Olfactory-evoked regional cerebral blood flow in Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Receptive and expressive language activations for sentences: a PET study

Most language mapping studies have focussed on activations for single-word tasks. We examined activations for verbal auditory and generation tasks using sentence stimuli. [15O]-water PET was performed in 4 female and 5 male normal adults. Listening to sentences (minus rest) activated the superior and middle temporal gyri bilaterally, but mean activation was significantly stronger on the left. The strongest activation for sentence generation (minus repetition) was seen in the left middle and inferior frontal gyri (area 46). This focus appears to be anterior to activations reported for single-word generation, possibly due to greater verbal working memory demands of the sentential task. Additional activation of the left inferior temporal lobe can be attributed to lexicosemantic processing.     

Systemic administration of kainate induces marked increases of endogenous kynurenic acid in various brain regions and plasma of rats

The endogenous neuroinhibitory and neuroprotective excitatory amino acid receptor antagonist kynurenic acid has been hypothetically linked to the pathogenesis of epilepsy and several other brain disorders. In the present study, alterations in kynurenic acid levels were examined in the kainate model of temporal lobe epilepsy. Kainate was systemically injected in rats at a dose (10 mg/kg s.c.) which induces a characteristic behavioural syndrome with stereotypies and focal (limbic) and generalized seizures, eventually progressing into severe status epilepticus. Kynurenic acid was determined 3 h after kainate injection in various brain regions (olfactory bulb, frontal cortex, piriform cortex, amygdala, hippocampus, nucleus accumbens, caudate/putamen, thalamus, superior and inferior colliculus, pons and medulla, and cerebellar cortex) and in plasma, using a sensitive high-performance liquid chromatographic method. When data were analysed irrespective of individual seizure severity, significant increases in kynurenic acid were determined in all brain regions examined except the hippocampus, nucleus accumbens and pons/medulla. The most marked (200-500%) increases above controls were seen in the piriform cortex, amygdala, and cerebellar cortex. Furthermore, a significant kynurenic acid increase of about 200% above control was determined in plasma. When kynurenic acid levels were determined in subgroups of rats with different behavioural alterations in response to kainate, the most marked kynurenic acid increases were seen in subgroups with status epilepticus. Rats which only developed mild (focal) seizures or stereotyped behaviours (wet dog shakes) also exhibited significantly increased kynurenic acid levels, thus indicating that the increase in kynurenic acid in response to kainate was not solely due to sustained convulsive seizure activity. Whereas it was previously proposed that kynurenic acid is involved only in later stages of seizure disorders, the present data demonstrate that marked increases in central and peripheral kynurenic acid levels occur early after the onset of neuroexcitation, at least in the kainate model.     

Protein synthesis inhibitors delay transneuronal death in the piriform cortex of young adult rats

It has been demonstrated that apoptotic cell death is an active process that is dependent on RNA and protein synthesis. The question remains as to whether neuronal death in adult, mammalian brains can also be demonstrated in vivo to be dependent on protein synthesis. To address this question we have analysed transneuronal death in the piriform (olfactory) cortex. Following unilateral olfactory bulb ablation in young adult rats, layer IIa of the piriform cortex undergoes rapid degeneration, that commences 12 h after ablation and that is almost complete at 48 h. In order to block protein synthesis, three to six subcutaneous injections of the short acting protein synthesis inhibitor anisomycin, were given at 2 h intervals beginning just before the ablation of the olfactory bulb. In other cases a single injection of the long acting protein synthesis inhibitor emetine were made intracerebrally just before or after olfactory bulb ablation. The number of dying cells was then counted in sections through the rostrocaudal extent of the piriform cortex. Both anisomycin and emetine injections markedly reduced the number of pyknotic cells in layer IIa of the piriform cortex after olfactory bulb ablation. The effect of anisomycin was dose-dependent, near lethal doses leading to an almost complete absence of cell death (six injections of 100 mg/kg). As the doses of anisomycin were reduced, more dying cells were observed. Emetine was only effective at near lethal doses (10 mg/kg) and showed a greater capacity to reduce the levels of cell death when injected into structures near the piriform cortex (e.g., accumbens nucleus) than when injected into more distant structures. To further confirm that the cell death observed was due to apoptosis, we analysed sections by tunel staining to demonstrate DNA fragmentation. We found that tunel-positive cells were also always pyknotic, one of the landmarks of apoptosis. The appearance of pyknotic cells labelled by the tunel method demonstrated that the dying cells in the piriform cortex did indeed undergo apoptosis.     

Investigation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone for in vivo and iIn vitro murine embryopathy and embryonic ras mutations

The evoked potential recorded in the rat piriform cortex in response to electrical stimulation of the olfactory bulb is composed of an early component occasionally followed by a late component (60-70 ms). We previously showed that the late component occurrence was enhanced following an olfactory learning. In the present study carried out in naive rats, we investigated the precise conditions of induction of this late component, and its spatiotemporal distribution along the olfactory pathways. In the anaesthetized rat, a stimulating electrode was implanted in the olfactory bulb. Four recording electrodes were positioned, respectively, in the olfactory bulb, the anterior and posterior parts of the piriform cortex, and the entorhinal cortex. Simultaneous recording of signals evoked in the four sampled structures in response to stimulation of the olfactory bulb revealed that the late component was detected in anterior and posterior piriform cortex as well as in entorhinal cortex, but not in the olfactory bulb. The late component occurred reliably for a narrow range of low intensities of stimulation delivered at frequencies not exceeding 1 Hz. Comparison of late component amplitude and latency across the different recorded sites showed that this component appeared first and with the greatest amplitude in the posterior piriform cortex. In addition to showing a functional dissociation between anterior and posterior parts of the piriform cortex, these data suggest that the posterior piriform cortex could be the locus of generation of this late high amplitude synchronized activity, which would then propagate to the neighbouring regions.     

ATP-sensitive voltage- and calcium-dependent chloride channels in sarcoplasmic reticulum vesicles from rabbit skeletal muscle

In addition to its role in olfaction and as a primary epileptogenic site, the anterior piriform cortex has been suggested to play a role in neuroperception of deficiencies or imbalances in physiologically essential amino acids. In recent studies, amino acid deficient diets were shown to induce expression of c-fos in the anterior piriform cortex within the rapid time frame associated with the normal anorectic response to such diets. It became important to examine the neurocytochemical architecture of this region for clues as to how and more precisely where dietary amino acid deficiency or imbalance might be monitored. The relationships of neuropeptide Y-, somatostatin-, and cholecystokinin-containing neurons were of particular interest because ongoing studies indicate that those peptides administered to the anterior piriform cortex alter intake of diets deficient in essential amino acids. The neuropeptides were endogenous to intrinsic neurons only; none resembled pyramidal projection neurons. Peptidergic neurons and fibers were concentrated most heavily in layer III of the paleocortex. The cytoarchitecture suggests that neuropeptide Y-, somatostatin-, and cholecystokin-containing neurons of the anterior piriform cortex may relate synaptically or multisynaptically to local circuit neurons during electrical activity, modulation of olfactory information, and neuroperception of essential amino acids.     

Strategic processing and memory for temporal order in patients with frontal lobe lesions.

This study evaluated whether deficits in memory for temporal order in patients with frontal lobe lesions result from impaired automatic encoding of temporal information or are secondary to deficits in effortful processes, such as the use of organizational strategies and control of interference. Patients with lesions in the dorsolateral prefrontal cortex and control participants were tested on temporal order reconstruction of semantically related and unrelated word lists learned under intentional or incidental conditions. Memory for temporal order in patients with frontal lobe lesions was sensitive to semantic relatedness but not to intention to learn. Tests of item free recall and recognition using similar encoding manipulations indicated that order performance in these patients was dissociable from item memory. Results indicate that automatic processing of temporal information is intact in patients with frontal lobe lesions but that strategic processing of this information is impaired. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cerebral blood flow relationships associated with a difficult tone recognition task in trained normal volunteers

Tone recognition is partially subserved by neural activity in the right frontal and primary auditory cortices. First we determined the brain areas associated with tone perception and recognition. This study then examined how regional cerebral blood flow (rCBF) in these and other brain regions correlates with the behavioral characteristics of a difficult tone recognition task. rCBF changes were assessed using H2(15)O positron emission tomography. Subtraction procedures were used to localize significant change regions and correlational analyses were applied to determine how response times (RT) predicted rCBF patterns. Twelve trained normal volunteers were studied in three conditions: REST, sensory motor control (SMC) and decision (DEC). The SMC-REST contrast revealed bilateral activation of primary auditory cortices, cerebellum and bilateral inferior frontal gyri. DEC-SMC produced significant clusters in the right middle and inferior frontal gyri, insula and claustrum; the anterior cingulate gyrus and supplementary motor area; the left insula/claustrum; and the left cerebellum. Correlational analyses, RT versus rCBF from DEC scans, showed a positive correlation in right inferior and middle frontal cortex; rCBF in bilateral auditory cortices and cerebellum exhibited significant negative correlations with RT These changes suggest that neural activity in the right frontal, superior temporal and cerebellar regions shifts back and forth in magnitude depending on whether tone recognition RT is relatively fast or slow, during a difficult, accurate assessment.     

Renal cell carcinoma in acquired renal cystic disease 3 years after successful kidney transplantation. Two case reports and review of the literature

Brief implantation of a 33-ga cannula in the locus coeruleus (LC) of the rat caused widespread and intense ipsilateral activation of c-fos throughout the forebrain. Areas showing heavy staining included the cingulate, piriform, parietal, frontal cortex, and the olfactory tubercle. Prior lesion of the LC with 6-hydroxydopamine (6-OHDA) abolished the response. It is concluded that the mechanical stimulation and/or trauma involved in the implantation of a cannula in the LC is sufficient to cause widespread activation of noradrenergic neurotransmission throughout the forebrain. The use of this procedure for drug delivery should therefore be reevaluated.     

Dynamic pattern of brain activation during sequencing of word strings evaluated by fMRI

An impaired ability to recite highly automated word strings (e.g., the names of the months of the year) in reverse order concomitant with preserved production of the conventional sequence has been considered a salient sign of frontal lobe dysfunction. Using functional magnetic resonance imaging (fMRI), the spatial and temporal pattern of brain activation during covert performance of these tasks was evaluated in healthy subjects. As compared to the response obtained during forward recitation, re-sequencing of the word string yielded additional activation of the bilateral middle and inferior frontal gyri, the posterior parietal cortex and the left anterior cingulate gyrus. The prefrontal responses are in accordance with the clinical findings referred to. However, the set of activated areas, as a whole, presumably reflects contribution of the various components of the working memory system to the sequencing of word strings. During successive periods of task administration, subjects showed a linear increase of production speed. Analysis of corresponding dynamic changes of regional hemodynamic responses revealed a significant increase at the level of the left inferior parietal cortex and a decrease within the mesial aspect of the left superior frontal gyrus. Presumably, the former finding reflects increasing demands on the phonological short-term memory store, due to faster updating of its content under increased word production rate. Decreasing activation within the superior frontal gyrus might indicate contribution of this area to the initiation of the cognitive processes subserving the sequencing of verbal items. These findings demonstrate the capability of fMRI as a powerful tool for the analysis of dynamic brain activation.     

Olfactory prodromal symptoms and unilateral olfactory dysfunction are associated in patients with right mesial temporal lobe epilepsy

PURPOSE: We report a patient with mesial temporal lobe epilepsy (MTLE) with olfactory prodromal symptoms manifested as an unpleasant smell of onions, who was found to have an ipsilateral deficit of olfactory naming (olfactory agnosia). METHODS AND RESULTS: Preoperative olfactory testing revealed a selective right-sided olfactory deficit for naming of odors. Olfactory threshold was within the normal range. The patient has been seizure free after selective amygdalohippocampectomy for 4 months. No olfactory prodromal events have occurred since surgery. Olfactory testing 3 months after resection showed that right-sided odor naming was still impaired. CONCLUSIONS: We conclude that olfactory prodromal symptoms may be associated with unilateral olfactory dysfunction, and lateralization of seizure origin may be possible by unilateral olfactory testing.     

Behaviour-related effects of nicotine on slow EEG waves in basal nucleus-lesioned rats

The basal magnocellular nucleus is assumed to play a crucial role in cholinergic activation of the cortical EEG. The aim of this study was to establish whether intraperitoneally applied nicotine may counteract the power asymmetry of the slow waves in the cortical EEG of both hemispheres after an unilateral lesion in the basal nucleus. In 17 rats the basal nucleus (substantia innominata/ventral pallidum) was unilaterally lesioned by ibotenic acid. The lesion produced unilateral power increases of all frequencies up to 20 Hz in the frontal EEG that increased with higher arousal level. Additionally, synchronized spike and wave discharges appeared in the frontal EEG. The results indicate that the basal nucleus suppresses especially the delta EEG waves in the frontal motor cortex during motor active behaviour. Nicotine (0.1 and 1 mg/kg) partially counteracts the power asymmetry of frontal slow waves (2-6 Hz) only during exploratory sniffing but not during grooming and waking immobility. Physostigmine (1 mg/kg) was also effective during exploratory sniffing. The results may indicate a role of nicotinic mechanisms in the information input component of exploratory behaviour.     

Postoperative arachnoiditis diagnosed by high resolution fast spin-echo MRI of the lumbar spine

Concentrations of 11 trace elements were determined in 56 control and 98 Alzheimer's disease (AD) olfactory bulb, olfactory tract, olfactory trigone, piriform cortex and amygdala specimens by instrumental neutron activation analysis. Iron and zinc were significantly elevated and bromine was significantly depleted in olfactory regions of AD patients, compared with normal age-matched control subjects. Elevated iron could possibly play a role in neuronal degeneration in AD by enhancing reactive free radical formation.     

Flavor and the frontal cortex.

Rats were trained to discriminate an aqueous compound of an odor and taste (amyl acetate and NaCl) from the components of the compound before removal of one olfactory bulb and the contralateral ventrolateral frontal cortex. In postoperative tests, experimental rats performed much more poorly than nonlesioned controls or controls which had all lesions made in the same hemisphere. However, there were no significant differences among groups on tests for detection of amyl acetate and NaCl. These results provide evidence that integration of taste and smell in the production of flavor occurs in the ventrolateral frontal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

How synchronization properties among second-order sensory neurons can mediate stimulus salience.

Spatial patterns of glomerular activity in the vertebrate olfactory bulb and arthropod antennal lobe reflect an important component of first-order olfactory representation and contribute to odorant identification. Higher concentration odor stimuli evoke broader glomerular activation patterns, resulting in greater spatial overlap among different odor representations. However, behavioral studies demonstrate results contrary to what these data might suggest: Honeybees are more, not less, able to discriminate among odorants applied at higher concentrations. Using a computational model of the honeybee antennal lobe, the authors show that changes in synchronization patterns among antennal lobe projection neurons, as observed electrophysiologically, could parsimoniously underlie these observations. The results suggest that stimulus salience, as defined behaviorally, is directly correlated with the degree of synchronization among second-order olfactory neurons. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.     

Beta-frequency (15-35 Hz) electroencephalogram activities elicited by toluene and electrical stimulation in the behaving rat

Bursts of beta-frequency (15-35 Hz) electroencephalogram activity occur in the olfactory system during odour sampling, but their mode of propagation within the olfactory system and potential contribution to the mechanisms of learning and memory are unclear. We have elicited large-amplitude beta activity in the rat olfactory system by applying noxious olfactory stimuli (toluene), and have monitored the bursts via chronically-implanted electrodes. Following exposure to toluene, coherent bursts with a peak frequency of 19.8 +/- 0.9 Hz were observed in the olfactory bulb, piriform cortex, entorhinal cortex and dentate gyrus. The timing of the bursts and the phases of electroencephalogram cross-spectra indicate that beta bursts propagate in a caudal direction from the olfactory bulb to the entorhinal cortex. The time delays between peaks of bursts in these structures were similar to latency differences for field potentials evoked by olfactory bulb or piriform cortex test-pulses. Peaks of burst cycles in the dentate region, however, were observed just prior to those in the entorhinal cortex. Surprisingly, power in toluene-induced beta-frequency oscillations was not increased following long-term potentiation induced by tetanic stimulation of the olfactory bulb, piriform cortex and entorhinal cortex. The activity of local inhibitory mechanisms may therefore counteract the effects of synaptic enhancements in afferent pathways during beta bursts. Low-frequency electrical stimulation of the piriform cortex was most effective in inducing coherent oscillatory responses in the entorhinal cortex and dentate gyrus at stimulation frequencies between 12 and 16 Hz. The results show that repetitive polysynaptic volleys at frequencies in the beta band induced by either toluene or electrical stimulation are transmitted readily within the olfactory system. The propagation of neural activity within this frequency range may therefore contribute to the transmission of olfactory signals to the hippocampal formation, particularly for those odours which induce high-amplitude bursts of beta activity.     

Overestimation and unreliability in "feeling-of-doing" judgements about temporal ordering performance: impaired self-awareness following frontal lobe damage

"Feeling-of-doing" accuracy in a temporal ordering task in 33 patients with frontal lobe lesions and a matched control group was investigated. The temporal ordering task used word lists that had high, medium, or no semantic interrelatedness. Patients with frontal lobe lesions showed an impairment in temporal ordering across all three word lists. Both groups performed better on the lists with higher semantic interrelatedness. Patients with frontal lobe lesions overestimated their ability to order words accurately. On the less semantically interrelated lists, metamemory judgment in patients with frontal lesions did not correlate with their performance. These results indicate that both temporal order judgment and metacognitive decisions about temporal order judgment are subserved by the prefrontal cortex and further clarifies the role of the frontal lobes in behavioral monitoring.     

Cholinergic agonist carbachol enables associative long-term potentiation in piriform cortex slices

Pyramidal cells in piriform (olfactory) cortex receive afferent input from the olfactory bulb as well as intrinsic association input from piriform cortex and other cortical areas. These two functionally distinct inputs terminate on adjacent apical dendritic segments of the pyramidal cells located in layer Ia and layer Ib of piriform cortex. Studies with bath-applied cholinergic agonists have shown suppression of the fast component of the inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of the association fibers. It was previously demonstrated that an associative form of LTP can be induced by coactivation of the two fiber systems after blockade of the fast, gamma-aminobutyric acid-A-mediated IPSP. In this report, we demonstrate that an associative form of long-term potentiation can be induced by coactivation of afferent and intrinsic fibers in the presence of the cholinergic agonist carbachol.     

Posttraumatic olfactory dysfunction: MR and clinical evaluation

PURPOSE: To evaluate the sites of injury in patients with posttraumatic olfactory deficits and to compare damage with findings on clinical olfactory tests. METHODS: Twenty-five patients with posttraumatic olfactory dysfunction were examined by means of olfactory testing, endoscopy, and MR imaging. MR surface-coil scans through the olfactory bulbs and tracts and head-coil scans of the temporal lobes were evaluated. Quantitative and qualitative gradings of damage to the olfactory bulbs, tracts, subfrontal region, hippocampus, and temporal lobes were compared with results on tests of odor identification, detection, memory, and discrimination. RESULTS: Twelve patients were anosmic, eight had severe impairment, and five were mildly impaired. Injuries to the olfactory bulbs and tracts (88% of patients), subfrontal region (60%), and temporal lobes (32%) were found, but these did not correlate well with individual olfactory test scores. Volumetric analysis showed that patients without smell function had greater volume loss in olfactory bulbs and tracts than did those posttraumatic patients who retained some sense of smell. Qualitative and quantitative assessments of damage showed few significant correlations with olfactory tests, probably because of multifocal injuries, primary olfactory nerve damage, and the constraints of a small sample size on the detection of clinically significant differences. CONCLUSION: MR imaging shows abnormalities in patients with posttraumatic olfactory dysfunction at a very high rate (88%), predominantly in the olfactory bulbs and tracts and the inferior frontal lobes.