Chrystalina A. Antoniades

Principal Component Analysis of the Cytokine and Chemokine Response to Human Traumatic Brain Injury

There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI). This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR) of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study.

An internationally standardised antisaccade protocol

Detailed measurements of saccadic latency--the time taken to make an eye movement to a suddenly-presented visual target--have proved a valuable source of detailed and quantitative information in a wide range of neurological conditions, as well as shedding light on the mechanisms of decision, currently of intense interest to cognitive neuroscientists. However, there is no doubt that more complex oculomotor tasks, and in particular the antisaccade task in which a participant must make a saccade in the opposite direction to the target, are potentially more sensitive indicators of neurological dysfunction, particularly in neurodegenerative conditions. But two obstacles currently hinder their widespread adoption for this purpose. First, that much of the potential information from antisaccade experiments, notably about latency distribution and amplitude, is typically thrown away. Second, that there is no standardised protocol for carrying out antisaccade experiments, so that results from one laboratory cannot easily be compared with those from another. This paper, the outcome of a recent international meeting of oculomotor scientists and clinicians with an unusually wide experience of such measurements, sets out a proposed protocol for clinical antisaccade trials: its adoption will greatly enhance the clinical and scientific benefits of making these kinds of measurements.

Saccadometry: a new tool for evaluating presymptomatic Huntington patients.

Saccadic reaction time or latency reflects the operation of the largely cortical mechanisms that decide where to look. An unusual feature of latency is that it varies randomly from trial to trial. In the past, this variation has been regarded as a nuisance, but analysis of its statistical properties has turned out to provide much insight into the underlying cerebral decision mechanisms. Thanks to recent technological improvements, large number of data can be gathered quickly and noninvasively using miniature, portable devices, offering the possibility of using saccadometry as a biomarker to enhance the diagnosis and monitoring of neurological conditions. Here we show that this technique can robustly distinguish genetically identified presymptomatic and symptomatic Huntingtons disease patients from age-matched controls, largely through an increase in the number of unusually early responses, which might reflect an impairment of the tonic suppression of the colliculus normally mediated by pathways through the basal ganglia.

Antisaccades and executive dysfunction in early drug-naive Parkinson's disease: The discovery study

Cognitive impairment is well recognized in Parkinsons disease (PD), but when it begins to develop is unclear. The aim of this study was to identify early signs of cognitive impairment along with abnormalities in saccadic behavior in newly diagnosed unmedicated PD patients.

Learning and Recognition of a Non-conscious Sequence of Events in Human Primary Visual Cortex.

Summary Human primary visual cortex (V1) has long been associated with learning simple low-level visual discriminations [1] and is classically considered outside of neural systems that support high-level cognitive behavior in contexts that differ from the original conditions of learning, such as recognition memory [2, 3]. Here, we used a novel fMRI-based dichoptic masking protocol—designed to induce activity in V1, without modulation from visual awareness—to test whether human V1 is implicated in human observers rapidly learning and then later (15–20 min) recognizing a non-conscious and complex (second-order) visuospatial sequence. Learning was associated with a change in V1 activity, as part of a temporo-occipital and basal ganglia network, which is at variance with the cortico-cerebellar network identified in prior studies of “implicit” sequence learning that involved motor responses and visible stimuli (e.g., [4]). Recognition memory was associated with V1 activity, as part of a temporo-occipital network involving the hippocampus, under conditions that were not imputable to mechanisms associated with conscious retrieval. Notably, the V1 responses during learning and recognition separately predicted non-conscious recognition memory, and functional coupling between V1 and the hippocampus was enhanced for old retrieval cues. The results provide a basis for novel hypotheses about the signals that can drive recognition memory, because these data (1) identify human V1 with a memory network that can code complex associative serial visuospatial information and support later non-conscious recognition memory-guided behavior (cf. [5]) and (2) align with mouse models of experience-dependent V1 plasticity in learning and memory [6].

Diagnostic potential of saccadometry in progressive supranuclear palsy

BACKGROUND Progressive supranuclear palsy (PSP), an atypical parkinsonian syndrome characterized by extrapyramidal features, imbalance, supranuclear gaze paresis and dementia, can be difficult to diagnose, especially in the early stages. From the clinicians point of view, the main difficulty with this disorder is the inability to provide an accurate diagnosis, at least for the initial stages of the disease, where symptoms are often confused with other parkinsonian disorders. This inability complicates the recruitment of patients with early-stage parkinsonism to trials of disease-modifying therapy. OBJECTIVES To determine whether quantitative, objective examination of saccadic latency distributions can help to distinguish PSP patients from other groups of parkinsonian patients. MATERIALS & METHODS We used a newly developed portable saccadometer to compare saccadic latency distributions of a group of PSP patients with two other groups in whom the initial differential diagnosis included PSP: one of these groups had Parkinsons disease and the other had developed a range of parkinsonian conditions (multiple system atrophy, dementia with Lewy bodies and corticobasal degeneration). RESULTS The use of a combination of saccadic parameters provided a greater discriminative power than the use of only one parameter, such as median latency. Statistical analysis and parameterization of the distributions robustly distinguished the three groups. CONCLUSIONS This approach appears to have considerable diagnostic potential in allowing a more accurate diagnosis of PSP, and may help particularly to eliminate misdiagnosis with other parkinsonian conditions.

Ocular motor abnormalities in neurodegenerative disorders

Eye movements are a source of valuable information to both clinicians and scientists as abnormalities of them frequently act as clues to the localization of a disease process. Classically, they are divided into two main types: those that hold the gaze, keeping images steady on the retina (vestibulo-ocular and optokinetic reflexes) and those that shift gaze and redirect the line of sight to a new object of interest (saccades, vergence, and smooth pursuit). Here we will review some of the major ocular motor abnormalities present in neurodegenerative disorders.

Deep Brain Stimulation: Eye Movements Reveal Anomalous Effects of Electrode Placement and Stimulation

One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinsons disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: similar improvements in saccadic and manual responses.

The purpose of this study was to determine whether the very large effects of saccadic latency distribution, generated by deep brain stimulation of the subthalamic nuclei are reflected in quantitatively corresponding changes for manual responses, rather than representing a reflection of the specific role of the subthalamus in controlling saccades. Saccadic and manual reaction times were measured under as nearly identical conditions as possible in six patients with implanted subthalamic electrodes and in six age-matched controls with the stimulation either on or off. Median latency was found to be reduced by stimulation in a similar way to saccadic latency; in neither case was there a significant change in the Linear Approach to Threshold with Ergotic Rate parameter &sgr;. For both types of response, the effect is to move the responses proportionately in the direction of average of responses in the control group. We therefore conclude that the previously described effects of stimulation on latency are not a phenomenon peculiar to saccades, increasing confidence in using saccadic latency measurements as a surrogate for more general responses when determining the efficacy of deep brain stimulation.

A Computational Cognitive Biomarker for Early-Stage Huntington's Disease.

Huntington’s disease (HD) is genetically determined but with variability in symptom onset, leading to uncertainty as to when pharmacological intervention should be initiated. Here we take a computational approach based on neurocognitive phenotyping, computational modeling, and classification, in an effort to provide quantitative predictors of HD before symptom onset. A large sample of subjects—consisting of both pre-manifest individuals carrying the HD mutation (pre-HD), and early symptomatic—as well as healthy controls performed the antisaccade conflict task, which requires executive control and response inhibition. While symptomatic HD subjects differed substantially from controls in behavioral measures [reaction time (RT) and error rates], there was no such clear behavioral differences in pre-HD. RT distributions and error rates were fit with an accumulator-based model which summarizes the computational processes involved and which are related to identified mechanisms in more detailed neural models of prefrontal cortex and basal ganglia. Classification based on fitted model parameters revealed a key parameter related to executive control differentiated pre-HD from controls, whereas the response inhibition parameter declined only after symptom onset. These findings demonstrate the utility of computational approaches for classification and prediction of brain disorders, and provide clues as to the underlying neural mechanisms.