Current pathophysiological theories of schizophrenia highlight the role of altered brain connectivity. This dysconnectivity could manifest 1) anatomically, through structural changes of association ...fibers at the cellular level, and/or 2) functionally, through aberrant control of synaptic plasticity at the synaptic level. In this article, we review the evidence for these theories, focusing on the modulation of synaptic plasticity. In particular, we discuss how dysconnectivity, observed between brain regions in schizophrenic patients, could result from abnormal modulation of N-methyl-
d-aspartate (NMDA)-dependent plasticity by other neurotransmitter systems. We focus on the implication of the dysconnection hypothesis for functional imaging at the systems level. In particular, we review recent advances in measuring plasticity in the human brain using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) that can be used to address dysconnectivity in schizophrenia. Promising experimental paradigms include perceptual and reinforcement learning. We describe how theoretical and causal models of brain responses might contribute to a mechanistic understanding of synaptic plasticity in schizophrenia.
There is increasing interest in the assessment of learning and memory in typically developing children as well as in children with neurodevelopmental disorders. However, neuropsychological ...assessments have been hampered by the dearth of standardised tests that enable direct comparison between distinct memory processes or between types of stimulus materials. We developed a tablet-based paired-associate learning paradigm, the Pair Test, based on neurocognitive models of learning and memory. The aims are to (i) establish the utility of this novel memory tool for use with children across a wide age range, and (ii) examine test validity, reliability and reproducibility of the construct. The convergent validity of the test was found to be adequate, and higher test reliability was shown for the Pair Test compared to standardised measures. Moderate test–retest reproducibility was shown, despite a long time interval between sessions (14 months). Moreover, the Pair Test is able to capture developmental changes in memory, and can therefore chart the developmental trajectory of memory and learning functions across childhood and adolescence. Finally, we used this novel instrument to acquire normative data from 130 typically developing children, aged 8–18 years. Age-stratified normative data are provided for learning, delayed recall and delayed recognition, for measures of verbal and non-verbal memory. The Pair Test thus provides measures of learning and memory accounting for encoding, consolidation and retrieval processes. As such, the standardised test results can be used to determine the status of learning and memory in healthy children, and also to identify deficits in paediatric patients at risk of damage to the neural network underlying mnemonic functions.
Pathophysiological explanations of epilepsy typically focus on either the micro/mesoscale (e.g. excitation-inhibition imbalance), or on the macroscale (e.g. network architecture). Linking ...abnormalities across spatial scales remains difficult, partly because of technical limitations in measuring neuronal signatures concurrently at the scales involved. Here we use light sheet imaging of the larval zebrafish brain during acute epileptic seizure induced with pentylenetetrazole. Spectral changes of spontaneous neuronal activity during the seizure are then modelled using neural mass models, allowing Bayesian inference on changes in effective network connectivity and their underlying synaptic dynamics. This dynamic causal modelling of seizures in the zebrafish brain reveals concurrent changes in synaptic coupling at macro- and mesoscale. Fluctuations of both synaptic connection strength and their temporal dynamics are required to explain observed seizure patterns. These findings highlight distinct changes in local (intrinsic) and long-range (extrinsic) synaptic transmission dynamics as a possible seizure pathomechanism and illustrate how our Bayesian model inversion approach can be used to link existing neural mass models of seizure activity and novel experimental methods.
There has been extensive interest in assessing the long-term effects of preterm birth on brain white matter microstructure using diffusion MRI. Our aim in this study is to explore diffusion MRI ...differences between adolescents born preterm and term born controls, with a specific interest in characterising how such differences are manifested in white matter regions containing predominantly single or crossing fibre populations. Probabilistic high angular resolution tractography together with large deformation spatial normalisation were used to objectively investigate diffusion tensor parameters at regular intervals along fibre tracts of 45 adolescents born before 33weeks of gestation and 30 term-born typically developing adolescents.
Diffusion parameters were significantly different between preterms and controls at several levels along the cortico-spinal, thalamo-cortical and transcallosal pathways. Within the predominantly single fibre regions of the corpus callosum and internal capsule, in the preterms mean diffusivity (MD) was found to be increased while fractional anisotropy (FA) was decreased compared to controls. In contrast, however, where these pathways traversed the centrum semiovale, FA and MD were both significantly increased. The major contributor to reduced FA in preterms in predominantly single fibre regions was the increased radial eigenvalue (i.e. increased radial diffusivity). In predominantly crossing-fibre regions, the tensor eigenvalues are not meaningful, and the observed increase in FA is likely to be due to a decrease in anisotropy in one of the contributing fibre bundles. Similar differences (although less pronounced) were observed after excluding preterms with radiological signs of preterm brain injury from the sample.
In summary, white matter microstructure was found to be altered in motor pathways in adolescents born preterm. Disruption of white matter (WM) microstructure in a single fibre region with resulting higher radial diffusivity leads to lower FA, whereas selective disruption of one fibre population in a crossing fibre region is observed to lead to higher FA. These findings challenge the common simplistic interpretation of FA as a measure of WM tract integrity.
•Microstructural changes in motor tracts were shown in adolescents born preterm.•Probabilistic fibre tractography based on HARDI identified motor tracts.•DTI parameters along tracts were different in single than in crossing fibre regions.•Disruption of one tract in a crossing fibre region can result in higher FA.•Results challenge the simplistic interpretation of FA as a measure of WM integrity.
Using dynamic causal modelling (DCM), we have presented provisional evidence to suggest: (i) the mismatch negativity (MMN) is generated by self-organised interactions within a hierarchy of cortical ...sources Garrido, M.I., Kilner, J.M., Kiebel, S.J., Stephan, K.E., Friston, K.J., 2007. Dynamic causal modelling of evoked potentials: a reproducibility study. NeuroImage 36, 571–580 and (ii) the MMN rests on plastic change in both extrinsic (between-source) and intrinsic (within source) connections (Garrido et al., under review). In this work we re-visit these two key issues in the context of the roving paradigm. Critically, this paradigm allows us to discount any differential response to differences in the stimuli per se, because the standards and oddballs are physically identical. We were able to confirm both the hierarchical nature of the MMN generation and the conjoint role of changes in extrinsic and intrinsic connections. These findings are consistent with a predictive coding account of repetition–suppression and the MMN, which gracefully accommodates two important mechanistic perspectives; the model-adjustment hypothesis Winkler, I., Karmos, G., Näätänen, R., 1996. Adaptive modelling of the unattended acoustic environment reflected in the mismatch negativity event-related potential. Brain Res. 742, 239–252; Näätänen, R., Winkler, I., 1999. The concept of auditory stimulus representation in cognitive neuroscience. Psychol Bull 125, 826–859; Sussman, E., Winkler, I., 2001. Dynamic sensory updating in the auditory system. Brain Res. Cogn Brain Res. 12, 431–439 and the adaptation hypothesis May, P., Tiitinen, H., Ilmoniemi, R.J., Nyman, G., Taylor, J.G., Näätänen, R., 1999. Frequency change detection in human auditory cortex. J. Comput. Neurosci. 6, 99–120; Jääskeläinen, I.P., Ahveninen, J., Bonmassar, G., Dale, A.M., Ilmoniemi, R.J., Levänen, S., Lin, F.H., May, P., Melcher, J., Stufflebeam, S., Tiitinen, H., Belliveau, J.W., 2004. Human posterior auditory cortex gates novel sounds to consciousness. Proc. Natl. Acad. Sci. U. S. A. 101, 6809–6814.
Objective
This retrospective, cross‐sectional study evaluated the feasibility and potential benefits of incorporating deep‐learning on structural magnetic resonance imaging (MRI) into planning ...stereoelectroencephalography (sEEG) implantation in pediatric patients with diagnostically complex drug‐resistant epilepsy. This study aimed to assess the degree of colocalization between automated lesion detection and the seizure onset zone (SOZ) as assessed by sEEG.
Methods
A neural network classifier was applied to cortical features from MRI data from three cohorts. (1) The network was trained and cross‐validated using 34 patients with visible focal cortical dysplasias (FCDs). (2) Specificity was assessed in 20 pediatric healthy controls. (3) Feasibility of incorporation into sEEG implantation plans was evaluated in 34 sEEG patients. Coordinates of sEEG contacts were coregistered with classifier‐predicted lesions. sEEG contacts in seizure onset and irritative tissue were identified by clinical neurophysiologists. A distance of <10 mm between SOZ contacts and classifier‐predicted lesions was considered colocalization.
Results
In patients with radiologically defined lesions, classifier sensitivity was 74% (25/34 lesions detected). No clusters were detected in the controls (specificity = 100%). Of the total 34 sEEG patients, 21 patients had a focal cortical SOZ, of whom eight were histopathologically confirmed as having an FCD. The algorithm correctly detected seven of eight of these FCDs (86%). In patients with histopathologically heterogeneous focal cortical lesions, there was colocalization between classifier output and SOZ contacts in 62%. In three patients, the electroclinical profile was indicative of focal epilepsy, but no SOZ was localized on sEEG. In these patients, the classifier identified additional abnormalities that had not been implanted.
Significance
There was a high degree of colocalization between automated lesion detection and sEEG. We have created a framework for incorporation of deep‐learning–based MRI lesion detection into sEEG implantation planning. Our findings support the prospective evaluation of automated MRI analysis to plan optimal electrode trajectories.
Focal cortical dysplasia is a congenital abnormality of cortical development and the leading cause of surgically remediable drug-resistant epilepsy in children. Post-surgical outcome is improved by ...presurgical lesion detection on structural MRI. Automated computational techniques have improved detection of focal cortical dysplasias in adults but have not yet been effective when applied to developing brains. There is therefore a need to develop reliable and sensitive methods to address the particular challenges of a paediatric cohort. We developed a classifier using surface-based features to identify focal abnormalities of cortical development in a paediatric cohort. In addition to established measures, such as cortical thickness, grey-white matter blurring, FLAIR signal intensity, sulcal depth and curvature, our novel features included complementary metrics of surface morphology such as local cortical deformation as well as post-processing methods such as the "doughnut" method - which quantifies local variability in cortical morphometry/MRI signal intensity, and per-vertex interhemispheric asymmetry. A neural network classifier was trained using data from 22 patients with focal epilepsy (mean age = 12.1 ± 3.9, 9 females), after intra- and inter-subject normalisation using a population of 28 healthy controls (mean age = 14.6 ± 3.1, 11 females). Leave-one-out cross-validation was used to quantify classifier sensitivity using established features and the combination of established and novel features. Focal cortical dysplasias in our paediatric cohort were correctly identified with a higher sensitivity (73%) when novel features, based on our approach for detecting local cortical changes, were included, when compared to the sensitivity using only established features (59%). These methods may be applicable to aiding identification of subtle lesions in medication-resistant paediatric epilepsy as well as to the structural analysis of both healthy and abnormal cortical development.
Cognitive impairment in schizophrenia is an important predictor of clinical and social outcome. In this preliminary study, the correlation between cognitive status and deficits in mismatch negativity ...(MMN) generation was explored. The MMN response to tone duration deviants was recorded using a new stimulation protocol with continuously changing (‘roving’) standard stimuli in order to measure the effect of standard repetitions on MMN (memory trace effect). Cognitive status of the patient group (
n=28) was assessed using neuropsychological screening. Healthy participants (
n=20) served as age-matched comparison group.
In patients, MMN amplitude in frontal electrodes as well as the MMN memory trace effect was diminished compared to controls. While both measures were inversely related to patient's age and disease severity, only the MMN memory trace effect was robustly correlated with the degree of neuropsychological impairment. This suggests that ERP measures of auditory system adaptability more appropriately characterise the pathophysiological processes underlying cognitive impairment in schizophrenia than static measures of ERP magnitude.
Objective
Focal cortical dysplasia (FCD) lesion detection and subtyping remain challenging on conventional MRI. New diffusion models such as the spherical mean technique (SMT) and neurite orientation ...dispersion and density imaging (NODDI) provide measurements that potentially produce more specific maps of abnormal tissue microstructure. This study aims to assess the SMT and NODDI maps for computational and radiological lesion characterization compared to standard fractional anisotropy (FA) and mean diffusivity (MD).
Methods
SMT, NODDI, FA, and MD maps were calculated for 33 pediatric patients with suspected FCD (18 histologically confirmed). Two neuroradiologists scored lesion visibility on clinical images and diffusion maps. Signal profile changes within lesions and homologous regions were quantified using a surface‐based approach. Diffusion parameter changes at multiple cortical depths were statistically compared between FCD type IIa and type IIb.
Results
Compared to fluid‐attenuated inversion recovery (FLAIR) or T1‐weighted imaging, lesions conspicuity on NODDI intracellular volume fraction (ICVF) maps was better/equal/worse in 5/14/14 patients, respectively, while on SMT intra‐neurite volume fraction (INVF) in 3/3/27. Compared to FA or MD, lesion conspicuity on the ICVF was better/equal/worse in 27/4/2, while on the INVF in 20/7/6. Quantitative signal profiling demonstrated significant ICVF and INVF reductions in the lesions, whereas SMT microscopic mean, radial, and axial diffusivities were significantly increased. FCD type IIb exhibited greater changes than FCD type IIa. No changes were detected on FA or MD profiles.
Significance
FCD lesion‐specific signal changes were found in ICVF and INVF but not in FA and MD maps. ICVF and INVF showed greater contrast than FLAIR in some cases and had consistent signal changes specific to FCD, suggesting that they could improve current presurgical pediatric epilepsy imaging protocols and can provide features useful for automated lesion detection.
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