Anatomy and Neuroscience - Research Publications
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ItemMulti-Modal Neuroimaging in Premanifest and Early Huntington's Disease: 18 Month Longitudinal Data from the IMAGE-HD Study(PUBLIC LIBRARY SCIENCE, 2013-09-16)IMAGE-HD is an Australian based multi-modal longitudinal magnetic resonance imaging (MRI) study in premanifest and early symptomatic Huntington's disease (pre-HD and symp-HD, respectively). In this investigation we sought to determine the sensitivity of imaging methods to detect macrostructural (volume) and microstructural (diffusivity) longitudinal change in HD. We used a 3T MRI scanner to acquire T1 and diffusion weighted images at baseline and 18 months in 31 pre-HD, 31 symp-HD and 29 controls. Volume was measured across the whole brain, and volume and diffusion measures were ascertained for caudate and putamen. We observed a range of significant volumetric and, for the first time, diffusion changes over 18 months in both pre-HD and symp-HD, relative to controls, detectable at the brain-wide level (volume change in grey and white matter) and in caudate and putamen (volume and diffusivity change). Importantly, longitudinal volume change in the caudate was the only measure that discriminated between groups across all stages of disease: far from diagnosis (>15 years), close to diagnosis (<15 years) and after diagnosis. Of the two diffusion metrics (mean diffusivity, MD; fractional anisotropy, FA), only longitudinal FA change was sensitive to group differences, but only after diagnosis. These findings further confirm caudate atrophy as one of the most sensitive and early biomarkers of neurodegeneration in HD. They also highlight that different tissue properties have varying schedules in their ability to discriminate between groups along disease progression and may therefore inform biomarker selection for future therapeutic interventions.
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ItemOptic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes(PUBLIC LIBRARY SCIENCE, 2013-12-26)BACKGROUND: Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). OBJECTIVES: To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. METHODS: Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. RESULTS: Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. CONCLUSIONS: These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
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ItemQuantitative meta-analysis of fMRI and PET studies reveals consistent activation in fronto-striatal-parietal regions and cerebellum during antisaccades and prosaccades(FRONTIERS MEDIA SA, 2013-10-16)The antisaccade task is a classic task of oculomotor control that requires participants to inhibit a saccade to a target and instead make a voluntary saccade to the mirror opposite location. By comparison, the prosaccade task requires participants to make a visually-guided saccade to the target. These tasks have been studied extensively using behavioral oculomotor, electrophysiological, and neuroimaging in both non-human primates and humans. In humans, the antisaccade task is under active investigation as a potential endophenotype or biomarker for multiple psychiatric and neurological disorders. A large and growing body of literature has used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study the neural correlates of the antisaccade and prosaccade tasks. We present a quantitative meta-analysis of all published voxel-wise fMRI and PET studies (18) of the antisaccade task and show that consistent activation for antisaccades and prosaccades is obtained in a fronto-subcortical-parietal network encompassing frontal and supplementary eye fields (SEFs), thalamus, striatum, and intraparietal cortex. This network is strongly linked to oculomotor control and was activated to a greater extent for antisaccade than prosaccade trials. Antisaccade but not prosaccade trials additionally activated dorsolateral and ventrolateral prefrontal cortices. We also found that a number of additional regions not classically linked to oculomotor control were activated to a greater extent for antisaccade vs. prosaccade trials; these regions are often reported in antisaccade studies but rarely commented upon. While the number of studies eligible to be included in this meta-analysis was small, the results of this systematic review reveal that antisaccade and prosaccade trials consistently activate a distributed network of regions both within and outside the classic definition of the oculomotor network.
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ItemLed into Temptation? Rewarding Brand Logos Bias the Neural Encoding of Incidental Economic Decisions(PUBLIC LIBRARY SCIENCE, 2012-03-30)Human decision-making is driven by subjective values assigned to alternative choice options. These valuations are based on reward cues. It is unknown, however, whether complex reward cues, such as brand logos, may bias the neural encoding of subjective value in unrelated decisions. In this functional magnetic resonance imaging (fMRI) study, we subliminally presented brand logos preceding intertemporal choices. We demonstrated that priming biased participants' preferences towards more immediate rewards in the subsequent temporal discounting task. This was associated with modulations of the neural encoding of subjective values of choice options in a network of brain regions, including but not restricted to medial prefrontal cortex. Our findings demonstrate the general susceptibility of the human decision making system to apparently incidental contextual information. We conclude that the brain incorporates seemingly unrelated value information that modifies decision making outside the decision-maker's awareness.
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ItemOptic Nerve Magnetisation Transfer Ratio after Acute Optic Neuritis Predicts Axonal and Visual Outcomes(PUBLIC LIBRARY SCIENCE, 2012-12-18)Magnetisation transfer ratio (MTR) can reveal the degree of proton exchange between free water and macromolecules and was suggested to be pathological informative. We aimed to investigate changes in optic nerve MTR over 12 months following acute optic neuritis (ON) and to determine whether MTR measurements can predict clinical and paraclinical outcomes at 6 and 12 months. Thirty-seven patients with acute ON were studied within 2 weeks of presentation and at 1, 3, 6 and 12 months. Assessments included optic nerve MTR, retinal nerve fibre layer (RNFL) thickness, multifocal visual evoked potential (mfVEP) amplitude and latency and high (100%) and low (2.5%) contrast letter acuity. Eleven healthy controls were scanned twice four weeks apart for comparison with patients. Patient unaffected optic nerve MTR did not significantly differ from controls at any time-point. Compared to the unaffected nerve, affected optic nerve MTR was significantly reduced at 3 months (mean percentage interocular difference = -9.24%, p = 0.01), 6 months (mean = -12.48%, p<0.0001) and 12 months (mean = -7.61%, p = 0.003). Greater reduction in MTR at 3 months in patients was associated with subsequent loss of high contrast letter acuity at 6 (ρ = 0.60, p = 0.0003) and 12 (ρ = 0.44, p = 0.009) months, low contrast letter acuity at 6 (ρ = 0.35, p = 0.047) months, and RNFL thinning at 12 (ρ = 0.35, p = 0.044) months. Stratification of individual patient MTR time courses based on flux over 12 months (stable, putative remyelination and putative degeneration) predicted RNFL thinning at 12 months (F(2,32) = 3.59, p = 0.02). In conclusion, these findings indicate that MTR flux after acute ON is predictive of axonal degeneration and visual disability outcomes.
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ItemAutomated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: The IMAGE-HD study(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-03)We investigated two measures of neural integrity, T1-weighted volumetric measures and diffusion tensor imaging (DTI), and explored their combined potential to differentiate pre-diagnosis Huntington's disease (pre-HD) individuals from healthy controls. We applied quadratic discriminant analysis (QDA) to discriminate pre-HD individuals from controls and we utilised feature selection and dimension reduction to increase the robustness of the discrimination method. Thirty six symptomatic HD (symp-HD), 35 pre-HD, and 36 control individuals participated as part of the IMAGE-HD study and underwent T1-weighted MRI, and DTI using a Siemens 3 Tesla scanner. Volume and DTI measures [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for each group within five regions of interest (ROI; caudate, putamen, pallidum, accumbens and thalamus). QDA was then performed in a stepwise manner to differentiate pre-HD individuals from controls, based initially on unimodal analysis of motor or neurocognitive measures, or on volume, MD or FA measures from within the caudate, pallidum and putamen. We then tested for potential improvements to this model, by examining multi-modal MRI classifications (volume, FA and MD), and also included motor and neurocognitive measures, and additional brain regions (i.e., accumbens and thalamus). Volume, MD and FA differed across the three groups, with pre-HD characterised by significant volumetric reductions and increased FA within caudate, putamen and pallidum, relative to controls. The QDA results demonstrated that the differentiation of pre-HD from controls was highly accurate when both volumetric and diffusion data sets from basal ganglia (BG) regions were used. The highest discriminative accuracy however was achieved in a multi-modality approach and when including all available measures: motor and neurocognitive scores and multi-modal MRI measures from the BG, accumbens and thalamus. Our QDA findings provide evidence that combined multi-modal imaging measures can accurately classify individuals up to 15 years prior to onset when therapeutic intervention is likely to have maximal effects in slowing the trajectory of disease development.
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ItemPrefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: The IMAGE-HD study(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-01)Functional integrity of prefrontal cortico-striatal circuits underlying executive functioning may be compromised by basal ganglia degeneration during Huntington's disease (HD). This study investigated challenged inhibitory attentional control with a shifting response-set (SRS) task whilst assessing neural response via functional magnetic resonance imaging (fMRI) in 35 healthy controls, 35 matched pre-symptomatic (pre-HD) and 30 symptomatic (symp-HD) participants. A ≥70% performance accuracy threshold allowed confident identification of neural activity associated with SRS performance in a sub-set of 33 healthy controls, 32 pre-HD and 20 symp-HD participants. SRS activated dorsolateral prefrontal and dorsal anterior cingulate cortices, premotor, parietal, and basal ganglia regions and deactivated subgenual anterior cingulate cortex. Symp-HD participants showed greater prefrontal functional responses relative to controls and pre-HD, including larger activations and larger deactivations in response to cognitive challenge, consistent with compensatory neural recruitment. We then investigated associations between prefrontal BOLD responses, SRS performance accuracy and neuropsychiatric disturbance in all participants, including those below SRS performance accuracy threshold. We observed that reduced prefrontal responsivity in symp-HD was associated with reduced accuracy in SRS performance, and with increased neuropsychiatric disturbance within domains including executive dysfunction, pathological impulses, disinhibition, and depression. These findings demonstrate prefrontal response during inhibitory attentional control usefully characterises cognitive and neuropsychiatric status in symp-HD. The functional integrity of compensatory prefrontal responses may provide a useful marker for treatments which aim to sustain cognitive function and delay executive and neuropsychiatric disturbance.
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ItemFiltering induces correlation in fMRI resting state data(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-01-01)Correlation-based functional MRI connectivity methods typically impose a temporal sample independence assumption on the data. However, the conventional use of temporal filtering to address the high noise content of fMRI data may introduce sample dependence. Violation of the independence assumption has ramifications for the distribution of sample correlation which, if unaccounted for, may invalidate connectivity results. To enable the use of temporal filtering for noise suppression while maintaining the integrity of connectivity results, we derive the distribution of sample correlation between filtered timeseries as a function of the filter frequency response. Corrected distributions are also derived for statistical inference tests of sample correlation between filtered timeseries, including Fisher's z-transformation and the Student's t-test. Crucially, the proposed corrections are valid for any unknown true correlation and arbitrary filter specifications. Empirical simulations demonstrate the potential for temporal filtering to artificially induce connectivity by introducing sample dependence, and verify the utility of the proposed corrections in mitigating this effect. The importance of our corrections is exemplified in a resting state fMRI connectivity analysis: seed-voxel correlation maps generated from filtered data using uncorrected test variates yield an unfeasible number of connections to the left primary motor cortex, suggesting artificially induced connectivity, while maps acquired from filtered data using corrected test variates exhibit bilateral connectivity in the primary motor cortex, in conformance with expected results as seen in the literature.
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ItemManganese-enhanced MRI reflects seizure outcome in a model for mesial temporal lobe epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2013-03)The neurobiological processes resulting in epilepsy, known as epileptogenesis, are incompletely understood. Manganese-enhanced MRI (MEMRI) can potentially aide in this quest as it provides superior tissue contrast, particularly of the hippocampal subregions. This longitudinal study aims to characterise the changes in the hippocampus of the post kainic acid-induced status epilepticus (KASE) rat model of mesial temporal lobe epilepsy using MEMRI in vivo. Serial acquisition of T(1)-weighted MEMRI images were taken before, 2 days and 6 weeks after KASE (10-30 mg/kg, i.p.) in 14 rats and in 11 control rats, while a second cohort of control (N=6) and epileptic animals (N=10) was imaged at 2 months post KASE only. MnCl(2) (50 mM, 10 μl) was administered in the right lateral ventricle 1 day before scanning. Regions of interest were drawn around the hippocampus and several subregions of the hippocampus (CA1, CA3 and dentate gyrus). Markers of epilepsy such as spontaneous recurrent seizures, hippocampal neuronal loss and mossy fiber sprouting were quantified. A persistent increase in MEMRI signal intensity was found in the hippocampus, CA1 and dentate gyrus in the KASE group compared to the control group (ANOVA P<0.05). The intensity signal in the hippocampus and subregions correlated inversely with the frequency of spontaneous recurrent seizures in the chronic epileptic phase, however there was no relationship observed between histopathological changes such as cell loss and mossy fiber sprouting with seizures. This study demonstrates that MEMRI is able to detect imaging changes in the hippocampus during the course of epileptogenesis relevant for seizure expression. These data strongly indicate a relationship between manganese enhancement and spontaneous seizure outcome, suggesting that MEMRI could provide a preclinical biomarker for the severity of epileptogenesis in vivo in animal models.
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ItemAdolescent Toluene Inhalation in Rats Affects White Matter Maturation with the Potential for Recovery Following Abstinence(PUBLIC LIBRARY SCIENCE, 2012-09-18)Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T₂-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene-induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that contain toluene during adolescence and early adulthood appear to differentially affect white matter maturation and behavioural outcomes, although recovery can occur following abstinence.