Cryotherapy and joint position sense in healthy participants: a systematic review

Objective: To (1) search the English-language literature for original research addressing the effect of cryotherapy on joint position sense (JPS) and (2) make recommendations regarding how soon healthy athletes can safely return to participation after cryotherapy. Data Sources: We performed an exhaustive search for original research using the AMED, CINAHL, MEDLINE, and SportDiscus databases from 1973 to 2009 to gather information on cryotherapy and JPS. Key words used were cryotherapy and proprioception, cryotherapy and joint position sense, cryotherapy, and proprioception. Study Selection: The inclusion criteria were (1) the literature was written in English, (2) participants were human, (3) an outcome measure included JPS, (4) participants were healthy, and (5) participants were tested immediately after a cryotherapy application to a joint. Data Extraction: The means and SDs of the JPS outcome measures were extracted and used to estimate the effect size (Cohen d) and associated 95% confidence intervals for comparisons of JPS before and after a cryotherapy treatment. The numbers, ages, and sexes of participants in all 7 selected studies were also extracted. Data Synthesis: The JPS was assessed in 3 joints: ankle (n 5 2), knee (n 5 3), and shoulder (n 5 2). The average effect size for the 7 included studies was modest, with effect sizes ranging from 20.08 to 1.17, with a positive number representing an increase in JPS error. The average methodologic score of the included studies was 5.4/10 (range, 5–6) on the Physiotherapy Evidence Database scale. Conclusions: Limited and equivocal evidence is available to address the effect of cryotherapy on proprioception in the form of JPS. Until further evidence is provided, clinicians should be cautious when returning individuals to tasks requiring components of proprioceptive input immediately after a cryotherapy treatment.

Aromatic l-amino acid decarboxylase : histochemical localization in rat kidney and lack of effect of dietary potassium or sodium loading on enzyme distribution

Utilizing a mono-specific antiserum produced in rabbits to hog kidney aromatic L-amino acid decarboxylase (AADC), the enzyme was localized in rat kidney by immunoperoxidase staining. AADC was located predominantly in the proximal convoluted tubules; there was also weak staining in the distal convoluted tubules and collecting ducts. An increase in dietary potassium or sodium intake produced no change in density or distribution of AADC staining in kidney. An assay of AADC enzyme activity showed no difference in cortex or medulla with chronic potassium loading. A change in distribution or activity of renal AADC does not explain the postulated dopaminergic modulation of renal function that occurs with potassium or sodium loading.

BabelFuse data fusion unit with precision wireless clock synchronisation

A significant issue encountered when fusing data received from multiple sensors is the accuracy of the timestamp associated with each piece of data. This is particularly important in applications such as Simultaneous Localisation and Mapping (SLAM) where vehicle velocity forms an important part of the mapping algorithms; on fastmoving vehicles, even millisecond inconsistencies in data timestamping can produce errors which need to be compensated for. The timestamping problem is compounded in a robot swarm environment due to the use of non-deterministic readily-available hardware (such as 802.11-based wireless) and inaccurate clock synchronisation protocols (such as Network Time Protocol (NTP)). As a result, the synchronisation of the clocks between robots can be out by tens-to-hundreds of milliseconds making correlation of data difficult and preventing the possibility of the units performing synchronised actions such as triggering cameras or intricate swarm manoeuvres. In this thesis, a complete data fusion unit is designed, implemented and tested. The unit, named BabelFuse, is able to accept sensor data from a number of low-speed communication buses (such as RS232, RS485 and CAN Bus) and also timestamp events that occur on General Purpose Input/Output (GPIO) pins referencing a submillisecondaccurate wirelessly-distributed "global" clock signal. In addition to its timestamping capabilities, it can also be used to trigger an attached camera at a predefined start time and frame rate. This functionality enables the creation of a wirelessly-synchronised distributed image acquisition system over a large geographic area; a real world application for this functionality is the creation of a platform to facilitate wirelessly-distributed 3D stereoscopic vision. A ‘best-practice’ design methodology is adopted within the project to ensure the final system operates according to its requirements. Initially, requirements are generated from which a high-level architecture is distilled. This architecture is then converted into a hardware specification and low-level design, which is then manufactured. The manufactured hardware is then verified to ensure it operates as designed and firmware and Linux Operating System (OS) drivers are written to provide the features and connectivity required of the system. Finally, integration testing is performed to ensure the unit functions as per its requirements. The BabelFuse System comprises of a single Grand Master unit which is responsible for maintaining the absolute value of the "global" clock. Slave nodes then determine their local clock o.set from that of the Grand Master via synchronisation events which occur multiple times per-second. The mechanism used for synchronising the clocks between the boards wirelessly makes use of specific hardware and a firmware protocol based on elements of the IEEE-1588 Precision Time Protocol (PTP). With the key requirement of the system being submillisecond-accurate clock synchronisation (as a basis for timestamping and camera triggering), automated testing is carried out to monitor the o.sets between each Slave and the Grand Master over time. A common strobe pulse is also sent to each unit for timestamping; the correlation between the timestamps of the di.erent units is used to validate the clock o.set results. Analysis of the automated test results show that the BabelFuse units are almost threemagnitudes more accurate than their requirement; clocks of the Slave and Grand Master units do not di.er by more than three microseconds over a running time of six hours and the mean clock o.set of Slaves to the Grand Master is less-than one microsecond. The common strobe pulse used to verify the clock o.set data yields a positive result with a maximum variation between units of less-than two microseconds and a mean value of less-than one microsecond. The camera triggering functionality is verified by connecting the trigger pulse output of each board to a four-channel digital oscilloscope and setting each unit to output a 100Hz periodic pulse with a common start time. The resulting waveform shows a maximum variation between the rising-edges of the pulses of approximately 39¥ìs, well below its target of 1ms.

V1-inspired features induce a weighted margin in SVMs

Image representations derived from simplified models of the primary visual cortex (V1), such as HOG and SIFT, elicit good performance in a myriad of visual classification tasks including object recognition/detection, pedestrian detection and facial expression classification. A central question in the vision, learning and neuroscience communities regards why these architectures perform so well. In this paper, we offer a unique perspective to this question by subsuming the role of V1-inspired features directly within a linear support vector machine (SVM). We demonstrate that a specific class of such features in conjunction with a linear SVM can be reinterpreted as inducing a weighted margin on the Kronecker basis expansion of an image. This new viewpoint on the role of V1-inspired features allows us to answer fundamental questions on the uniqueness and redundancies of these features, and offer substantial improvements in terms of computational and storage efficiency.

Iron nodules in ferric soils of the Fraser Coast, Australia : relicts of laterisation or features of contemporary weathering and pedogenesis?

The genesis of ferruginous nodules and pisoliths in soils and weathering profiles of coastal southern and eastern Australia has long been debated. It is not clear whether iron (Fe) nodules are redox accumulations, residues of Miocene laterite duricrust, or the products of contemporary weathering of Fe-rich sedimentary rocks. This study combines a catchment-wide survey of Fe nodule distribution in Poona Creek catchment (Fraser Coast, Queensland) with detailed investigations of a representative ferric soil profile to show that Fe nodules are derived from Fe-rich sandstones. Where these crop out, they are broken down, transported downslope by colluvial processes, and redeposited. Chemical and physical weathering transforms these eroded rock fragments into non-magnetic Fe nodules. Major features of this transformation include lower hematite/goethite and kaolinite/gibbsite ratios, increased porosity, etching of quartz grains, and development of rounded morphology and a smooth outer cortex. Iron nodules are commonly concentrated in ferric horizons. We show that these horizons form as the result of differential biological mixing of the soil. Bioturbation gradually buries nodules and rock fragments deposited at the surface of the soil, resulting in a largely nodule-free 'biomantle' over a ferric 'stone line'. Maghemite-rich magnetic nodules are a prominent feature of the upper half of the profile. These are most likely formed by the thermal alteration of non-magnetic nodules located at the top of the profile during severe bushfires. They are subsequently redistributed through the soil profile by bioturbation. Iron nodules occurring in the study area are products of contemporary weathering of Fe-rich rock units. They are not laterite duricrust residues nor are they redox accumulations, although redox-controlled dissolution/re-precipitation is an important component of post-depositional modification of these Fe nodules.

Cone signals and activity in myopia and emmetropia

Myopia (short-sightedness) is a common ocular disorder of children and young adults. Studies primarily using animal models have shown that the retina controls eye growth and the outer retina is likely to have a key role. One theory is that the proportion of L (long-wavelength-sensitive) and M (medium-wavelength-sensitive) cones is related to myopia development; with a high L/M cone ratio predisposing individuals to myopia. However, not all dichromats (persons with red-green colour vision deficiency) with extreme L/M cone ratios have high refractive errors. We predict that the L/M cone ratio will vary in individuals with normal trichromatic colour vision but not show a systematic difference simply due to refractive error. The aim of this study was to determine if L/M cone ratios in the central 30° are different between myopic and emmetropic young, colour normal adults. Information about L/M cone ratios was determined using the multifocal visual evoked potential (mfVEP). The mfVEP can be used to measure the response of visual cortex to different visual stimuli. The visual stimuli were generated and measurements performed using the Visual Evoked Response Imaging System (VERIS 5.1). The mfVEP was measured when the L and M cone systems were separately stimulated using the method of silent substitution. The method of silent substitution alters the output of three primary lights, each with physically different spectral distributions to control the excitation of one or more photoreceptor classes without changing the excitation of the unmodulated photoreceptor classes. The stimulus was a dartboard array subtending 30° horizontally and 30° vertically on a calibrated LCD screen. The m-sequence of the stimulus was 215-1. The N1-P1 amplitude ratio of the mfVEP was used to estimate the L/M cone ratio. Data were collected for 30 young adults (22 to 33 years of age), consisting of 10 emmetropes (+0.3±0.4 D) and 20 myopes (–3.4±1.7 D). The stimulus and analysis techniques were confirmed using responses of two dichromats. For the entire participant group, the estimated central L/M cone ratios ranged from 0.56 to 1.80 in the central 3°-13° diameter ring and from 0.94 to 1.91 in the more peripheral 13°-30° diameter ring. Within 3°-13°, the mean L/M cone ratio of the emmetropic group was 1.20±0.33 and the mean was similar, 1.20±0.26, for the myopic group. For the 13°-30° ring, the mean L/M cone ratio of the emmetropic group was 1.48±0.27 and it was slightly lower in the myopic group, 1.30±0.27. Independent-samples t-test indicated no significant difference between the L/M cone ratios of the emmetropic and myopic group for either the central 3°-13° ring (p=0.986) or the more peripheral 13°-30° ring (p=0.108). The similar distributions of estimated L/M cone ratios in the sample of emmetropes and myopes indicates that there is likely to be no association between the L/M cone ratio and refractive error in humans.

Regulation of the Fear Network by Mediators of Stress: Norepinephrine Alters the Balance between Cortical and Subcortical Afferent Excitation of the Lateral Amygdala

Pavlovian auditory fear conditioning involves the integration of information about an acoustic conditioned stimulus (CS) and an aversive unconditioned stimulus in the lateral nucleus of the amygdala (LA). The auditory CS reaches the LA subcortically via a direct connection from the auditory thalamus and also from the auditory association cortex itself. How neural modulators, especially those activated during stress, such as norepinephrine (NE), regulate synaptic transmission and plasticity in this network is poorly understood. Here we show that NE inhibits synaptic transmission in both the subcortical and cortical input pathway but that sensory processing is biased toward the subcortical pathway. In addition binding of NE to β-adrenergic receptors further dissociates sensory processing in the LA. These findings suggest a network mechanism that shifts sensory balance toward the faster but more primitive subcortical input

Comparison between electrically-evoked and voluntary wrist movements on sensorimotor and prefrontal cortical activation : A multi-channel time domain fNIRS study

Neuromuscular electrical stimulation (NMES) has been consistently demonstrated to improve skeletal muscle function in neurological populations with movement disorders, such as poststroke and incomplete spinal cord injury (Vanderthommen and Duchateau, 2007). Recent research has documented that rapid, supraspinal central nervous system reorganisation/neuroplastic mechanisms are also implicated during NMES (Chipchase et al., 2011). Functional neuroimaging studies have shown NMES to activate a network of sub-cortical and cortical brain regions, including the sensorimotor (SMC) and prefrontal (PFC) cortex (Blickenstorfer et al., 2009; Han et al., 2003; Muthalib et al., 2012). A relationship between increase in SMC activation with increasing NMES current intensity up to motor threshold has been previously reported using functional MRI (Smith et al., 2003). However, since clinical neurorehabilitation programmes commonly utilise NMES current intensities above the motor threshold and up to the maximum tolerated current intensity (MTI), limited research has determined the cortical correlates of increasing NMES current intensity at or above MTI (Muthalib et al., 2012). In our previous study (Muthalib et al., 2012), we assessed contralateral PFC activation using 1-channel functional near infrared spectroscopy (fNIRS) during NMES of the elbow flexors by increasing current intensity from motor threshold to greater than MTI and showed a linear relationship between NMES current intensity and the level of PFC activation. However, the relationship between NMES current intensity and activation of the motor cortical network, including SMC and PFC, has not been clarified. Moreover, it is of scientific and clinical relevance to know how NMES affects the central nervous system, especially in comparison to voluntary (VOL) muscle activation. Therefore, the aim of this study was to utilise multi-channel time domain fNIRS to compare SMC and PFC activation between VOL and NMESevoked wrist extension movements.

Effects of textured insoles on balance in people with Parkinson’s Disease

Background Degradation of the somatosensory system has been implicated in postural instability and increased falls risk for older people and Parkinson’s disease (PD) patients. Here we demonstrate that textured insoles provide a passive intervention that is an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet. Methods 20 healthy older adults (controls) and 20 participants with PD were recruited for the study. We evaluated effects of manipulating somatosensory information from the plantar surface of the feet using textured insoles. Participants performed standing tests, on two different surfaces (firm and foam), under three footwear conditions: 1) barefoot; 2) smooth insoles; and 3) textured insoles. Standing balance was evaluated using a force plate yielding data on the range of anterior-posterior and medial-lateral sway, as well as standard deviations for anterior-posterior and medial-lateral sway. Results On the firm surface with eyes open both the smooth and textured insoles reduced medial-lateral sway in the PD group to a similar level as the controls. Only the textured insole decreased medial-lateral sway and medial-lateral sway standard deviation in the PD group on both surfaces, with and without visual input. Greatest benefits were observed in the PD group while wearing the textured insoles, and when standing on the foam surface with eyes closed. Conclusions Data suggested that textured insoles may provide a low-cost means of improving postural stability in high falls-risk groups, such as people with PD.

In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure

Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.

Interleukin-1β stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-β-dependent mechanism

One of the hallmarks of progressive renal disease is the development of tubulointerstitial fibrosis. This is frequently preceded by macrophage infiltration, raising the possibility that macrophages relay fibrogenic signals to resident tubulointerstitial cells. The aim of this study was to investigate the potentially fibrogenic role of interleukin-1beta (IL-1beta), a macrophage-derived inflammatory cytokine, on cortical fibroblasts (CFs). Primary cultures of human renal CFs were established and incubated for 24 hours in the presence or absence of IL-1beta. We found that IL-1beta significantly stimulated DNA synthesis (356.7% +/- 39% of control, P <.003), fibronectin secretion (261.8 +/- 11% of control, P <.005), collagen type 1 production, (release of procollagen type 1 C-terminal-peptide, 152.4% +/- 26% of control, P <.005), transforming growth factor-beta (TGF-beta) secretion (211% +/- 37% of control, P <.01), and nitric oxide (NO) production (342.8% +/- 69% of control, P <.002). TGF-beta (1 ng/mL) and the phorbol ester phorbol 12-myristate 13-acetate (PMA, 25 nmol/L) produced fibrogenic effects similar to those of IL-1beta. Neither a NO synthase inhibitor (N(G)-methyl-l-arginine, 1 mmol/L) nor a protein kinase C (PKC) inhibitor (bis-indolylmaleimide 1, 1 micromol/L) altered the enhanced level of fibronectin secretion or DNA synthesis seen in response to IL-1beta treatment. However, addition of a TGF-beta-neutralizing antibody significantly reduced IL-1beta-induced fibronectin secretion (IL-1beta + IgG, 262% +/- 72% vs IL-1beta + alphaTGF-beta 156% +/- 14%, P <.02), collagen type 1 production (IL-1beta + IgG, 176% +/- 28% vs IL-1beta + alphaTGF-beta, 120% +/- 14%, P <.005) and abrogated IL-1beta-induced DNA synthesis (245% +/- 49% vs 105% +/- 21%, P <.005). IL-1beta significantly stimulated CF DNA synthesis and production of fibronectin, collagen type 1, TGFbeta, and NO. The fibrogenic and proliferative action of IL-1beta on CF appears not to involve activation of PKC or production of NO but is at least partly TGFbeta-dependent.

Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production

BACKGROUND Tubulointerstitial lesions, characterized by tubular injury, interstitial fibrosis and the appearance of myofibroblasts, are the strongest predictors of the degree and progression of chronic renal failure. These lesions are typically preceded by macrophage infiltration of the tubulointerstitium, raising the possibility that these inflammatory cells promote progressive renal disease through fibrogenic actions on resident tubulointerstitial cells. The aim of the present study, therefore, was to investigate the potentially fibrogenic mechanisms of interleukin-1beta (IL-1beta), a macrophage-derived pro-inflammatory cytokine, on human proximal tubule cells (PTC). METHODS Confluent, quiescent, passage 2 PTC were established in primary culture from histologically normal segments of human renal cortex (N = 11) and then incubated in serum- and hormone-free media supplemented with either IL-1beta (0 to 4 ng/mL) or vehicle (control). RESULTS IL-1beta significantly enhanced fibronectin secretion by up to fourfold in a time- and concentration-dependent fashion. This was accompanied by significant (2.5- to 6-fold) increases in alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor beta (TGF-beta1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1beta. NG-methyl-l-arginine (L-NMMA; 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1beta-stimulated fibronectin secretion. In contrast, a pan-specific TGF-beta neutralizing antibody significantly blocked the effects of IL-1beta on PTC fibronectin secretion (IL-1beta, 268.1 +/- 30.6 vs. IL-1beta+alphaTGF-beta 157.9 +/- 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1beta 81.0 +/- 6.7% vs. IL-1beta+alphaTGF-beta 93.4 +/- 2.1%, of control values, P < 0.01). CONCLUSION IL-1beta acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote alpha-smooth muscle actin expression. These actions appear to be mediated by a TGF-beta1 dependent mechanism and are independent of nitric oxide release.

Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala

Glucocorticoids, released in high concentrations from the adrenal cortex during stressful experiences, bind to glucocorticoid receptors in nuclear and peri-nuclear sites in neuronal somata. Their classically known mode of action is to induce gene promoter receptors to alter gene transcription. Nuclear glucocorticoid receptors are particularly dense in brain regions crucial for memory, including memory of stressful experiences, such as the hippocampus and amygdala. While it has been proposed that glucocorticoids may also act via membrane bound receptors, the existence of the latter remains controversial. Using electron microscopy, we found glucocorticoid receptors localized to non-genomic sites in rat lateral amygdala, glia processes, presynaptic terminals, neuronal dendrites, and dendritic spines including spine organelles and postsynaptic membrane densities. The lateral nucleus of the amygdala is a region specifically implicated in the formation of memories for stressful experiences. These newly observed glucocorticoid receptor immunoreactive sites were in addition to glucocorticoid receptor immunoreactive signals observed using electron and confocal microscopy in lateral amygdala principal neuron and GABA neuron soma and nuclei, cellular domains traditionally associated with glucocorticoid immunoreactivity. In lateral amygdala, glucocorticoid receptors are thus also localized to non-nuclear-membrane translocation sites, particularly dendritic spines, where they show an affinity for postsynaptic membrane densities, and may have a specialized role in modulating synaptic transmission plasticity related to fear and emotional memory.

Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone

The development of effective therapeutic strategies against prostate cancer bone metastases has been impeded by the lack of adequate animal models that are able to recapitulate the biology of the disease in humans. Bioengineered approaches allow researchers to create sophisticated experimentally and physiologically relevant in vivo models to study interactions between cancer cells and their microenvironment under reproducible conditions. The aim of this study was to engineer a morphologically and functionally intact humanized organ bone which can serve as a homing site for human prostate cancer cells. Transplantation of biodegradable tubular composite scaffolds seeded with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone construct including a large number of human mesenchymal cells which were shown to be metabolically active and capable of producing extracellular matrix components. Micro-CT analysis demonstrated that the newly formed ossicle recapitulated the morphological features of a physiological organ bone with a trabecular network surrounded by a cortex-like outer structure. This microenvironment was supportive of the lodgement and maintenance of murine haematopoietic cell clusters, thus mimicking a functional organ bone. Bioluminescence imaging demonstrated that luciferase-transduced human PC3 cells reproducibly homed to the humanized tissue engineered bone constructs, proliferated, and developed macro-metastases. This model allows the analysis of interactions between human prostate cancer cells and a functional humanized bone organ within an immuno-incompetent murine host. The system can serve as a reproducible platform to study effects of therapeutics against prostate cancer bone metastases within a humanized microenvironment.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. Because fMRI records, through the monitoring of blood flow activity, the location of localised brain activity within the brain, the possibility of combining fMRI measurements with EEG, as a joint inversion activity, was discussed and examined in detail. (3) A major goal for the BRI is to improve understanding about ``when'' (at what time) an epileptic seizure actually commenced before it is identified on an eeg recording, ``where'' the source of this initiation is located in the brain, and ``what'' is the initiator. Because of the general agreement in the literature that, in one way or another, epileptic events and seizures represent abnormal synchronisations of localised and/or global brain activity the modelling of synchronisations was examined in some detail. References C. M. Michel, G. Thut, S. Morand, A. Khateb, A. J. Pegna, R. Grave de Peralta, S. Gonzalez, M. Seeck and T. Landis, Electric source imaging of human brain functions, Brain Res. Rev. , 36 (2--3), 2001, 108--118. doi:10.1016/S0165-0173(01)00086-8 S. Ogawa, R. S. Menon, S. G. Kim and K. Ugurbil, On the characteristics of functional magnetic resonance imaging of the brain, Annu. Rev. Bioph. Biom. , 27 , 1998, 447--474. doi:10.1146/annurev.biophys.27.1.447 C. D. Binnie and H. Stefan, Modern electroencephalography: its role in epilepsy management, Clin. Neurophysiol. , 110 (10), 1999, 1671--1697. doi:10.1016/S1388-2457(99)00125-X J. X. Tao, A. Ray, S. Hawes-Ebersole and J. S. Ebersole, Intracranial eeg substrates of scalp eeg interictal spikes, Epilepsia , 46 (5), 2005, 669--76. doi:10.1111/j.1528-1167.2005.11404.x S. Ogawa, D. W. Tank, R. Menon, J. M. Ellermann, S. G. Kim, H. Merkle and K. Ugurbil, Intrinsic signal changes accompanying sensory stimulation: Functional brain mapping with magnetic resonance imaging, P. Natl. Acad. Sci. USA , 89 (13), 1992, 5951--5955. doi:10.1073/pnas.89.13.5951 J. Engel Jr., Report of the ilae classification core group, Epilepsia , 47 (9), 2006, 1558--1568. doi:10.1111/j.1528-1167.2006.00215.x L. Lemieux, A. Salek-Haddadi, O. Josephs, P. Allen, N. Toms, C. Scott, K. Krakow, R. Turner and D. R. Fish, Event-related fmri with simultaneous and continuous eeg: description of the method and initial case r port, NeuroImage , 14 (3), 2001, 780--7. doi:10.1006/nimg.2001.0853 P. Federico, D. F. Abbott, R. S. Briellmann, A. S. Harvey and G. D. Jackson, Functional mri of the pre-ictal state, Brain , 128 (8), 2005, 1811-7. doi:10.1093/brain/awh533 C. S. Hawco, A. P. Bagshaw, Y. Lu, F. Dubeau and J. Gotman, bold changes occur prior to epileptic spikes seen on scalp eeg, NeuroImage , 35 (4), 2007, 1450--1458. doi:10.1016/j.neuroimage.2006.12.042 F. Moeller, H. R. Siebner, S. Wolff, H. Muhle, R. Boor, O. Granert, O. Jansen, U. Stephani and M. Siniatchkin, Changes in activity of striato-thalamo-cortical network precede generalized spike wave discharges, NeuroImage , 39 (4), 2008, 1839--1849. doi:10.1016/j.neuroimage.2007.10.058 V. Osharina, E. Ponchel, A. Aarabi, R. Grebe and F. Wallois, Local haemodynamic changes preceding interictal spikes: A simultaneous electrocorticography (ecog) and near-infrared spectroscopy (nirs) analysis in rats, NeuroImage , 50 (2), 2010, 600--607. doi:10.1016/j.neuroimage.2010.01.009 R. S. Fisher, W. Boas, W. Blume, C. Elger, P. Genton, P. Lee and J. Engel, Epileptic seizures and epilepsy: Definitions proposed by the international league against epilepsy (ilae) and the international bureau for epilepsy (ibe), Epilepsia , 46 (4), 2005, 470--472. doi:10.1111/j.0013-9580.2005.66104.x H. Berger, Electroencephalogram in humans, Arch. Psychiat. Nerven. , 87 , 1929, 527--570. C. M. Michel, M. M. Murray, G. Lantz, S. Gonzalez, L. Spinelli and R. G. de Peralta, eeg source imaging, Clin. Neurophysiol. , 115 (10), 2004, 2195--2222. doi:10.1016/j.clinph.2004.06.001 P. L. Nunez and R. B. Silberstein, On the relationship of synaptic activity to macroscopic measurements: Does co-registration of eeg with fmri make sense?, Brain Topogr. , 13 (2), 2000, 79--96. doi:10.1023/A:1026683200895 S. Ogawa, T. M. Lee, A. R. Kay and D. W. Tank, Brain magnetic resonance imaging with contrast dependent on blood oxygenation, P. Natl. Acad. Sci. USA , 87 (24), 1990, 9868--9872. doi:10.1073/pnas.87.24.9868 J. S. Gati, R. S. Menon, K. Ugurbil and B. K. Rutt, Experimental determination of the bold field strength dependence in vessels and tissue, Magn. Reson. Med. , 38 (2), 1997, 296--302. doi:10.1002/mrm.1910380220 P. A. Bandettini, E. C. Wong, R. S. Hinks, R. S. Tikofsky and J. S. Hyde, Time course EPI of human brain function during task activation, Magn. Reson. Med. , 25 (2), 1992, 390--397. K. K. Kwong, J. W. Belliveau, D. A. Chesler, I. E. Goldberg, R. M. Weisskoff, B. P. Poncelet, D. N. Kennedy, B. E. Hoppelm, M. S. Cohen and R. Turner, Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation, P. Natl. Acad. Sci. USA , 89 (12), 1992, 5675--5679. doi:10.1073/pnas.89.12.5675 J. Frahm, K. D. Merboldt and W. Hnicke, Functional mri of human brain activation at high spatial resolution, Magn. Reson. Med. , 29 (1), 1993, 139--144. P. A. Bandettini, A. Jesmanowicz, E. C. Wong and J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain, Magn. Reson. Med. , 30 (2), 1993, 161--173. K. J. Friston, P. Jezzard and R. Turner, Analysis of functional MRI time-series, Hum. Brain Mapp. , 1 (2), 1994, 153--171. B. Biswal, F. Z. Yetkin, V. M. Haughton and J. S. Hyde, Functional connectivity in the motor cortex of resting human brain using echo-planar mri, Mag. Reson. Med. , 34 (4), 1995, 537--541. doi:10.1002/mrm.1910340409 K. J. Friston, J. Ashburner, C. D. Frith, J. Poline, J. D. Heather and R. S. J. Frackowiak, Spatial registration and normalization of images, Hum. Brain Mapp. , 3 (3), 1995, 165--189. K. J. Friston, S. Williams, R. Howard, R. S. Frackowiak and R. Turner, Movement-related effects in fmri time-series, Magn. Reson. Med. , 35 (3), 1996, 346--355. G. H. Glover, T. Q. Li and D. Ress, Image-based method for retrospective correction of physiological motion effects in fmri: Retroicor, Magn. Reson. Med. , 44 (1), 2000, 162--167. doi:10.1002/1522-2594(200007)44:13.0.CO;2-E K. J. Friston, O. Josephs, G. Rees and R. Turner, Nonlinear event-related responses in fmri, Magn. Reson. Med. , 39 (1), 1998, 41--52. doi:10.1002/mrm.1910390109 K. Ugurbil, L. Toth and D. Kim, How accurate is magnetic resonance imaging of brain function?, Trends Neurosci. , 26 (2), 2003, 108--114. doi:10.1016/S0166-2236(02)00039-5 D. S. Kim, I. Ronen, C. Olman, S. G. Kim, K. Ugurbil and L. J. Toth, Spatial relationship between neuronal activity and bold functional mri, NeuroImage , 21 (3), 2004, 876--885. doi:10.1016/j.neuroimage.2003.10.018 A. Connelly, G. D. Jackson, R. S. Frackowiak, J. W. Belliveau, F. Vargha-Khadem and D. G. Gadian, Functional mapping of activated human primary cortex with a clinical mr imaging system, Radiology , 188 (1), 1993, 125--130. L. Allison, Hidden Markov Models, Technical Report , School of Computer and Software Engineering, Monash University, 2000. R. J. Elliott, L. Aggoun and J.B. Moore, Hidden Markov Models: Estimation and Control, Appl. Math.-Czech. , 2004. B. Bhavnagri, Discontinuities of plane functions projected from a surface with methods for finding these , Technical Report, 2009. B. Bhavnagri, Computer Vision using Shape Spaces , Technical Report,1996, University of Adelaide. B. Bhavnagri, A method for representing shape based on an equivalence relation on polygons, Pattern Recogn. , 27 (2), 1994, 247--260. doi:10.1016/0031-3203(94)90057-4 D. F. Abbott, A. B. Waites, A. S. Harvey and G. D. Jackson, Exploring epileptic seizure onset with fmri, NeuroImage , 36(S1) (344TH-PM), 2007. M. C. Mackey and L. Glass, Oscillation and chaos in physiological control systems, Science , 197 , 1977, 287--289. S. H. Strogatz, SYNC - The Emerging Science of Spontaneous Order , Theia, New York, 2003. J. W. Kim, J. A. Roberts and P. A. Robinson, Dynamics of epileptic seizures: Evolution, spreading, and suppression, J. Theor. Biol. , 257 (4), 2009, 527--532. doi:10.1016/j.jtbi.2008.12.009 Y. Kuramoto, T. Aoyagi, I. Nishikawa, T. Chawanya T and K. Okuda, Neural network model carrying phase information with application to collective dynamics, J. Theor. Phys. , 87 (5), 1992, 1119--1126. V. B. Mountcastle, The columnar organization of the neocortex, Brain , 120 (4), 1997, 701. doi:10.1093/brain/120.4.701 F. L. Silva, W. Blanes, S. N. Kalitzin, J. Parra, P. Suffczynski and D. N. Velis, Epilepsies as dynamical diseases of brain systems: Basic models of the transition between normal and epileptic activity, Epilepsia , 44 (12), 2003, 72--83. F. H. Lopes da Silva, W. Blanes, S. N. Kalitzin, J. Parra, P. Suffczynski and D. N. Velis, Dynamical diseases of brain systems: different routes to epileptic seizures, ieee T. Bio-Med. Eng. , 50 (5), 2003, 540. L.D. Iasemidis, Epileptic seizure prediction and control, ieee T. Bio-Med. Eng. , 50 (5), 2003, 549--558. L. D. Iasemidis, D. S. Shiau, W. Chaovalitwongse, J. C. Sackellares, P. M. Pardalos, J. C. Principe, P. R. Carney, A. Prasad, B. Veeramani, and K. Tsakalis, Adaptive epileptic seizure prediction system, ieee T. Bio-Med. Eng. , 50 (5), 2003, 616--627. K. Lehnertz, F. Mormann, T. Kreuz, R.G. Andrzejak, C. Rieke, P. David and C. E. Elger, Seizure prediction by nonlinear eeg analysis, ieee Eng. Med. Biol. , 22 (1), 2003, 57--63. doi:10.1109/MEMB.2003.1191451 K. Lehnertz, R. G. Andrzejak, J. Arnhold, T. Kreuz, F. Mormann, C. Rieke, G. Widman and C. E. Elger, Nonlinear eeg analysis in epilepsy: Its possible use for interictal focus localization, seizure anticipation, and prevention, J. Clin. Neurophysiol. , 18 (3), 2001, 209. B. Litt and K. Lehnertz, Seizure prediction and the preseizure period, Curr. Opin. Neurol. , 15 (2), 2002, 173. doi:10.1097/00019052-200204000-00008 B. Litt and J. Echauz, Prediction of epileptic seizures, Lancet Neurol. , 1 (1), 2002, 22--30. doi:10.1016/S1474-4422(02)00003-0 M. M{a}kiranta, J. Ruohonen, K Suominen, J. Niinim{a}ki, E. Sonkaj{a}rvi, V. Kiviniemi, T. Sepp{a}nen, S. Alahuhta, V. J{a}ntti and O. Tervonen, {bold} signal increase preceeds eeg spike activity--a dynamic penicillin induced focal epilepsy in deep anesthesia, NeuroImage , 27 (4), 2005, 715--724. doi:10.1016/j.neuroimage.2005.05.025 K. Lehnertz, F. Mormann, H. Osterhage, A. M{u}ller, J. Prusseit, A. Chernihovskyi, M. Staniek, D. Krug, S. Bialonski and C. E. Elger, State-of-the-art of seizure prediction, J. Clin. Neurophysiol. , 24 (2), 2007, 147. doi:10.1097/WNP.0b013e3180336f16 F. Mormann, T. Kreuz, C. Rieke, R. G. Andrzejak, A. Kraskov, P. David, C. E. Elger and K. Lehnertz, On the predictability of epileptic seizures, Clin. Neurophysiol. , 116 (3), 2005, 569--587. doi:10.1016/j.clinph.2004.08.025 F. Mormann, R. G. Andrzejak, C. E. Elger and K. Lehnertz, Seizure prediction: the long and winding road, Brain , 130 (2), 2007, 314--333. doi:10.1093/brain/awl241 Z. Rogowski, I. Gath and E. Bental, On the prediction of epileptic seizures, Biol. Cybern. , 42 (1), 1981, 9--15. Y. Salant, I. Gath, O. Henriksen, Prediction of epileptic seizures from two-channel eeg, Med. Biol. Eng. Comput. , 36 (5), 1998, 549--556. doi:10.1007/BF02524422 J. Gotman and D.J. Koffler, Interictal spiking increases after seizures but does not after decrease in medication, Evoked Potential , 72 (1), 1989, 7--15. J. Gotman and M. G. Marciani, Electroencephalographic spiking activity, drug levels, and seizure occurence in epileptic patients, Ann. Neurol. , 17 (6), 1985, 59--603. A. Katz, D. A. Marks, G. McCarthy and S. S. Spencer, Does interictal spiking change prior to seizures?, Electroen. Clin. Neuro. , 79 (2), 1991, 153--156. A. Granada, R. M. Hennig, B. Ronacher, A. Kramer and H. Herzel, Phase Response Curves: Elucidating the dynamics of couples oscillators, Method Enzymol. , 454 (A), 2009, 1--27. doi:10.1016/S0076-6879(08)03801-9 doi:10.1016/S0076-6879(08)03801-9 H. Kantz and T. Schreiber, Nonlinear time series analysis , 2004, Cambridge Univ Press. M. V. L. Bennett and R. S Zukin, Electrical coupling and neuronal synchronization in the mammalian brain, Neuron , 41 (4), 2004, 495 --511. doi:10.1016/S0896-6273(04)00043-1 L.D. Iasemidis, J. Chris Sackellares, H. P. Zaveri and W. J. Williams, Phase space topography and the Lyapunov exponent of electrocorticograms in partial seizures, Brain Topogr. , 2 (3), 1990, 187--201. doi:10.1007/BF01140588 M. Le Van Quyen, J. Martinerie, V. Navarro, M. Baulac and F. J. Varela, Characterizing neurodynamic changes before seizures, J. Clin. Neurophysiol. , 18 (3), 2001, 191. J. Martinerie, C. Adam, M. Le Van Quyen, M. Baulac, S. Clemenceau, B. Renault and F. J. Varela, Epileptic seizures can be anticipated by non-linear analysis, Nat. Med. , 4 (10), 1998, 1173--1176. doi:10.1038/2667 A. Pikovsky, M. Rosenblum, J. Kurths and R. C. Hilborn, Synchronization: A universal concept in nonlinear science, Amer. J. Phys. , 70 , 2002, 655. H. R. Wilson and J. D. Cowan, Excitatory and inhibitory interactions in localized populations of model neurons, Biophys. J. , 12 (1), 1972, 1--24. D. Cumin and C. P. Unsworth, Generalising the Kuramoto model for the study of neuronal synchronisation in the brain, Physica D , 226 (2), 2007, 181--196. doi:10.1016/j.physd.2006.12.004 F. K. Skinner, H. Bazzazi and S. A. Campbell, Two-cell to N-cell heterogeneous, inhibitory networks: Precise linking of multistable and coherent properties, J. Comput. Neurosci. , 18 (3), 2005, 343--352. doi:10.1007/s10827-005-0331-1 W. W. Lytton, Computer modelling of epilepsy, Nat. Rev. Neurosci. , 9 (8), 2008, 626--637. doi:10.1038/nrn2416 R. D. Traub, A. Bibbig, F. E. N. LeBeau, E. H. Buhl and M. A. Whittington, Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro, Ann. Rev. , 2004. R. D. Traub, A. Draguhn, M. A. Whittington, T. Baldeweg, A. Bibbig, E. H. Buhl and D. Schmitz, Axonal gap junc ions between principal neurons: A novel source of network oscillations, and perhaps epileptogenesis., Rev. Neuroscience , 13 (1), 2002, 1. doi:10.1146/annurev.neuro.27.070203.144303 M. Scheffer, J. Bascompte, W. A. Brock, V. Brovkin, S. R. Carpenter, V. Dakos, H. Held, E. H. van Nes, M. Rietkerk and G. Sugihara, Early-warning signals for critical transitions, Nature , 461 (7260), 2009, 53--59. doi:10.1038/nature08227 K. Murphy, A Brief Introduction to Graphical Models and Bayesian Networks , 2008, http://www.cs.ubc.ca/murphyk/Bayes/bnintro.html . R. C. Bradley, An elementary