A Flow Cytometry-Based Method for Assessing CAR Cell Binding Kinetics Using Stable CAR Jurkat Cells.

Chimeric antigen receptors (CARs) are synthetic fusion proteins that can reprogram immune cells to target specific antigens. CAR-expressing T cells have emerged as an effective treatment method for hematological cancers; despite this success, the mechanisms and structural properties that govern CAR responses are not fully understood. Here, we provide a simple assay to assess cellular avidity using a standard flow cytometer. This assay measures the interaction kinetics of CAR-expressing T cells and targets antigen-expressing target cells. By co-culturing stably transfected CAR Jurkat cells with target positive and negative cells for short periods of time in a varying effector-target gradient, we were able to observe the formation of CAR-target cell doublets, providing a readout of actively bound cells. When using the optimized protocol reported here, we observed unique cellular binding curves that varied between CAR constructs with differing antigen binding domains. The cellular binding kinetics of unique CARs remained consistent, were dependent on specific target antigen expression, and required active biological signaling. While existing literature is not clear at this time whether higher or lower CAR cell binding is beneficial to CAR therapeutic activity, the application of this simplified protocol for assessing CAR binding could lead to a better understanding of the proximal signaling events that regulate CAR functionality. Key features • Determines CAR receptor cellular interaction kinetics using a Jurkat cell model. • Can be used for a wide variety of CAR target antigens, including both hematological and solid tumor targets. • Experiments can be performed in under two hours with no staining using a standard flow cytometer. • Requires stable CAR Jurkat cells and target cells with stable fluorescent marker expression for optimal results.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

A simplified function-first method for the discovery and optimization of bispecific immune engaging antibodies.

Bi-specific T-cell engager antibodies (BiTEs) are synthetic fusion molecules that combine multiple antibody-binding domains to induce active contact between T-cells and antigen expressing cells in the body. Blinatumomab, a CD19-CD3 BiTE is now a widely used therapy for relapsed B-cell malignancies, and similar BiTE therapeutics have shown promise for treating various other forms of cancer. The current process for new BiTE development is time consuming and costly, requiring characterization of the individual antigen binding domains, followed by bi-specific design, protein production, purification, and eventually functional screening. Here, we sought to establish a more cost-efficient approach for generating novel BiTE sequences and assessing bioactivity through a function first approach without purification. We generate a plasmid with a bi-modular structure to allow high-throughput exchange of either binding arm, enabling rapid screening of novel tumour-targeting single chain variable (scFv) domains in combination with the well-characterized OKT3 scFv CD3-targeting domain. We also demonstrate two systems for high throughput functional screening of BiTE proteins based on Jurkat T cells (referred to as BiTE-J). Using BiTE-J we evaluate four EGFRvIII-scFv sequenced in BiTE format, identifying two constructs with superior activity for redirecting T-cells against the EGFRvIII-tumour specific antigen. We also confirm activity in primary T cells, where novel EGFRvIII-BiTEs induced T cell activation and antigen selective tumor killing. We finally demonstrate similar exchange the CD3-interacting element of our bi-modular plasmid. By testing several novel CD3-targeting scFv elements for activity in EGFRvIII-targeted BiTEs, we were able to identify highly active BiTE molecules with desirable functional activity for downstream development. In summary, BiTE-J presents a low cost, high-throughput method for the rapid assessment of novel BiTE molecules without the need for purification and quantification.

Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation.

Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors in vitro and in vivo. Overall, these results indicate that hinge length tuning provides a programmable strategy for throttling antigenic sensitivity in CARs targeting membrane-proximal epitopes, and could be employed for CAR-optimization and improved tumor selectivity.

Exploration of anomalous perceptual experiences in migraine between attacks using the Cardiff Anomalous Perceptions Scale.

Distortions in sensory experiences that precede a migraine attack have been extensively documented, the most well-known being the visual aura. Distortions in the experience of other senses are also reported as part of an aura, albeit less frequently, together with changes in the perception or ownership of the body or body parts. There are many examples of differences in aspects of visual perception between migraine and control groups, between attacks, but not as much on unusual experiences involving other senses, the sense of the body or the experience of the environment. Seventy-seven migraine (33 with aura) and 74 control participants took part. Anomalous perceptions were experienced by both migraine and control groups, but more with migraine experienced them and rated them as more distressing, intrusive and frequent. Associations with reports of visual triggers of migraine and visual discomfort are presented. This study is the first to show relationships between these factors.

A Review of Motion and Orientation Processing in Migraine.

Visual tests can be used as noninvasive tools to test models of the pathophysiology underlying neurological conditions, such as migraine. They may also be used to track changes in performance that vary with the migraine cycle or can track the efficacy of prophylactic treatments. This article reviews the literature on performance differences on two visual tasks, global motion discrimination and orientation, which, of the many visual tasks that have been used to compare differences between migraine and control groups, have yielded the most consistent patterns of group differences. The implications for understanding the underlying pathophysiology in migraine are discussed, but the main focus is on bringing together disparate areas of research and suggesting those that can reveal practical uses of visual tests to treat and manage migraine.

First record of recurring reproduction of captive tawny nurse sharks Nebrius ferrugineus.

Between 2008 and 2015, a group of tawny nurse sharks Nebrius ferrugineus reproduced successfully in a captive environment on the central Red Sea coast of Saudi Arabia. Births occurred on an annual basis, except for 2013. Of 12 confirmed birthing events, the most recent (2015) was observed and recorded in detail, which further contributes to the limited reproductive knowledge of this monotypic species.

A comparison of the effects of the colour and size of coloured overlays on young children's reading.

This study compared the effects of the colour and size of overlays on reading time, reading errors and on the clarity of text with young primary school children. The sample comprised a non-clinical, typical, sample from an East London primary school. One hundred and six children aged between four and seven years were asked to read 11 short passages of text (60 words) either with full page overlays or smaller reading rulers (53 in each group). This sample included younger children than has often been tested before. The 11 short passages allowed an assessment of baseline reading performance (no reading aid) and performance while reading with each of a set of ten coloured reading aids. Two different, yet beneficial, colours were determined: the most effective and the clearest/most comfortable. Both of these measures are not usually recorded. All but four children had reduced reading times with one of the reading aids and all but one reported their aid improved the perceived visual clarity of the text: the size of the reading aid did not affect reading time or visual clarity significantly. The numbers of skipped words and errors/mis-read words also decreased when reading with the most effective and most comfortable reading aid. Near visual acuity was assessed with and without each child's most effective coloured aid. The most effective aid improved acuity in over a third of the children. Acuity has not been assessed in previous studies. As reported previously, different colours helped different children. In conclusion, coloured reading overlays reduced reading times on the reading test employed here and the size of the reading aid was not crucial to facilitate performance. The largest reductions occurred for the youngest readers, suggesting these aids may be particularly effective for early readers.

Links between global and local shape perception, coloured backgrounds, colour discrimination, and non-verbal IQ.

This study explored associations between local and global shape perception on coloured backgrounds, colour discrimination, and non-verbal IQ (NVIQ). Five background colours were chosen for the local and global shape tasks that were tailored for the cone-opponent pathways early in the visual system (cardinal colour directions: L-M, loosely, reddish-greenish; and S-(L + M), or tritan colours, loosely, blueish-yellowish; where L, M and S refer to the long, middle and short wavelength sensitive cones). Participants also completed the Farnsworth-Munsell 100-hue test (FM100) to determine whether performance on the local and global shape tasks correlated with colour discrimination overall, or with performance on the L-M and tritan subsets of the FM100 test. Overall performance on the local and global shape tasks did correlate with scores on the FM100 tests, despite the colour of the background being irrelevant to the shape tasks. There were also significantly larger associations between scores for the L-M subset of the FM100 test, compared to the tritan subset, and accuracy on some of the shape tasks on the reddish, greenish and neutral backgrounds. Participants also completed the non-verbal components of the WAIS and the SPM+ version of Raven's progressive matrices, to determine whether performance on the FM100 test, and on the local and global shape tasks, correlated with NVIQ. FM100 scores correlated significantly with both WAIS and SPM+ scores. These results extend previous work that has indicated FM100 performance is not purely a measure of colour discrimination, but also involves aspects of each participant's NVIQ, such as the ability to attend to local and global aspects of the test, part-whole relationships, perceptual organisation and good visuomotor skills. Overall performance on the local and global shape tasks correlated only with the WAIS scores, not the SPM+. These results indicate that those aspects of NVIQ that engage spatial comprehension of local-global relationships and manual manipulation (WAIS), rather than more abstract reasoning (SPM+), are related to performance on the local and global shape tasks. Links are presented between various measures of NVIQ and performance on visual tasks, but they are currently seldom addressed in studies of either shape or colour perception. Further studies to explore these issues are recommended.

Visual motion processing in migraine: Enhanced motion after-effects are related to display contrast, visual symptoms, visual triggers and attack frequency.

Background Visual after-effects are illusions that occur after prolonged viewing of visual displays. The motion after-effect (MAE), for example, is an illusory impression of motion after viewing moving displays: subsequently, stationary displays appear to drift in the opposite direction. After-effects have been used extensively in basic vision research and in clinical settings, and are enhanced in migraine. Objective The objective of this article is to assess associations between ( 1 ) MAE duration and visual symptoms experienced during/between migraine/headache attacks, and ( 2 ) visual stimuli reported as migraine/headache triggers. Methods The MAE was elicited after viewing motion for 45 seconds. MAE duration was tested for three test contrast displays (high, medium, low). Participants also completed a headache questionnaire that included migraine/headache triggers. Results For each test contrast, the MAE was prolonged in migraine. MAE duration was associated with photophobia; visual triggers (flicker, striped patterns); and migraine or headache frequency. Conclusions Group differences on various visual tasks have been attributed to abnormal cortical processing in migraine, such as hyperexcitability, heightened responsiveness and/or a lack of intra-cortical inhibition. The results are not consistent with hyperexcitability simply from a general lack of inhibition. Alternative multi-stage models are discussed and suggestions for further research are recommended, including visual tests in clinical assessments/clinical trials.

Enhanced Motion Aftereffects in Migraine Are Related to Contrast Sensitivity: Implications for Models of Differences in Precortical/Cortical Function.

PURPOSE: Visual tests can be used as noninvasive tools to test models of the pathophysiology underlying neurological conditions, such as migraine. For example, there are reports that the motion aftereffect, which involves neural processing in several cortical areas, is prolonged in migraine. There also are reports of impaired contrast sensitivity in migraine, however, attributed to a precortical dysfunction. This study explored associations between these two tests of visual function. Specifically, it aimed to clarify whether the magnitude of the motion aftereffect is affected by contrast and contrast sensitivity. METHODS: The motion aftereffect was elicited after observers viewed a coherently moving pattern for 45 seconds. The duration of the subsequent aftereffect was measured with three different test display contrasts (high, medium, low). Contrast sensitivity also was assessed. RESULTS: For each test display contrast, the motion aftereffect was prolonged in migraine compared to the control group. Contrast sensitivity was poorer in the migraine group and was a significant predictor of motion aftereffect duration. CONCLUSIONS: These results suggest an anomaly in early motion processing pathways in migraine that likely is linked with those pathways underlying contrast sensitivity. They provide further evidence for differences in visual processing that begin early, potentially starting at the retina, which have consequences for performance on tasks that putatively examine cortical processing. Differences in precortical and cortical visual pathways are implicated in the pathophysiology underlying migraine.

Attention training normalises combat-related post-traumatic stress disorder effects on emotional Stroop performance using lexically matched word lists.

We examined two groups of combat veterans, one with post-traumatic stress disorder (PTSD) (n = 27) and another without PTSD (n = 16), using an emotional Stroop task (EST) with word lists matched across a series of lexical variables (e.g. length, frequency, neighbourhood size, etc.). Participants with PTSD exhibited a strong EST effect (longer colour-naming latencies for combat-relevant words as compared to neutral words). Veterans without PTSD produced no such effect, t < .918, p > .37. Participants with PTSD then completed eight sessions of attention training (Attention Control Training or Attention Bias Modification Training) with a dot-probe task utilising threatening and neutral faces. After training, participants-especially those undergoing Attention Control Training-no longer produced longer colour-naming latencies for combat-related words as compared to other words, indicating normalised attention allocation processes after treatment.

Age- and sex-specific differences in blood-borne microvesicles from apparently healthy humans.

BACKGROUND: Sex differences in incidence of cardiovascular disease may reflect age-associated intravascular cellular activation resulting in shedding of cell membrane-derived bioactive microvesicles (MV or microparticles) into the blood. Concentrations of cell-specific MV in blood have the potential to be a diagnostic/prognostic marker of pathology, but ranges of MV must first be established in healthy individuals. This study identified cellular origin of blood-borne MV >0.2 µm in blood of apparently healthy women and men aged from 20-70 years. METHODS: Venous blood from apparently healthy participants in the Mayo Clinic Biobank was collected into tubes containing protease inhibitors as the anticoagulant. MV were isolated by standardized differential centrifugation and characterized by digital flow cytometer. Each cellular origin of MV was verified by two different antibodies with strong correlation between the two distinct antibodies (e.g., for platelet-derived MV, r (2) = 0.97). RESULTS: MV derived from platelets were the most abundant type of MV in blood from women and men in all age groups. Total numbers of phosphatidylserine, P-selectin, and platelet- and endothelium-derived MV were significantly (P < 0.05) greater in women than men. Numbers of MV from erythrocytes and stem/progenitor cells were significantly lower in premenopausal women than age-matched men. Number of tissue factor pathway inhibitor positive MV were significantly (P < 0.05) lower whereas erythrocyte-derived MV were significantly higher in postmenopausal women compared to premenopausal women. In women, there was a positive relationship between age and erythrocyte-derived MV (ρ = 0.28; P = 0.009), while in men adipocyte-derived MV increased with age (ρ = 0.33; P = 0.01). CONCLUSIONS: This study provides ranges for cellular origin of blood-borne MV in age-matched, apparently healthy women and men from which to compare diagnostic and prognostic uses of blood-borne MV in larger studies and patient population. In addition, sex- and age-specific differences in phosphatidylserine, platelet-, endothelium-, erythrocyte-, and adipocyte-derived blood-borne MV may contribute to differential progression of cardiovascular disease in women compared to men.

Generality and specificity in the effects of musical expertise on perception and cognition.

Performing musicians invest thousands of hours becoming experts in a range of perceptual, attentional, and cognitive skills. The duration and intensity of musicians' training - far greater than that of most educational or rehabilitation programs - provides a useful model to test the extent to which skills acquired in one particular context (music) generalize to different domains. Here, we asked whether the instrument-specific and more instrument-general skills acquired during professional violinists' and pianists' training would generalize to superior performance on a wide range of analogous (largely non-musical) skills, when compared to closely matched non-musicians. Violinists and pianists outperformed non-musicians on fine-grained auditory psychophysical measures, but surprisingly did not differ from each other, despite the different demands of their instruments. Musician groups did differ on a tuning system perception task: violinists showed clearest biases towards the tuning system specific to their instrument, suggesting that long-term experience leads to selective perceptual benefits given a training-relevant context. However, we found only weak evidence of group differences in non-musical skills, with musicians differing marginally in one measure of sustained auditory attention, but not significantly on auditory scene analysis or multi-modal sequencing measures. Further, regression analyses showed that this sustained auditory attention metric predicted more variance in one auditory psychophysical measure than did musical expertise. Our findings suggest that specific musical expertise may yield distinct perceptual outcomes within contexts close to the area of training. Generalization of expertise to relevant cognitive domains may be less clear, particularly where the task context is non-musical.

An inability to exclude visual noise in migraine.

PURPOSE: People with migraine are relatively poor at judging the direction of motion of coherently moving signal dots when interspersed with noise dots drifting in random directions, a task known as motion coherence. Although this has been taken as evidence of impoverished global pooling of motion signals, it could also arise from unreliable coding of local direction (of each dot), or an inability to segment signal from noise (noise-exclusion). The aim of this study was to determine how these putative limits contribute to impoverished motion processing in migraine. METHODS: Twenty-two participants with migraine (mean age, 34.7 ± 8.3 years; 16 female) and 22 age- and sex-matched controls (mean age, 34.4 ± 6.2 years) performed a motion-coherence task and a motion-equivalent noise task, the latter quantifying local and global limits on motion processing. In addition, participants were tested on analogous equivalent noise paradigms involving judgments of orientation and size, so that the specificity of any findings (to visual dimension) could be ascertained. RESULTS: Participants with migraine exhibited higher motion-coherence thresholds than controls (P = 0.01, independent t-test). However, this difference could not be attributed to deficits in either local or global processing since they performed normally on all equivalent noise tasks (P > 0.05, multivariate ANOVA). CONCLUSIONS: These findings indicate that motion perception in the participants with migraine was limited by an inability to exclude visual noise. We suggest that this is a defining characteristic of visual dysfunction in migraine, a theory that has the potential to integrate a wide range of findings in the literature.

Color and spatial frequency are related to visual pattern sensitivity in migraine.

OBJECTIVE: To assess the potential for particular colors to alleviate visual discomfort when people with migraine view repetitive geometric or striped patterns. BACKGROUND: Visual stimuli, such as flicker, glare, or stripes, can trigger migraine and headache. They can also elicit feelings of discomfort and aversion. There are reports that color can be used to decrease the experience of discomfort and reduce migraine frequency. DESIGN/METHODS: Five sets of striped patterns (3, 12 cycles per degree [cpd]) were created using cardinal colors tailored to selectively stimulate the early visual pathways: achromatic (black/white), tritan (black/purple, black/yellow), protan/deutan (black/red, black/green). All had the same high luminance contrast (0.9 Michelson contrast). Twenty-eight migraine (14 migraine with aura, 14 migraine without aura) and 14 control participants rated the discomfort and described the distortions seen in these patterns. They were also assessed for visual migraine/headache triggers, contrast sensitivity, color vision, acuity, stereopsis, visual discomfort from reading, and dyslexia. RESULTS: In the migraine groups, a comparable number of illusions were seen with the 3 and 12 cpd achromatic gratings, whereas in the control group the greatest number was seen with the 3 cpd grating. In the migraine groups only, all 4 colors reduced, to some extent, the number of illusions and 2 decreased the discomfort, particularly for the 12 cpd gratings. There were significant group differences for contrast sensitivity, reported visual migraine/headache triggers, and the visual discomfort scale. There were a few significant correlations between the different measures, notably between the achromatic visual discomfort measures and reports of visual migraine triggers. CONCLUSIONS: Color, independent of luminance or particular color contrasts, can have therapeutic effects for people with visually triggered migraine as it can reduce the number of perceived illusions when viewing stripes or text. The effect was not color-specific and was greatest for the 12 cpd gratings. Given the significant associations between the achromatic discomfort measures and reports of visual triggers, and the lack of significant associations between the chromatic discomfort measures and reports of visual triggers, further research is recommended to explore the potential to reduce the number of visually triggered migraines with color in addition to alleviating visual discomfort.

Motion processing deficits in migraine are related to contrast sensitivity.

BACKGROUND: There are conflicting reports concerning the ability of people with migraine to detect and discriminate visual motion. Previous studies used different displays and none adequately assessed other parameters that could affect performance, such as those that could indicate precortical dysfunction. METHODS: Motion-direction detection, discrimination and relative motion thresholds were compared from participants with and without migraine. Potentially relevant visual covariates were included (contrast sensitivity; acuity; stereopsis; visual discomfort, stress, triggers; dyslexia). RESULTS: For each task, migraine participants were less accurate than a control group and had impaired contrast sensitivity, greater visual discomfort, visual stress and visual triggers. Only contrast sensitivity correlated with performance on each motion task; it also mediated performance. CONCLUSIONS: Impaired performance on certain motion tasks can be attributed to impaired contrast sensitivity early in the visual system rather than a deficit in cortical motion processing per se. There were, however, additional differences for global and relative motion thresholds embedded in noise, suggesting changes in extrastriate cortex in migraine. Tasks to study the effects of noise on performance at different levels of the visual system and across modalities are recommended. A battery of standard visual tests should be included in any future work on the visual system and migraine.

Visual metacontrast masking in migraine.

BACKGROUND: In visual metacontrast masking, the visibility of a brief target stimulus can be reduced substantially if it is preceded (forward masking) or followed (backward masking) by a non-overlapping mask. These effects have been attributed to inhibitory processes within the visual system. Two previous studies have used metacontrast masking to assess inhibitory function in migraine and control groups, however, each used different types of masking and obtained different results. SUBJECTS AND METHODS: Forward, backward and combined forward and backward masking were compared in migraine (15 with visual aura, 15 without) and control (n = 15) groups. Baseline trials were also included (target only). RESULTS: For all types of masking, both migraine groups were more accurate than the control group. When performance for the masking trials was expressed relative to baseline, however, there were no significant group differences. Performance in certain conditions nevertheless correlated significantly with migraine frequency and with the recency of the last attack. CONCLUSIONS: The inhibitory processes involved in the masking tasks employed in this study do not appear to be impaired in migraine. Their better overall performance may reflect a sensitivity difference, perhaps as a consequence of a heightened neuronal response, which varies with the migraine cycle.

Peri-ictal changes of cortical excitability in children suffering from migraine without aura.

In adult patients with migraine, transcranial magnetic stimulation (TMS) has been used to examine cortical excitability between attacks, but there have been discrepant results. No TMS study has examined cortical excitability in children or adolescents with migraine. Here, we employed TMS to study regional excitability of the occipital (phosphene threshold [PT] and suppression of visual perception) and motor (resting motor threshold and cortical silent period) cortex in ten children suffering from migraine without aura and ten healthy age-matched controls. Patients were studied 1-2 days before and after a migraine attack as well as during the inter-migraine interval. The motion aftereffect was also investigated at each time-point as an index of cortical reactivity to moving visual stimuli. Migraineurs had lower PTs compared to healthy participants at each time-point, indicating increased occipital excitability. This increase in occipital excitability was attenuated 1-2 days before a migraine attack as indicated by a relative increase in PTs. The increase in PTs before the next attack was associated with a stronger TMS-induced suppression of visual perception and a prolongation of the motion aftereffect. Motor cortex excitability was not altered in patients and did not change during the migraine cycle. These findings show that pediatric migraine without aura is associated with a systematic shift in occipital excitability preceding the migraine attack. Similar systematic fluctuations in cortical excitability might be present in adult migraineurs and may reflect either a protective mechanism or an abnormal decrease in cortical excitability that predisposes an individual to a migraine attack.

Visual pattern adaptation in subjects with photoparoxysmal EEG response: evidence for increased visual cortical excitability.

PURPOSE: Photosensitivity, or photoparoxysmal response (PPR), is an abnormal EEG reaction to intermittent photic stimulation (IPS), consisting of spikes, spike-waves, and intermittent slow waves. Depending on the spread of the abnormal activity, PPR subgroups have been defined as having either propagating PPR or localized, occipital spikes (OS) only. Recent research suggests an enhanced excitability in the occipital cortex may underlie this reaction during IPS, but it remains unclear whether changes in excitability affect the function of the occipital cortex to other, less provocative visual stimuli. In this study, cortical function in photosensitivity was assessed using two visual aftereffects that occur after prolonged adaptation. METHODS: Motion and tilt aftereffects were compared in healthy subjects with (n = 14, seven with propagating PPR, seven with OS) or without (n = 14) PPR. RESULTS: The duration of the motion aftereffect was shorter in the PPR group than in the control group. The size of the tilt aftereffect did not differ between the groups. Thirteen from each group had participated in an earlier study in which occipital transcranial magnetic stimulation (TMS) was used to elicit phosphenes and to suppress the perception of briefly presented letters. The TMS intensity required to elicit phosphenes correlated with the size of the tilt aftereffect (TAE) in the PPR group only. CONCLUSIONS: This study provides further evidence of enhanced cortical excitability in subjects with photosensitivity, which is likely to reflect changes in excitatory neurotransmission.