Clustering and periodicity of neurofibrillary tangles in the upper and lower cortical laminae in Alzheimer's disease

In Alzheimer's disease (AD), neurofibrillary tangles (NFT) occur within neurons in both the upper and lower cortical laminae. Using a statistical method that estimates the size and spacing of NFT clusters along the cortex parallel to the pia mater, two hypotheses were tested: 1) that the cluster size and distribution of the NFT in gyri of the temporal lobe reflect degeneration of the feedforward (FF) and feedback (FB) cortico-cortical pathways, and 2) that there is a spatial relationship between the clusters of NFT in the upper and lower laminae. In 16 temporal lobe gyri from 10 cases of sporadic AD, NFT were present in both the upper and lower laminae in 11/16 (69%) gyri and in either the upper or lower laminae in 5/16 (31%) gyri. Clustering of the NFT was observed in all gyri. A significant peak-to-peak distance was observed in the upper laminae in 13/15 (87%) gyri and in the lower laminae in 8/ 12 (67%) gyri, suggesting a regularly repeating pattern of NFT clusters along the cortex. The regularly distributed clusters of NFT were between 500 and 800 μm in size, the estimated size of the cells of origin of the FF and FB cortico-cortical projections, in the upper laminae of 6/13 (46%) gyri and in the lower laminae of 2/8 (25%) gyri. Clusters of NFT in the upper laminae were spatially correlated (in phase) with those in the lower laminae in 5/16 (31%) gyri. The clustering patterns of the NFT are consistent with their formation in relation to the FF and FB cortico-cortical pathways. In most gyri, NFT clusters appeared to develop independently in the upper and lower laminae.

The missing link:Analogous human and primate cortical gamma oscillations

Recent animal studies highlighting the relationship between functional imaging signals and the underlying neuronal activity have revealed the potential capabilities of non-invasive methods. However, the valuable exchange of information between animal and human studies remains restricted by the limited evidence of direct physiological links between species. In this study we used magnetoencephalography (MEG) to investigate the occurrence of 30-70 Hz (gamma) oscillations in human visual cortex, induced by the presentation of visual stimuli of varying contrast. These oscillations, well described in the animal literature, were observed in retinotopically concordant locations of visual cortex and show striking similarity to those found in primate visual cortex using surgically implanted electrodes. The amplitude of the gamma oscillations increases linearly with stimulus contrast in strong correlation with the gamma oscillations found in the local field potential (LFP) of the macaque. We demonstrate that non-invasive magnetic field measurements of gamma oscillations in human visual cortex concur with invasive measures of activation in primate visual cortex, suggesting both a direct representation of underlying neuronal activity and a concurrence between human and primate cortical activity. © 2005 Elsevier Inc. All rights reserved.

Elementary units of cortical activity? The rise and fall of the cortical column

The roots of the concept of cortical columns stretch far back into the history of neuroscience. The impulse to compartmentalise the cortex into functional units can be seen at work in the phrenology of the beginning of the nineteenth century. At the beginning of the next century Korbinian Brodmann and several others published treatises on cortical architectonics. Later, in the middle of that century, Lorente de No writes of chains of ‘reverberatory’ neurons orthogonal to the pial surface of the cortex and called them ‘elementary units of cortical activity’. This is the first hint that a columnar organisation might exist. With the advent of microelectrode recording first Vernon Mountcastle (1957) and then David Hubel and Torsten Wiesel provided evidence consistent with the idea that columns might constitute units of physiological activity. This idea was backed up in the 1970s by clever histochemical techniques and culminated in Hubel and Wiesel’s well-known ‘ice-cube’ model of the cortex and Szentogathai’s brilliant iconography. The cortical column can thus be seen as the terminus ad quem of several great lines of neuroscientific research: currents originating in phrenology and passing through cytoarchitectonics; currents originating in neurocytology and passing through Lorente de No. Famously, Huxley noted the tragedy of a beautiful hypothesis destroyed by an ugly fact. Famously, too, human visual perception is orientated toward seeing edges and demarcations when, perhaps, they are not there. Recently the concept of cortical columns has come in for the same radical criticism that undermined the architectonics of the early part of the twentieth century. Does history repeat itself? This paper reviews this history and asks the question.

Accuracy and applications of group MEG studies using cortical source locations estimated from participants' scalp surfaces

We contend that powerful group studies can be conducted using magnetoencephalography (MEG), which can provide useful insights into the approximate distribution of the neural activity detected with MEG without requiring magnetic resonance imaging (MRI) for each participant. Instead, a participant's MRI is approximated with one chosen as a best match on the basis of the scalp surface from a database of available MRIs. Because large inter-individual variability in sulcal and gyral patterns is an inherent source of blurring in studies using grouped functional activity, the additional error introduced by this approximation procedure has little effect on the group results, and offers a sufficiently close approximation to that of the participants to yield a good indication of the true distribution of the grouped neural activity. T1-weighted MRIs of 28 adults were acquired in a variety of MR systems. An artificial functional image was prepared for each person in which eight 5 × 5 × 5 mm regions of brain activation were simulated. Spatial normalisation was applied to each image using transformations calculated using SPM99 with (1) the participant's actual MRI, and (2) the best matched MRI substituted from those of the other 27 participants. The distribution of distances between the locations of points using real and substituted MRIs had a modal value of 6 mm with 90% of cases falling below 12.5 mm. The effects of this -approach on real grouped SAM source imaging of MEG data in a verbal fluency task are also shown. The distribution of MEG activity in the estimated average response is very similar to that produced when using the real MRIs. © 2003 Wiley-Liss, Inc.

Laminar distribution of cortical Lewy bodies and neurofibrillary tangles in dementia with Lewy bodies

The laminar distribution of Lewy bodies (LB) and neurofibrillary tangles (NFT) was studied in twelve cases of dementia with Lewy bodies (DLB). LB density was maximal in the lower cortex in 59% of cortical areas, in the upper cortex in 31% of areas while densities were similar in the upper and lower cortex in 9% of areas. The distribution of LB was either unimodal with a lower cortical peak, or bimodal with density peaks in the upper and lower cortex. The density of NFT was maximal in the upper cortex in all tissues. The distributions of LB and NFT were similar in temporal and frontal cortex and in cases with and without Alzheimer’s disease (AD). The vertical densities of LB and NFT were not significantly correlated. LB formation may affect the feedback cortico-cortical pathway and the efferent cortical projections whereas NFT formation may affect the feedforward cortico-cortical pathway.

An investigation into the synaptic conditions and celluar mechanisms underlying cerebellar synaptic plasticity

The direction of synaptic plasticity at the connection between parallel fibres (PFs) and Purkinje cells can be modified by PF stimulation alone. Strong activation (Hartell, 1996) or high frequency stimulation (Schreurs and Alkon, 1993) of PFs induced a long-term depression (LTD) of PF-mediated excitatory postsynaptic currents. Brief raised frequency molecular layer stimulation produced a cAMP-dependent long-temi potentiation (LTP) of field potential (FP) responses (Salin et al., 1998). Thin slices of cerebellar vermis were prepared from 14-21 day old male Wistar rats decapitated under Halothane anaesthesia. FP's were recorded from the Purkinje cell layer in response to alternate 0.2Hz activation of stimulating electrodes placed in the molecular layer. In the presence of picrotoxin, FPs displayed two tetrodotoxin-sensitive, negative-going components termed N1 and N2. EPs were graded responses with paired pulse facilitation and were selectively blocked by 101AM 6-cyano-7-nitroquinoxaline-2,3-dicne (CNQX) an antagonist at iy,-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type ionotropic glutamate receptors (AMPAR) suggesting that they were primarily PE-mediated. The effects of raised stimulus intensity (RS) and/or increased frequency (IF) activation of the molecular layer on FP responses were examined. In sagittai and transverse slices combined RS and IF molecular layer activation induced a LTD of the N2 component of FP responses. RSIF stimulation produced fewer incidences of LTD in sagittal slices when an inhibitor of nitric oxide synthase (NOS), guanylate cyclase (GC), protein kinase G (PKG) or the GABAB receptor antagonist CGP62349 was included into the perfusion medium. Application of a nitric oxide (NO) donor, a cyclic guanosine monophosphate (cGMP) analogue or a phosphodiesterase (PDE) type V inhibitor to prevent cGMP breakdown paired with IF stimulation produced an acute depression, Raised frequency (RF) molecular layer stimulation produced a slowly emerging LTD of N2 in sagittal slices that was largely blocked in the presence of NOS, cGMP or PKG inhibitors. In transverse slices RE stimulation produced a LTP of the N2 component that was prevented by an inhibitor of protein kinase A or NOS. Inhibition of cGMP-signalling frequently revealed an underlying potentiation suggesting that cGMP activity might mask the effects of cAMP. In sagittal slices RE stimulation resulted in a potentiation of FPs when the cAMP-specific PDE type IV inhibitor rolipram was incorporated into the perfusion medium. In summary, raised levels of PE stimulation can alter the synaptic efficacy at PF-Purkinje cell synapses. The results provide support for a role of NO/cGMP/PKG signalling in the induction of LTD in the cerebellar cortex and suggest that activation of GABAa receptors might also be important. The level of cyclic nucleotide-specific PDE activities may be crucial in determining the level of cGMP and CAMP activity and hence the direction of synaptic plasticity.

Magnetoencephalography:technical improvements in image co-registration and studies of visual cortical oscillations

The work presented in this thesis is divided into two distinct sections. In the first, the functional neuroimaging technique of Magnetoencephalography (MEG) is described and a new technique is introduced for accurate combination of MEG and MRI co-ordinate systems. In the second part of this thesis, MEG and the analysis technique of SAM are used to investigate responses of the visual system in the context of functional specialisation within the visual cortex. In chapter one, the sources of MEG signals are described, followed by a brief description of the necessary instrumentation for accurate MEG recordings. This chapter is concluded by introducing the forward and inverse problems of MEG, techniques to solve the inverse problem, and a comparison of MEG with other neuroimaging techniques. Chapter two provides an important contribution to the field of research with MEG. Firstly, it is described how MEG and MRI co-ordinate systems are combined for localisation and visualisation of activated brain regions. A previously used co-registration methods is then described, and a new technique is introduced. In a series of experiments, it is demonstrated that using fixed fiducial points provides a considerable improvement in the accuracy and reliability of co-registration. Chapter three introduces the visual system starting from the retina and ending with the higher visual rates. The functions of the magnocellular and the parvocellular pathways are described and it is shown how the parallel visual pathways remain segregated throughout the visual system. The structural and functional organisation of the visual cortex is then described. Chapter four presents strong evidence in favour of the link between conscious experience and synchronised brain activity. The spatiotemporal responses of the visual cortex are measured in response to specific gratings. It is shown that stimuli that induce visual discomfort and visual illusions share their physical properties with those that induce highly synchronised gamma frequency oscillations in the primary visual cortex. Finally chapter five is concerned with localization of colour in the visual cortex. In this first ever use of Synthetic Aperture Magnetometry to investigate colour processing in the visual cortex, it is shown that in response to isoluminant chromatic gratings, the highest magnitude of cortical activity arise from area V2.

Investigations of attentional processing in parietal and occipital human cortical regions with magnetoencephalography

Attention defines our mental ability to select and respond to stimuli, internal or external, on the basis of behavioural goals in the presence of competing, behaviourally irrelevant, stimuli. The frontal and parietal cortices are generally agreed to be involved with attentional processing, in what is termed the 'fronto-parietal' network. The left parietal cortex has been seen as the site for temporal attentional processing, whereas the right parietal cortex has been seen as the site for spatial attentional processing. There is much debate about when the modulation of the primary visual cortex occurs, whether it is modulated in the feedforward sweep of processing or modulated by feedback projections from extrastriate and higher cortical areas. MEG and psychophysical measurements were used to look at spatially selective covert attention. Dual-task and cue-based paradigms were used. It was found that the posterior parietal cortex (PPC), in particular the SPL and IPL, was the main site of activation during these experiments, and that the left parietal lobe was activated more strongly than the right parietal lobe throughout. The levels of activation in both parietal and occipital areas were modulated in accordance with attentional demands. It is likely that spatially selective covert attention is dominated by the left parietal lobe, and that this takes the form of the proposed sensory-perceptual lateralization within the parietal lobes. Another form of lateralization is proposed, termed the motor-processing lateralization, the side of dominance being determined by handedness, being reversed in left- relative to right-handers. In terms of the modulation of the primary visual cortex, it was found that it is unlikely that V1 is modulated initially; rather the modulation takes the form of feedback from higher extrastriate and parietal areas. This fits with the idea of preattentive visual processing, a commonly accepted idea which, in itself, prevents the concept of initial modulation of V1.

Synchronization processes in nonlinear systems and their relation to cortical oscillatory dynamics

This thesis was focused on theoretical models of synchronization to cortical dynamics as measured by magnetoencephalography (MEG). Dynamical systems theory was used in both identifying relevant variables for brain coordination and also in devising methods for their quantification. We presented a method for studying interactions of linear and chaotic neuronal sources using MEG beamforming techniques. We showed that such sources can be accurately reconstructed in terms of their location, temporal dynamics and possible interactions. Synchronization in low-dimensional nonlinear systems was studied to explore specific correlates of functional integration and segregation. In the case of interacting dissimilar systems, relevant coordination phenomena involved generalized and phase synchronization, which were often intermittent. Spatially-extended systems were then studied. For locally-coupled dissimilar systems, as in the case of cortical columns, clustering behaviour occurred. Synchronized clusters emerged at different frequencies and their boundaries were marked through oscillation death. The macroscopic mean field revealed sharp spectral peaks at the frequencies of the clusters and broader spectral drops at their boundaries. These results question existing models of Event Related Synchronization and Desynchronization. We re-examined the concept of the steady-state evoked response following an AM stimulus. We showed that very little variability in the AM following response could be accounted by system noise. We presented a methodology for detecting local and global nonlinear interactions from MEG data in order to account for residual variability. We found crosshemispheric nonlinear interactions of ongoing cortical rhythms concurrent with the stimulus and interactions of these rhythms with the following AM responses. Finally, we hypothesized that holistic spatial stimuli would be accompanied by the emergence of clusters in primary visual cortex resulting in frequency-specific MEG oscillations. Indeed, we found different frequency distributions in induced gamma oscillations for different spatial stimuli, which was suggestive of temporal coding of these spatial stimuli. Further, we addressed the bursting character of these oscillations, which was suggestive of intermittent nonlinear dynamics. However, we did not observe the characteristic-3/2 power-law scaling in the distribution of interburst intervals. Further, this distribution was only seldom significantly different to the one obtained in surrogate data, where nonlinear structure was destroyed. In conclusion, the work presented in this thesis suggests that advances in dynamical systems theory in conjunction with developments in magnetoencephalography may facilitate a mapping between levels of description int he brain. this may potentially represent a major advancement in neuroscience.

Cortical activity during rotational and linear transformations

Neuroimaging studies of cortical activation during image transformation tasks have shown that mental rotation may rely on similar brain regions as those underlying visual perceptual mechanisms. The V5 complex, which is specialised for visual motion, is one region that has been implicated. We used functional magnetic resonance imaging (fMRI) to investigate rotational and linear transformation of stimuli. Areas of significant brain activation were identified for each of the primary mental transformation tasks in contrast to its own perceptual reference task which was cognitively matched in all respects except for the variable of interest. Analysis of group data for perception of rotational and linear motion showed activation in areas corresponding to V5 as defined in earlier studies. Both rotational and linear mental transformations activated Brodman Area (BA) 19 but did not activate V5. An area within the inferior temporal gyrus, representing an inferior satellite area of V5, was activated by both the rotational perception and rotational transformation tasks, but showed no activation in response to linear motion perception or transformation. The findings demonstrate the extent to which neural substrates for image transformation and perception overlap and are distinct as well as revealing functional specialisation within perception and transformation processing systems.

Abnormal left and right amygdala-orbitofrontal cortical functional connectivity to emotional faces:state versus trait vulnerability markers of depression in bipolar disorder

Background - Amygdala-orbitofrontal cortical (OFC) functional connectivity (FC) to emotional stimuli and relationships with white matter remain little examined in bipolar disorder individuals (BD). Methods - Thirty-one BD (type I; n = 17 remitted; n = 14 depressed) and 24 age- and gender-ratio-matched healthy individuals (HC) viewed neutral, mild, and intense happy or sad emotional faces in two experiments. The FC was computed as linear and nonlinear dependence measures between amygdala and OFC time series. Effects of group, laterality, and emotion intensity upon amygdala-OFC FC and amygdala-OFC FC white matter fractional anisotropy (FA) relationships were examined. Results - The BD versus HC showed significantly greater right amygdala-OFC FC (p = .001) in the sad experiment and significantly reduced bilateral amygdala-OFC FC (p = .007) in the happy experiment. Depressed but not remitted female BD versus female HC showed significantly greater left amygdala-OFC FC (p = .001) to all faces in the sad experiment and reduced bilateral amygdala-OFC FC to intense happy faces (p = .01). There was a significant nonlinear relationship (p = .001) between left amygdala-OFC FC to sad faces and FA in HC. In BD, antidepressants were associated with significantly reduced left amygdala-OFC FC to mild sad faces (p = .001). Conclusions - In BD, abnormally elevated right amygdala-OFC FC to sad stimuli might represent a trait vulnerability for depression, whereas abnormally elevated left amygdala-OFC FC to sad stimuli and abnormally reduced amygdala-OFC FC to intense happy stimuli might represent a depression state marker. Abnormal FC measures might normalize with antidepressant medications in BD. Nonlinear amygdala-OFC FC–FA relationships in BD and HC require further study.

Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats

The rodent ventrobasal (VB) thalamus receives sensory inputs from the whiskers and projects to the cortex, from which it receives reciprocal excitatory afferents. Much is known about the properties and functional roles of these glutamatergic inputs to thalamocortical neurons in the VB, but no data are available on how these afferents can affect thalamic glial cells. In this study, we used combined electrophysiological recordings and intracellular calcium ([Ca(2+)](i)) imaging to investigate glial cell responses to synaptic afferent stimulation. VB thalamus glial cells can be divided into two groups based on their [Ca(2+)](i) and electrophysiological responses to sensory and corticothalamic stimulation. One group consists of astrocytes, which stain positively for S100B and preferentially load with SR101, have linear current-voltage relations and low input resistance, show no voltage-dependent [Ca(2+)](i) responses, but express mGluR5-dependent [Ca(2+)](i) transients following stimulation of the sensory and/or corticothalamic excitatory afferent pathways. Cells of the other glial group, by contrast, stain positively for NG2, and are characterized by high input resistance, the presence of voltage-dependent [Ca(2+)](i) elevations and voltage-gated inward currents. There were no synaptically induced [Ca(2+)](i) elevations in these cells under control conditions. These results show that thalamic glial cell responses to synaptic input exhibit different properties to those of thalamocortical neurons. As VB astrocytes can respond to synaptic stimulation and signal to neighbouring neurons, this glial cell organization may have functional implications for the processing of somatosensory information and modulation of behavioural state-dependent thalamocortical network activities.

Hand somatosensory subcortical and cortical sources assessed by functional source separation:an EEG study

We propose a novel electroencephalographic application of a recently developed cerebral source extraction method (Functional Source Separation, FSS), which starts from extracranial signals and adds a functional constraint to the cost function of a basic independent component analysis model without requiring solutions to be independent. Five ad-hoc functional constraints were used to extract the activity reflecting the temporal sequence of sensory information processing along the somatosensory pathway in response to the separate left and right median nerve galvanic stimulation. Constraints required only the maximization of the responsiveness at specific latencies following sensory stimulation, without taking into account that any frequency or spatial information. After source extraction, the reliability of identified FS was assessed based on the position of single dipoles fitted on its retroprojected signals and on a discrepancy measure. The FS positions were consistent with previously reported data (two early subcortical sources localized in the brain stem and thalamus, the three later sources in cortical areas), leaving negligible residual activity at the corresponding latencies. The high-frequency component of the oscillatory activity (HFO) of the extracted component was analyzed. The integrity of the low amplitude HFOs was preserved for each FS. On the basis of our data, we suggest that FSS can be an effective tool to investigate the HFO behavior of the different neuronal pools, recruited at successive times after median nerve galvanic stimulation. As FSs are reconstructed along the entire experimental session, directional and dynamic HFO synchronization phenomena can be studied.