Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors

Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were rested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 mu g/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggestinga primary involvement of the 5-HT1A receptor in the observed defecit. Based on physiological and pharmacological data,we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

Top-down influences on lexical selection during spoken word production: A 4T fMRI investigation of refractory effects in picture naming

Spoken word production is assumed to involve stages of processing in which activation spreads through layers of units comprising lexical-conceptual knowledge and their corresponding phonological word forms. Using high-field (4T) functional magnetic resonance imagine (fMRI), we assessed whether the relationship between these stages is strictly serial or involves cascaded-interactive processing, and whether central (decision/control) processing mechanisms are involved in lexical selection. Participants performed the competitor priming paradigm in which distractor words, named from a definition and semantically related to a subsequently presented target picture, slow picture-naming latency compared to that with unrelated words. The paradigm intersperses two trials between the definition and the picture to be named, temporally separating activation in the word perception and production networks. Priming semantic competitors of target picture names significantly increased activation in the left posterior temporal cortex, and to a lesser extent the left middle temporal cortex, consistent with the predictions of cascaded-interactive models of lexical access. In addition, extensive activation was detected in the anterior cingulate and pars orbitalis of the inferior frontal gyrus. The findings indicate that lexical selection during competitor priming is biased by top-down mechanisms to reverse associations between primed distractor words and target pictures to select words that meet the current goal of speech.

Brain activity during automatic semantic priming revealed by event-related functional magnetic resonance imaging

Semantic priming occurs when a subject is faster in recognising a target word when it is preceded by a related word compared to an unrelated word. The effect is attributed to automatic or controlled processing mechanisms elicited by short or long interstimulus intervals (ISIs) between primes and targets. We employed event-related functional magnetic resonance imaging (fMRI) to investigate blood oxygen level dependent (BOLD) responses associated with automatic semantic priming using an experimental design identical to that used in standard behavioural priming tasks. Prime-target semantic strength was manipulated by using lexical ambiguity primes (e.g., bank) and target words related to dominant or subordinate meaning of the ambiguity. Subjects made speeded lexical decisions (word/nonword) on dominant related, subordinate related, and unrelated word pairs presented randomly with a short ISI. The major finding was a pattern of reduced activity in middle temporal and inferior prefrontal regions for dominant versus unrelated and subordinate versus unrelated comparisons, respectively. These findings are consistent with both a dual process model of semantic priming and recent repetition priming data that suggest that reductions in BOLD responses represent neural priming associated with automatic semantic activation and implicate the left middle temporal cortex and inferior prefrontal cortex in more automatic aspects of semantic processing.

Laminar distribution of neurofilament inclusions and swollen achromatic neurons in neurofilament inclusion disease (NID)

The laminar distribution of the neurofilament inclusions (NI) and swollen achromatic neurons (SN) was studied in gyri of the temporal cortex in four patients with neurofilament inclusion disease (NID). In 84% of gyri analysed, the density of the NI was maximal in the lower cortical laminae. The distribution of the SN was more variable than the NI. Density was maximal in the lower cortex in 46% of gyri, in the upper cortical laminae in 8% of gyri, and a bimodal distribution in 15% of gyri. In the remaining gyri, there was a more even distribution of SN with cortical depth. In 31% of gyri, the vertical density of the NI was positively correlated with that of the SN. The data suggest that cortical degeneration in the temporal lobe of NID initially affects neurons in the lower laminae. Subsequently, the pathology may spread to affect much of the cortical profile, the SN preceding the appearance of the NI.

Comparing neural correlates of configural processing in faces and objects:An ERP study of the thatcher illusion

In the Thatcher illusion, a face with inverted eyes and mouth looks abnormal when upright but not when inverted. Behavioral studies have shown that thatcherization of an upright face disrupts perceptual processing of the local configuration. We recorded high-density EEG from normal observers to study ERP correlates of the illusion during the perception of faces and nonface objects, to determine whether inversion and thatcherization affect similar neural mechanisms. Observers viewed faces and houses in four conditions (upright vs. inverted, and normal vs. thatcherized) while detecting an oddball category (chairs). Thatcherization delayed the N170 component over occipito-temporal cortex to faces, but not to houses. This modulation matched the illusion as it was larger for upright than inverted faces. The P1 over medial occipital regions was delayed by face inversion but unaffected by thatcherization. Finally, face thatcherization delayed P2 over occipito-temporal but not over parietal regions, while inversion affected P2 across categories. All effects involving thatcherization were face-specific. These results indicate that effects of face inversion and feature inversion (in thatcherized faces) can be distinguished on a functional as well as neural level, and that they affect configural processing of faces in different time windows. © 2006 Elsevier Inc.

Neuroimaging in human amblyopia

Functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and magnetoencephalography (MEG) have been the principal neuroimaging tools used to assess the site and nature of cortical deficits in human amblyopia. A review of this growing body of work is presented here with particular reference to various controversial issues, including whether or not the primary visual cortex is dysfunctional, the involvement of higher-order visual areas, neural differences between strabismic and anisometropic amblyopes, and the effects of modern-day drug treatments. We also present our own recent MEG work in which we used the analysis technique of synthetic aperture magnetometry (SAM) to examine the effects of strabismic amblyopia on cortical function. Our results provide evidence that the neuronal assembly associated with form perception in the extrastriate cortex may be dysfunctional in amblyopia, and that the nature of this dysfunction may relate to a change in the normal temporal pattern of neuronal discharges. Based on these results and existing literature, we conclude that a number of cortical areas show reduced levels of activation in amblyopia, including primary and secondary visual areas and regions within the parieto-occipital cortex and ventral temporal cortex. Copyright © 2006 Taylor & Francis Group, LLC.

Clustering of cerebral cortical lesions in patients with corticobasal degeneration

Clustering of ballooned neurons (BN) and tau positive neurons with inclusion bodies (tau+ neurons) was studied in the upper and lower laminae of the frontal, parietal and temporal cortex in 12 patients with corticobasal degeneration (CBD). In a significant proportion of brain areas examined, BN and tau+ neurons exhibited clustering with a regular distribution of clusters parallel to the pia mater. A regular pattern of clustering of BN and tau+ neurons was observed equally frequently in all cortical areas examined and in the upper and lower laminae. No significant correlations were observed between the cluster sizes of BN or tau+ neurons in the upper compared with the lower cortex or between the cluster sizes of BN and tau+ neurons. The results suggest that BN and tau+ neurons in CBD exhibit the same type of spatial pattern as lesions in Alzheimer's disease, Lewy body dementia and Pick's disease. The regular periodicity of the cerebral cortical lesions is consistent with the degeneration of the cortico-cortical projections in CBD.

Laminar distribution of amyloid-beta (Abeta) deposits in dementia with Lewy bodies: comparison with Alzheimer's disease

Significant amyloid-beta (Abeta) deposition in cases of dementia with Lewy bodies (DLB) may represent concurrent Alzheimer's disease (AD). To test this hypothesis, the laminar distribution of the diffuse, primitive, and classic Abeta deposits was studied in the frontal and temporal cortex in cases of DLB and were compared with AD. In DLB, the diffuse and primitive deposits exhibited two common patterns of distribution; either maximum density occurred in the upper cortical laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. In addition, a bimodal distribution of the classic deposits was observed in approximately half of the cortical areas analysed. A number of differences in the laminar distributions of Abeta deposits were observed in DLB and AD. First, the proportion of the primitive relative to the diffuse and classic deposits present was lower in DLB compared with AD. Second, the primitive deposits were more frequently bimodally distributed in DLB. Third, the density of the diffuse deposits reached a maximum lower in the cortical profile in AD. These data suggest differences in the pattern of cortical degeneration in the two disorders and therefore, DLB cases with significant Abeta pathology may not represent the coexistence of DLB and AD.

Laminar distribution of ballooned neurons and tau positive neurons with inclusions in patients with corticobasal degeneration

The laminar distribution of ballooned neurons (BN) and tau positive neurons with inclusions (tau+ neurons) was studied in the frontal and temporal cortex in twelve patients with corticobasal degeneration (CBD). In the majority of brain areas, the density of BN and tau+ neurons was maximal in the lower and upper cortical laminae respectively. The densities of tau+ neurons in the upper and lower cortex were positively correlated. In the majority of brain areas, however, no correlations were observed between the densities of BN and tau+ neurons. The laminar distribution of the BN may reflect the degeneration of the feedback cortico-cortical and/or the efferent cortical pathways. By contrast, the distribution of the tau+ neurons may reflect the degeneration of the feed-forward cortico-cortical pathways. In addition, BN and tau+ neurons may arise as a result of distinct pathological processes.

A comparison of histological and immunohistochemical methods for quantifying the pathological lesions of Pick's disease

Counts of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were made in the frontal and temporal cortex from patients with Pick's disease (PD). Lesions were stained histologically with hematoxylin and eosin (HE) and the Bielschowsky silver impregnation method and labeled immunohistochemically with antibodies raised to ubiquitin and tau. The greatest numbers of PB were revealed by immunohistochemistry. Counts of PB revealed by ubiquitin and tau were highly positively correlated which suggested that the two antibodies recognized virtually identical populations of PB. The greatest numbers of PC were revealed by HE followed by the anti-ubiquitin antibody. However, the correlation between counts was poor, suggesting that HE and ubiquitin revealed different populations of PC. The greatest numbers of SP and NFT were revealed by the Bielschowsky method indicating the presence of Alzheimer-type lesions not revealed by the immunohistochemistry. In addition, more NFT were revealed by the anti-ubiquitin compared with the anti-tau antibody. The data suggested that in PD: (i) the anti-ubiquitin and anti-tau antibodies were equally effective at labeling PB; (ii) both HE and anti-ubiquitin should be used to quantitate PC; and (iii) the Bielschowsky method should be used to quantitate SP and NFT.

The spatial pattern of beta-amyloid (Abeta) deposits in Alzheimer’s disease patients is related to apolipoprotein genotype

The spatial patterns of the diffuse, primitive, and classic beta-amyloid (Abeta) deposits was studied in the frontal and temporal cortex in cases of Alzheimer’s disease (AD) expressing different apolipoprotein (Apo E) genotypes. No significant differences in the density of the three Abeta deposit subtypes were observed in individuals expressing genotypes e2/3 and e3/3 compared with those expressing e3/4 and e4/4. In all patients, Abeta deposit subtypes occurred in the tissue in clusters. Chi-square contingency analyses of the data suggested that the cluster size of the diffuse and classic Abeta deposits was unrelated to Apo E genotype. However, the primitive (‘neuritic’) type Abeta deposits occurred more frequently in smaller, denser clusters in individuals expressing genotypes e3/4 and e4/4 compared with those expressing e2/3 and e3/3. Hence, the presence of the e4 allele may be associated with a more specific pattern of neuronal degeneration in the frontal and temporal cortex in AD.

Spatial arrangement patterns of senile plaques in post-mortem senile dementia of the Alzheimer type brains

We have studied the spatial distribution of plaques in coronal and tangential sections of the parahippocampal gyrus (PHG), the hippocampus, the frontal lobe and the temporal lobe of five SDAT patients. Sections were stained with cresyl violet and examined at two magnifications (x100 and x400). in all cases (and at both magnifications) statistical analysis using the Poisson distribution showed that the plaques were arranged in clumps (x100: V/M = 1.48 - 4.49; x400 V/M = 1.17 - 1.95). this indicates that both large scale and small scale clumping occurs. Application of the statistical techniques of pattern analysis to coronal sections of frontal and temporal cortex and PHG showed. furthermore, that both large (3200-6400 micron) and small scale (100 - 400 micron) clumps were arranged with a high degree of regularity in the tissue. This suggests that the clumps of plaques reflect underlying neural structure.

A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD)

The objective of this study was to determine the degree of white matter pathology in the cerebral cortex in cases of variant Creutzfeldt-Jakob disease (vCJD) and to study the relationships between the white matter and grey matter pathologies. Hence, the pathological changes in cortical white matter were studied in individual gyri of the frontal, parietal, occipital, and temporal cortex in eleven cases of vCJD. Vacuolation (‘spongiform change’), deposition of the disease form of prion protein (PrPsc) in the form of discrete PrP deposits, and gliosis were observed in the white matter of virtually all cortical regions studied. Mean density of the vacuoles in the white matter was greater in the parietal lobe compared with the frontal, occipital, and temporal lobes but there were fewer glial cells in the occipital lobe compared with the other cortical regions. In the white matter of the frontal cortex, vacuole density was negatively correlated with the density of both glial cell nuclei and the PrP deposits. In addition, the densities of glial cells and PrP deposits were positively correlated in the frontal and parietal cortex. In the white matter of the frontal cortex and inferior temporal gyrus, there was a negative correlation between the densities of the vacuoles and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In addition, in the frontal cortex, vacuole density in the white matter was negatively correlated with the density of the diffuse PrP deposits in laminae II/III and V/VI of the adjacent grey matter. The densities of PrP deposits in the white matter of the frontal cortex were positively correlated with the density of the diffuse PrP deposits in laminae II/III and V/V1 and with the number of surviving neurons in laminae V/V1. The data suggest that in the white matter in vCJD, gliosis is associated with the development of PrP deposits while the appearance of the vacuolation is a later development. In addition, neuronal loss and PrP deposition in the lower cortical laminae of the grey matter may be a consequence of axonal degeneration within the white matter.

A quantitative study of the pathological changes in the cortical white matter in variant Creutzfeldt-Jakob disease (vCJD).

Objective: To quantify cortical white matter pathology in variant Creutzfeldt-Jakob disease (vCJD) and to correlate white and grey matter pathologies. Methods: Pathological changes were studied in immunolabeled sections of the frontal, parietal, occipital, and temporal cortex of eleven cases of vCJD. Results: Vacuolation ("spongiform change"), deposition of the disease form of prion protein (PrPsc), and a glial cell reaction were observed in the white matter. The density of the vacuoles was greatest in the white matter of the occipital cortex and glial cell density in the inferior temporal gyrus (ITG). Florid-type PrPsc deposits were present in approximately 50% of white matter regions studied. In the white matter of the frontal cortex (FC), vacuole density was negatively correlated with the densities of both glial cell nuclei and PrPsc deposits. In addition, in the frontal and parietal cortices the densities of glial cells and PrPsc deposits were positively correlated. In the FC and ITG, there was a negative correlation between the densities of the vacuoles in the white matter and the number of surviving neurons in laminae V/VI of the adjacent grey matter. In the FC, vacuole density in the white matter was negatively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI of the adjacent grey matter. In addition, the densities of PrPsc deposits in the white matter of the FC were positively correlated with the density of the diffuse PrPsc deposits in laminae II/III and V/VI and with the number of surviving neurons in laminae V/VI. Conclusion: The data suggest significant degeneration of cortical white matter in vCJD; the vacuolation being related to neuronal loss in the lower cortical laminae of adjacent grey matter, PrPsc deposits the result of leakage from damaged axons, and gliosis a reaction to these changes.

Spatial patterns of FUS-immunoreactive neuronal cytoplasmic inclusions (NCI) in neuronal intermediate filament inclusion disease (NIFID)

Neuronal intermediate filament inclusion disease (NIFID), a rare form of frontotemporal lobar degeneration (FTLD), is characterized neuropathologically by focal atrophy of the frontal and temporal lobes, neuronal loss, gliosis, and neuronal cytoplasmic inclusions (NCI) containing epitopes of ubiquitin and neuronal intermediate filament (IF) proteins. Recently, the 'fused in sarcoma' (FUS) protein (encoded by the FUS gene) has been shown to be a component of the inclusions of NIFID. To further characterize FUS proteinopathy in NIFID, we studied the spatial patterns of the FUS-immunoreactive NCI in frontal and temporal cortex of 10 cases. In the cerebral cortex, sectors CA1/2 of the hippocampus, and the dentate gyrus (DG), the FUS-immunoreactive NCI were frequently clustered and the clusters were regularly distributed parallel to the tissue boundary. In a proportion of cortical gyri, cluster size of the NCI approximated to those of the columns of cells was associated with the cortico-cortical projections. There were no significant differences in the frequency of different types of spatial patterns with disease duration or disease stage. Clusters of NCI in the upper and lower cortex were significantly larger using FUS compared with phosphorylated, neurofilament heavy polypeptide (NEFH) or a-internexin (INA) immunohistochemistry (IHC). We concluded: (1) FUS-immunoreactive NCI exhibit similar spatial patterns to analogous inclusions in the tauopathies and synucleinopathies, (2) clusters of FUS-immunoreactive NCI are larger than those revealed by NEFH or ???, and (3) the spatial patterns of the FUS-immunoreactive NCI suggest the degeneration of the cortico-cortical projections in NIFID.