Pulsed Magnetic Field Therapy… How Does It Work ?
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).
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]