4a and 7a, suggesting that the compounds interact with muscarinic receptors in a similar fashion. Taken together, the data indicate the general utility of amidine systems as suitable replacements for the ammonium group of acetylcholine in developing ligands with activity at M1 muscarinic receptors in the central nervous system. Such compounds might be useful in the treatment of patients with Alzheimer's disease.
PMID: 8064804 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

32: Cerebrovasc Brain Metab Rev. 1992 Spring;4(1):1-27. Related Articles, Links

PET correlates of normal and impaired memory functions.
Heiss WD, Pawlik G, Holthoff V, Kessler J, Szelies B.
Max-Planck-Institut fur neurologische Forschung, Koln, Germany.
To date, positron emission tomography (PET) has been the only technology for the quantitative imaging of the changes of regional cerebral glucose (rCMRGl) or oxygen metabolism and blood flow (rCBF) associated with psychophysical stimulation and with the performance of mental tasks. So far, the majority of studies performed in healthy subjects demonstrated activation patterns involving not only certain limbic structures, most of all hippocampus, amygdala, parahippocampus, and cingulate, but also temporal, parietal, and occipital association cortex, depending on the applied paradigm. Indeed, the closest correlation between regional metabolism and memory test scores was found in mesiotemporal structures during the performance of memory tasks. Metabolic or CBF studies also seem to indicate that memorizing strategies may differ among individuals. PET was repeatedly used to investigate metabolic and/or blood flow abnormalities in patients with various amnestic syndromes. In cases with uni- or bilateral lesions of mesiotemporal structures, caused by surgery, herpes simplex encephalitis, or permanent ischemic, anoxic, or toxic damage, disturbances of metabolism and blood flow typically extended far beyond the morphological defects detected by computed tomography or magnetic resonance. In acute transient global amnesia, CBF and metabolism were decreased bilaterally in the mesiotemporal lobes, where hypometabolism persisted for some time, while higher values were observed in thalamus and some cortical areas. Diencephalic lesions causing Korsakoff's syndrome were associated with decreased rCMRGl in the hippocampal formation, upper brainstem, cingulate, and thalamus. Discrete thalamic infarcts caused amnesia and metabolic depression in the morphologically intact ipsilateral thalamus and in various projection areas of the infarcted nuclei. In ischemic forebrain lesions, amnestic deficits could be related to involvement of the anterior cingulate and of basal cholinergic nuclei. A large number of pathologies are diffusely spread out in the brain and affect partially or predominantly structures in memory processing. This holds true especially in the various dementias where memory disturbances are a consistent and often leading feature. Notably, Alzheimer's disease can be distinguished from other dementias by its characteristic pattern of metabolic dysfunction, with the most prominent changes occurring in parietotemporal and frontal association cortex whose residual metabolism is related to the severity of the disease. Therefore, activation studies using paradigms involving memory functions enhance that typical pattern. Only in the activated state is metabolism of mesiotemporal structures significantly correlated with the performance in memory tests. Other dementias also affect some of the distributed memory networks, with Huntington's disease suggesting a role of the striatum in memory processing.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
* Review
* Review, Academic

PMID: 1562450 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

33: Acupunct Electrother Res. 1992;17(2):107-48. Related Articles, Links

Common factors contributing to intractable pain and medical problems with insufficient drug uptake in areas to be treated, and their pathogenesis and treatment: Part I. Combined use of medication with acupuncture, (+) Qi gong energy-stored material, soft laser or electrical stimulation.
Omura Y, Losco BM, Omura AK, Takeshige C, Hisamitsu T, Shimotsuura Y, Yamamoto S, Ishikawa H, Muteki T, Nakajima H, et al.
Heart Disease Research Foundation, New York.
Most frequently encountered causes of intractable pain and intractable medical problems, including headache, post-herpetic neuralgia, tinnitus with hearing difficulty, brachial essential hypertension, cephalic hypertension and hypotension, arrhythmia, stroke, osteo-arthritis, Minamata disease, Alzheimer's disease and neuromuscular problems, such as Amyotrophic Lateral Sclerosis, and cancer are often found to be due to co-existence of 1) viral or bacterial infection, 2) localized microcirculatory disturbances, 3) localized deposits of heavy metals, such as lead or mercury, in affected areas of the body, 4) with or without additional harmful environmental electro-magnetic or electric fields from household electrical devices in close vicinity, which create microcirculatory disturbances and reduced acetylcholine. The main reason why medications known to be effective prove ineffective with intractable medical problems, the authors found, is that even effective medications often cannot reach these affected areas in sufficient therapeutic doses, even though the medications can reach the normal parts of the body and result in side effects when doses are excessive. These conditions are often difficult to treat or may be considered incurable in both Western and Oriental medicine. As solutions to these problems, the authors found some of the following methods can improve circulation and selectively enhance drug uptake: 1) Acupuncture, 2) Low pulse repetition rate electrical stimulation (1-2 pulses/second), 3) (+) Qi Gong energy, 4) Soft lasers using Ga-As diode laser or He-Ne gas laser, 5) Certain electro-magnetic fields or rapidly changing or moving electric or magnetic fields, 6) Heat or moxibustion, 7) Individually selected Calcium Channel Blockers, 8) Individually selected Oriental herb medicines known to reduce or eliminate circulatory disturbances. Each method has advantages and limitations and therefore the individually optimal method has to be selected. Applications of (+) Qi Gong energy stored paper or cloth every 4 hours, along with effective medications, were often found to be effective, as Qigongnized materials can often be used repeatedly, as long as they are not exposed to rapidly changing electric, magnetic or electro-magnetic fields. Application of (+) Qi Gong energy-stored paper or cloth, soft laser or changing electric field for 30-60 seconds on the area above the medulla oblongata, vertebral arteries or endocrine representation area at the tail of pancreas reduced or eliminated microcirculatory disturbances and enhanced drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Types:
* Clinical Trial

PMID: 1353650 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

34: J Neurol Neurosurg Psychiatry. 1991 May;54(5):443-8. Related Articles, Links

Posterior cortical dementia with alexia: neurobehavioural, MRI, and PET findings.
Freedman L, Selchen DH, Black SE, Kaplan R, Garnett ES, Nahmias C.
Department of Psychology, Mississauga Hospital, Ontario, Canada.
A progressive disorder of relatively focal but asymmetric biposterior dysfunction is described in a 54 year old right handed male. Initial clinical features included letter-by-letter alexia, visual anomia, acalculia, mild agraphia, constructional apraxia, and visuospatial compromise. Serial testing demonstrated relentless deterioration with additional development of transcortical sensory aphasia, Gerstmann's tetrad, and severe visuoperceptual impairment. Amnesia was not an early clinical feature. Judgment, personality, insight, and awareness remained preserved throughout most of the clinical course. Extinction in the right visual field to bilateral stimulation was the sole neurological abnormality. Early CT was normal and late MRI showed asymmetrical bioccipitoparietal atrophy with greater involvement of the left hemisphere. Results from positron emission tomography (PET) showed bilaterally asymmetric (left greater than right) occipitotemporoparietal hypometabolism. The metabolic decrement was strikingly asymmetric with a 50% reduction in glucose consumption confined to the left occipital cortex. The picture of occipitotemporoparietal compromise verified by MRI, PET, and neurobehavioural testing would be unusual for such degenerative dementias as Alzheimer's (AD) and Pick's disease, although atypical AD with predominant occipital lobe involvement cannot be excluded. This case supports the concepts of posterior cortical dementia (PCD) as a clinically distinct entity and for the first time documents its corresponding metabolic deficit using PET.
PMID: 1865209 [PubMed - indexed for MEDLINE]

------------------------------------------------------------------------

35: Eur Neurol. 1991;31(4):259-69. Related Articles, Links

Mapping of event-related potentials to auditory and visual odd-ball paradigms in patients affected by different forms of dementia.
Onofrj M, Gambi D, Del Re ML, Fulgente T, Bazzano S, Colamartino P, Malatesta G.
Istituto di Clinica Neurologica, Universita G. D'Annunzio, Chieti, Italia.
The paper reports the results of recordings and maps of event-related potentials (ERPs) in patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and in subjects affected by dementia in multiple sclerosis (MS). ERPs were recorded from 19 scalp electrode derivations using both visual and acoustic paradigms. In 43% of AD patients, ERPs were normal; in 20%, although present, ERP components were delayed, while in the other 37% none of the N2 and P3 peaks could be recorded, because of abnormal topography of potentials on the scalp. In patients with PSP, the normal ERP sequence was not identified. In patients with MS delayed ERPs (50%), abnormal topography of ERPs (30%) and absence of ERPs (20%) were observed. The follow-up of AD patients showed a progressive alteration of ERPs. ERP topography alterations were observed in AD, PSP and MS patients with poorest cognitive performances.
PMID: 1868869 [PubMed - indexed for MEDLINE]