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1.  The cortical microstructural basis of lateralized cognition: a review 
The presence of asymmetry in the human cerebral hemispheres is detectable at both the macroscopic and microscopic scales. The horizontal expansion of cortical surface during development (within individual brains), and across evolutionary time (between species), is largely due to the proliferation and spacing of the microscopic vertical columns of cells that form the cortex. In the asymmetric planum temporale (PT), minicolumn width asymmetry is associated with surface area asymmetry. Although the human minicolumn asymmetry is not large, it is estimated to account for a surface area asymmetry of approximately 9% of the region’s size. Critically, this asymmetry of minicolumns is absent in the equivalent areas of the brains of other apes. The left-hemisphere dominance for processing speech is thought to depend, partly, on a bias for higher resolution processing across widely spaced minicolumns with less overlapping dendritic fields, whereas dense minicolumn spacing in the right hemisphere is associated with more overlapping, lower resolution, holistic processing. This concept refines the simple notion that a larger brain area is associated with dominance for a function and offers an alternative explanation associated with “processing type.” This account is mechanistic in the sense that it offers a mechanism whereby asymmetrical components of structure are related to specific functional biases yielding testable predictions, rather than the generalization that “bigger is better” for any given function. Face processing provides a test case – it is the opposite of language, being dominant in the right hemisphere. Consistent with the bias for holistic, configural processing of faces, the minicolumns in the right-hemisphere fusiform gyrus are thinner than in the left hemisphere, which is associated with featural processing. Again, this asymmetry is not found in chimpanzees. The difference between hemispheres may also be seen in terms of processing speed, facilitated by asymmetric myelination of white matter tracts (Anderson et al., 1999 found that axons of the left posterior superior temporal lobe were more thickly myelinated). By cross-referencing the differences between the active fields of the two hemispheres, via tracts such as the corpus callosum, the relationship of local features to global features may be encoded. The emergent hierarchy of features within features is a recursive structure that may functionally contribute to generativity – the ability to perceive and express layers of structure and their relations to each other. The inference is that recursive generativity, an essential component of language, reflects an interaction between processing biases that may be traceable in the microstructure of the cerebral cortex. Minicolumn organization in the PT and the prefrontal cortex has been found to correlate with cognitive scores in humans. Altered minicolumn organization is also observed in neuropsychiatric disorders including autism and schizophrenia. Indeed, altered interhemispheric connections correlated with minicolumn asymmetry in schizophrenia may relate to language-processing anomalies that occur in the disorder. Schizophrenia is associated with over-interpretation of word meaning at the semantic level and over-interpretation of relevance at the level of pragmatic competence, whereas autism is associated with overly literal interpretation of word meaning and under-interpretation of social relevance at the pragmatic level. Both appear to emerge from a disruption of the ability to interpret layers of meaning and their relations to each other. This may be a consequence of disequilibrium in the processing of local and global features related to disorganization of minicolumnar units of processing.
PMCID: PMC4115615  PMID: 25126082
minicolumn; cytoarchitecture; lateralization; asymmetry; face-processing; language; schizophrenia; autism
2.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
3.  Cognitive reserve, cortical plasticity and resistance to Alzheimer's disease 
There are aspects of the ageing brain and cognition that remain poorly understood despite intensive efforts to understand how they are related. Cognitive reserve is the concept that has been developed to explain how it is that some elderly people with extensive neuropathology associated with dementia show little in the way of cognitive decline. Cognitive reserve is intimately related to cortical plasticity but this also, as it relates to ageing, remains poorly understood at the present time. Despite the shortcomings in understanding, we do have some knowledge on which to base efforts to minimise the likelihood of an elderly person developing dementia. For some risks the evidence is far from secure, but resistance to Alzheimer's disease (AD) appears from epidemiological studies to be contributed to by avoiding hypertension in middle life, obesity, depression, smoking and diabetes and head injury and by undertaking extended years of education, physical exercise, and social and intellectual pursuits in middle and late life. Nutritional factors may also promote healthy brain ageing. Resistance to AD is also contributed to by genetic factors, particularly apolipoprotein E2, but some combinations of other genetic polymorphisms as well. Although multiple factors and possible interventions may influence cognitive reserve and susceptibility to dementia, much more work is required on the mechanisms of action in order to determine which, if any, may improve the clinical and epidemiological picture. Understanding of how such factors operate may lead to new initiatives to keep the elderly population in the 21st century able to lead active and fulfilling lives.
PMCID: PMC3334540  PMID: 22380508
4.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
5.  Auditory cortex asymmetry, altered minicolumn spacing and absence of ageing effects in schizophrenia 
Brain  2008;131(12):3178-3192.
The superior temporal gyrus, which contains the auditory cortex, including the planum temporale, is the most consistently altered neocortical structure in schizophrenia (Shenton ME, Dickey CC, Frumin M, McCarley RW. A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1–52). Auditory hallucinations are associated with abnormalities in this region and activation in Heschl's gyrus. Our review of 34 MRI and 5 post-mortem studies of planum temporale reveals that half of those measuring region size reported a change in schizophrenia, usually consistent with a reduction in the left hemisphere and a relative increase in the right hemisphere. Furthermore, female subjects are under-represented in the literature and insight from sex differences may be lost. Here we present evidence from post-mortem brain (N = 21 patients, compared with 17 previously reported controls) that normal age-associated changes in planum temporale are not found in schizophrenia. These age-associated differences are reported in an adult population (age range 29–90 years) and were not found in the primary auditory cortex of Heschl's gyrus, indicating that they are selective to the more plastic regions of association cortex involved in cognition. Areas and volumes of Heschl's gyrus and planum temporale and the separation of the minicolumns that are held to be the structural units of the cerebral cortex were assessed in patients. Minicolumn distribution in planum temporale and Heschl's gyrus was assessed on Nissl-stained sections by semi-automated microscope image analysis. The cortical surface area of planum temporale in the left hemisphere (usually asymmetrically larger) was positively correlated with its constituent minicolumn spacing in patients and controls. Surface area asymmetry of planum temporale was reduced in patients with schizophrenia by a reduction in the left hemisphere (F = 7.7, df 1,32, P < 0.01). The relationship between cortical asymmetry and the connecting, interhemispheric callosal white matter was also investigated; minicolumn asymmetry of both Heschl's gyrus and planum temporale was correlated with axon number in the wrong subregions of the corpus callosum in patients. The spacing of minicolumns was altered in a sex-dependent manner due to the absence of age-related minicolumn thinning in schizophrenia. This is interpreted as a failure of adult neuroplasticity that maintains neuropil space. The arrested capacity to absorb anomalous events and cognitive demands may confer vulnerability to schizophrenic symptoms when adult neuroplastic demands are not met.
PMCID: PMC2724907  PMID: 18819990
auditory processing; neuroplasticity; cerebral asymmetry; corpus callosum; language processing; schizophrenia

Results 1-5 (5)