Individual Subject Analyses Research Articles

Double jeopardy in inferring cognitive processes.

Inferences we make about underlying cognitive processes can be jeopardized in two ways due to problematic forms of aggregation. First, averaging across individuals is typically considered a very useful tool for removing random variability. The threat is that averaging across subjects leads to averaging across different cognitive strategies, thus harming our inferences. The second threat comes from the construction of inadequate research designs possessing a low diagnostic accuracy of cognitive processes. For that reason we introduced the systems factorial technology (SFT), which has primarily been designed to make inferences about underlying processing order (serial, parallel, coactive), stopping rule (terminating, exhaustive), and process dependency. SFT proposes that the minimal research design complexity to learn about n number of cognitive processes should be equal to 2n. In addition, SFT proposes that (a) each cognitive process should be controlled by a separate experimental factor, and (b) The saliency levels of all factors should be combined in a full factorial design. In the current study, the author cross combined the levels of jeopardies in a 2 × 2 analysis, leading to four different analysis conditions. The results indicate a decline in the diagnostic accuracy of inferences made about cognitive processes due to the presence of each jeopardy in isolation and when combined. The results warrant the development of more individual subject analyses and the utilization of full-factorial (SFT) experimental designs.

The role of the dominant versus the non-dominant hemisphere: An fMRI study of Aphasia recovery following stroke

Background: Speech production is one of the most frequently affected cognitive functions following stroke; however, the neural mechanisms underlying the recovery of speech function are still incompletely understood.Aims: The current study aims to address the differential contributions of the dominant and non-dominant hemispheres in recovery from aphasia following stroke by comparing data from four stroke patients and 12 control participants to assess the patterns of activation during speech production tasks during functional magnetic resonance imaging (fMRI) scanning.Methods & Procedures: Four chronic stroke patients (three left-hemisphere lesion and one right-hemisphere lesion) diagnosed with Broca’s aphasia at the acute phase, but now recovered to near normal speech ability, were tested on speech production tasks (phonemic fluency, categorical fluency and picture naming) whilst undergoing fMRI. These patients were compared with 12 healthy controls undergoing the same procedure.Outcomes & Results: Individual subject analysis showed activation peaks in perilesional areas in three out of four patients. This included one patient with right-hemisphere lesion, who also showed predominant perilesional activation. Group analysis of control participants showed predominately left-hemisphere activation, but not exclusively so. Laterality indexes were calculated and showed predominant left-hemisphere lateralisation in the control group (LI = 0.4). Three out of the four patients showed speech lateralised to the same hemisphere as their lesion and the fourth patient showed speech lateralised to the opposite hemisphere to their lesion. Different speech production tasks resulted in varying lateralisation indices (LIs) within participants.Conclusions: The data suggest that perilesional areas support recovery of speech in the chronic phase post-stroke regardless of the site of the lesion. The study has implications for the understanding of functional recovery as well as for the paradigms used in fMRI to localise speech production areas. Specifically, a variety of speech tasks are required to elicit activation that is representative of the range of cortical involvement in speech in healthy adults and that also allows for accurate reporting of the extent of recovery experienced in patients.

Geodesic distances to landmarks for dense correspondence on ensembles of complex shapes.

Establishing correspondence points across a set of biomedical shapes is an important technology for a variety of applications that rely on statistical analysis of individual subjects and populations. The inherent complexity (e.g. cortical surface shapes) and variability (e.g. cardiac chambers) evident in many biomedical shapes introduce significant challenges in finding a useful set of dense correspondences. Application specific strategies, such as registration of simplified (e.g. inflated or smoothed) surfaces or relying on manually placed landmarks, provide some improvement but suffer from limitations including increased computational complexity and ambiguity in landmark placement. This paper proposes a method for dense point correspondence on shape ensembles using geodesic distances to a priori landmarks as features. A novel set of numerical techniques for fast computation of geodesic distances to point sets is used to extract these features. The proposed method minimizes the ensemble entropy based on these features, resulting in isometry invariant correspondences in a very general, flexible framework.

Comparison of 2D and 3D single-shot ASL perfusion fMRI sequences

Arterial spin labeling (ASL) can be implemented by combining different labeling schemes and readout sequences. In this study, the performance of 2D and 3D single-shot pulsed-continuous ASL (pCASL) sequences was assessed in a group of young healthy volunteers undergoing a baseline perfusion and a functional study with a sensory-motor activation paradigm. The evaluated sequences were 2D echo-planar imaging (2D EPI), 3D single-shot fast spin-echo with in-plane spiral readout (3D FSE spiral), and 3D single-shot gradient-and-spin-echo (3D GRASE). The 3D sequences were implemented with and without the addition of an optimized background suppression (BS) scheme. Labeling efficiency, signal-to-noise ratio (SNR), and gray matter (GM) to white matter (WM) contrast ratio were assessed in baseline perfusion measurements. 3D acquisitions without BS yielded 2-fold increments in spatial SNR, but no change in temporal SNR. The addition of BS to the 3D sequences yielded a 3-fold temporal SNR increase compared to the unsuppressed sequences. 2D EPI provided better GM-to-WM contrast ratio than the 3D sequences. The analysis of functional data at the subject level showed a 3-fold increase in statistical power for the BS 3D sequences, although the improvement was attenuated at the group level. 3D without BS did not increase the maximum t-values, however, it yielded larger activation clusters than 2D. These results demonstrate that BS 3D single-shot imaging sequences improve the performance of pCASL in baseline and activation studies, particularly for individual subject analyses where the improvement in temporal SNR translates into markedly enhanced power for task activation detection.

FMRI group analysis combining effect estimates and their variances

Conventional functional magnetic resonance imaging (FMRI) group analysis makes two key assumptions that are not always justified. First, the data from each subject is condensed into a single number per voxel, under the assumption that within-subject variance for the effect of interest is the same across all subjects or is negligible relative to the cross-subject variance. Second, it is assumed that all data values are drawn from the same Gaussian distribution with no outliers. We propose an approach that does not make such strong assumptions, and present a computationally efficient frequentist approach to FMRI group analysis, which we term mixed-effects multilevel analysis (MEMA), that incorporates both the variability across subjects and the precision estimate of each effect of interest from individual subject analyses. On average, the more accurate tests result in higher statistical power, especially when conventional variance assumptions do not hold, or in the presence of outliers. In addition, various heterogeneity measures are available with MEMA that may assist the investigator in further improving the modeling. Our method allows group effect t-tests and comparisons among conditions and among groups. In addition, it has the capability to incorporate subject-specific covariates such as age, IQ, or behavioral data. Simulations were performed to illustrate power comparisons and the capability of controlling type I errors among various significance testing methods, and the results indicated that the testing statistic we adopted struck a good balance between power gain and type I error control. Our approach is instantiated in an open-source, freely distributed program that may be used on any dataset stored in the universal neuroimaging file transfer (NIfTI) format. To date, the main impediment for more accurate testing that incorporates both within- and cross-subject variability has been the high computational cost. Our efficient implementation makes this approach practical. We recommend its use in lieu of the less accurate approach in the conventional group analysis.

What Does Broca's Area Activation to Sentences Reflect?

There is no doubt that listening to or reading sentences activates the left frontal lobe structures in and around Brocaʼs area. The question is, what process(es) does this activation reflect? In our recent critical review of this literature (Rogalsky & Hickok, 2011) we questioned whether any of this activation reflects processes that are specific to receptive sentence processing. Specifically, we pointed out that sentence activation in the pars opercularis overlaps with activations induced by speech articulation, whereas more anterior (pars triangularis/orbitalis) and dorsal (middle frontal gyrus) sentence-elicited activations overlap with activations induced by cognitive control tasks. Given that sentence processing may be assisted by nonspecific functions such as articulatory rehearsal and cognitive control, this raises serious questions regarding the sentence specificity of activations in Brocaʼs area and vicinity during comprehension. We concluded that the pars opercularis supports sentence comprehension via articulatory rehearsal mechanisms (phonological STM), whereas more anterior and dorsal areas may support sentence processing via some, as yet undetermined, higher-order process such as cognitive control. Additional arguments for this position were also put forward. Federenko and Kanwisher (FK Daneman & Newson, 1992; Slowiaczek & Clifton, 1980; Baddeley, Thomson, & Buchanan, 1975), and an explicit memory probe task may induce articulatory rehearsal. There is little doubt that Brocaʼs area and vicinity play some role in speech production, including sentencerelated processes (e.g., agrammatism is a common correlate of left frontal lesions). Therefore, the differences between sentences and word lists in F&Kʼs data may be a result of covertly producing sentences rather than comprehending them. Our claims specifically target sentence comprehension. A previous study of ours directly assessed the role of production-related processes in driving activations in Brocaʼs area during the performance of a complex sentence comprehension task, semantic plausibility judgment (Rogalsky, Matchin, & Hickok, 2008). We reasoned that sentences that are particularly difficult to understand, such as object-relative clauses, may induce articulatory rehearsal to assist in task performance, compared with simpler sentences, which should rely to a lesser extent on such mechanisms. We found that Brocaʼs area responded more to complex than simple sentences, but that an articulation task, assessed within-subjects, completely overlapped the activation in posterior sectors (pars opercularis) and that the “sentence complexity effect” in this region did not emerge when subjects comprehended sentences during concurrent articulation (articulatory suppression). In other words, articulatory processes explain the Brocaʼs area activation to sentences, at least in the posterior sector. In the anterior sector (pars triangularis), a sentence complexity effect persisted even during concurrent articulation. However, this effect disappeared during a concurrent finger-tapping task, again suggesting that the sentence activations in Brocaʼs area are not sentence specific. University of California-Irvine, University of Southern California

Age-related differences in processing task-irrelevant stimulus properties: a single-trial ERP study

We quantified age-related differences in processing task-irrelevant stimulus properties. In each trial, thirteen young (<32 years old) and ten older (>60 years old) participants saw one of two pre-learnt faces colourised with red or green tones at one of eight phase noise levels while scalp ERPs were recorded. In one condition, subjects had to discriminate between the identities of the two faces ignoring colour, whereas they had to ignore face identity and discriminate colour in the other condition. Behavioural accuracy followed a noise dependent sigmoid in the identity task: older participants had a significantly higher 75% correct discrimination threshold and a lower maximum accuracy. Whereas in the colour task, performance was independent of the noise level and both groups showed equally high accuracy (above 98%). For each individual in the two tasks the time-course of phase noise sensitivity was obtained by entering ERPs into a single-trial general linear model [http://www.biomedcentral.com/1471-2202/9/98]. The model identified variations in neural activity statistically associated with changes in phase noise while regressing out the main ERP differences due to identity, colour and task. Group level analysis indicated that young adults showed higher noise sensitivity in the identity task than in the colour task between circa 170 and 270 ms post-stimulus, whereas older adults did not show any task differences. Results from our study, as well as from other recent studies that reported the absence of task effects in old participants in a variety of visual attention paradigms, suggest that the ability to process only relevant visual information may be compromised in all older adults. However, individual subject analysis revealed that most older subjects did show task modulations whose timing and duration varied extensively. We suggest that individual subject single-trial analysis is a useful tool which provides a deeper insight into age-related changes in top-down visual processing.

Risky decision-making in older adults without cognitive deficits: An fMRI study of VMPFC using the Iowa Gambling Task

Some older adults without neurological disease exhibit impaired decision-making in risky, nontransparent situations, like the Iowa Gambling Task (IGT). The prefrontal cortices are particularly vulnerable to age-related decline, and numerous studies implicate the ventromedial prefrontal cortex (VMPFC) in successful IGT performance. However, the relationship between IGT performance and VMPFC function in older adults has not yet been tested by fMRI. In the present study, older adults with seemingly no cognitive impairments performed the IGT and a non-gambling control task during fMRI. Group analyses indicate that in these older adults, regardless of IGT performance level, a right VMPFC subregion is activated during the IGT, while successful IGT performance is correlated with left VMPFC activation, suggesting that bilateral VMPFC during risky, nontransparent situations may contribute to successful decision-making in older adults. Individual subject analyses reveal substantial variation regarding the extent and location of VMPFC activation during the IGT, a finding not captured in the group analysis: There is no correlation between IGT performance and extent of activation in the right VMPFC, although there is such a correlation between left VMPFC activation and IGT performance.

Pharmacokinetics of Single-Dose Intravenous Ketorolac in Infants Aged 2–11 Months

Ketorolac is a parenterally available nonsteroidal antiinflammatory drug that nonselectively inhibits cyclooxygenase. Ketorolac is an attractive alternative to opioids in the pediatric population because of its favorable side effect profile; it provides postoperative analgesia similar to morphine, but is associated with significantly less respiratory depression, pruritus, and emesis. Despite the efficacy of ketorolac in young patients, there are minimal data to characterize the pharmacokinetic variables of ketorolac in infants younger than 6 months. In this study, 17 infants younger than 1 year old, without renal or liver disease, undergoing elective surgery received a single-dose of IV ketorolac 0.5 mg/kg. Blood was sampled at 0, 5, 10, 15, 30, 60, and 120 minutes, and at 4, 6, 12, and 24 hours. Ketorolac levels were analyzed using a specific and validated high-performance liquid chromatography method with mass spectrometry (LC-LC/MS/MS). Pharmacokinetic analysis of individual subjects and population pharmacokinetic modeling was performed using SAAM II and PopKinetics, respectively (SAAM Institute, University of Washington). Characterization of pharmacokinetic parameters was possible in 14 subjects. The data were best described by a 2-compartment model. Estimated individual parameters were clearance 1.49 ± 1.12 mL/min/kg, Vss (volume of distribution at steady state) 0.31 ± 0.11 L/kg, and half-life of 236 ± 169 minutes. Estimated population pharmacokinetic parameters were clearance 1.52 mL/min/kg and Vss 0.29 L/kg. There was a trend toward lower clearances in younger patients. This is the first report of individualized pharmacokinetic parameters of ketorolac in children in which the majority of subjects were younger than 6 months old.

Functional magnetic resonance imaging reveals age-related alterations to motor networks in weighted elbow flexion–extension movement

Objective: we investigated whether motor system activity in normal aging shows age-related alteration during a non-isomeric elbow flexion–extension movement task using weights.Methods: Twenty-six healthy, right-handed elderly and 20 healthy, right-handed young subjects without any psychiatric, neurological, or medical disease participated in this study. All subjects underwent two consecutive scanning sessions: one without weights, and one with weights. During the weights session, each subject held a small non-metallic bar (weighing approximately 1 kg) with their dominant hand and performed elbow flexion and extension movements. Functional magnetic resonance imaging BOLD contrast was obtained for each subject using a 3.0 T MRI scanner. Image processing and statistical analyses were carried out using SPM2. In fMRI data group analysis, contrast images from the analysis of individual subjects were analysed by one-sample t-tests, thereby generating a random-effects model, allowing inference to the general population. The SPM{t}s were thresholded at P<0.01, false discovery rate (FDR) corrected for multiple comparisons across the whole brain. Finally, the resulting activation maps were created and displayed by projection onto the anatomically standardized mean T1 image of all subjects to identify the anatomical correlates of the activity.Results: It was revealed that the main change in the aging brain was significant activation of the ipsilateral basal ganglia–thalamo–cortical motor loop in older subjects, suggesting the recruitment of additional brain areas during the execution of a weighted elbow motor task as a compensation process for age-related neurobiological change.Conclusion: The current study is the first to demonstrate significant differences in brain activation between old and young subjects during weighted elbow flexion–extension movement when both the old and young groups maintain the same performance level. In particular, overactivation of the basal ganglia in the aging brain appears to play a crucial role in counteracting age-related decline of force generation and to support the same level of performance as that of younger counterparts.

Cognitive and behavioural deficits associated with the orbitomedial prefrontal cortex in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis, a progressive disease affecting motor neurons, may variably affect cognition and behaviour. We tested the hypothesis that functions associated with orbitomedial prefrontal cortex are affected by evaluating the behavioural and cognitive performance of 18 participants with amyotrophic lateral sclerosis without dementia and 18 healthy, matched controls. We measured Theory of Mind (Faux Pas Task), emotional prosody recognition (Aprosodia Battery), reversal of behaviour in response to changes in reward (Probabilistic Reversal Learning Task), decision making without risk (Holiday Apartment Task) and aberrant behaviour (Neuropsychiatric Inventory). We also assessed dorsolateral prefrontal function, using verbal and written fluency and planning (One-touch Stockings of Cambridge), to determine whether impairments in tasks sensitive to these two prefrontal regions co-occur. The patient group was significantly impaired at identifying social faux pas, recognizing emotions and decision-making, indicating mild, but consistent impairment on most measures sensitive to orbitomedial prefrontal cortex. Significant levels of aberrant behaviour were present in 50% of patients. Patients were also impaired on verbal fluency and planning. Individual subject analyses involved computing classical dissociations between tasks sensitive to different prefrontal regions. These revealed heterogeneous patterns of impaired and spared cognitive abilities: 33% of participants had classical dissociations involving orbitomedial prefrontal tasks, 17% had classical dissociations involving dorsolateral prefrontal tasks, 22% had classical dissociations between tasks of both regions, and 28% had no classical dissociations. These data indicate subtle changes in behaviour, emotional processing, decision-making and altered social awareness, associated with orbitomedial prefrontal cortex, may be present in a significant proportion of individuals with amyotrophic lateral sclerosis without dementia, some with no signs of dysfunction in tasks sensitive to other regions of prefrontal cortex. This demonstration of variability in cognitive integrity supports previous research indicating amyotrophic lateral sclerosis is a heterogeneous disease.

Advances and pitfalls in the analysis and interpretation of resting-state FMRI data

The last 15 years have witnessed a steady increase in the number of resting-state functional neuroimaging studies. The connectivity patterns of multiple functional, distributed, large-scale networks of brain dynamics have been recognised for their potential as useful tools in the domain of systems and other neurosciences. The application of functional connectivity methods to areas such as cognitive psychology, clinical diagnosis and treatment progression has yielded promising preliminary results, but is yet to be fully realised. This is due, in part, to an array of methodological and interpretative issues that remain to be resolved. We here present a review of the methods most commonly applied in this rapidly advancing field, such as seed-based correlation analysis and independent component analysis, along with examples of their use at the individual subject and group analysis levels and a discussion of practical and theoretical issues arising from this data ‘explosion’. We describe the similarities and differences across these varied statistical approaches to processing resting-state functional magnetic resonance imaging signals, and conclude that further technical optimisation and experimental refinement is required in order to fully delineate and characterise the gross complexity of the human neural functional architecture.

Late Emergence of Cognitive Deficits After Unilateral Neonatal Stroke

Neonatal arterial ischemic stroke (AIS) affects a surprisingly large number of children each year, yet little is known about the long-term neuropsychological implications. Using age-appropriate Wechsler scales of intellectual ability, this longitudinal study examined 26 children with a history of acutely diagnosed unilateral neonatal AIS as preschoolers (3 years 6 months to 5 years 11 months) and again as grade-school students (6 years 1 month to 12 years 5 months), and contrasted performance with the normative sample of the test. As preschoolers, patients' performance did not differ from the normative sample for Full Scale IQ, Verbal IQ, or Performance IQ, and there were no significant differences associated with infarct laterality. As school-age children, performance was significantly lower than the normative sample for Full Scale IQ Working Memory and Processing Speed, but not for Verbal IQ or Performance IQ. Contrasts between Time 1 and Time 2 revealed a significant decline in Full Scale IQ, which reflected emerging deficits in nonverbal reasoning, working memory, and processing speed. Individual subject analyses revealed that 69% of the children showed significant declines in 1 or more IQ index measures. We found no significant differences in cognitive performance associated with lesion laterality, though males performed more poorly than females on several cognitive measures at Time 2. These findings suggest that children with unilateral neonatal stroke, particularly males, are at increased risk for emerging deficits in higher-level cognitive skills during the school years. Continued follow-up of these children is needed, even those with no apparent deficits as toddlers or preschoolers.

Expertise with characters in alphabetic and nonalphabetic writing systems engage overlapping occipito-temporal areas

Parts of the left ventral visual pathway are engaged selectively during the perception of words, letter strings, and even single letters. While studies have shown overlap between activations for letters and characters across writing systems, they adopted group analyses with very limited spatial resolution, or used words and letter strings that have been shown to activate different regions from those activated by single characters. The current study compared activity within individual participants for the perception of single characters from different writing systems. Roman letters, Chinese characters, objects, and faces were presented to Chinese–English bilinguals and English readers with no Chinese reading experience. Individual subject analyses revealed a large overlap between Roman- and Chinese-selective areas in the bilinguals. In general, the activity in the Roman-selective area of the left hemisphere is associated with experience with the script, as non-Chinese readers showed lower activations to Chinese characters than to Roman letters. Further analyses found considerable variation within non-Chinese readers in the activation for Chinese characters: While the majority had no selectivity for Chinese characters at all, some showed activations for Chinese characters at locations similar to those selective for Roman letters. The results suggest that both stimulus properties and experience are important factors in determining the response to single characters across writing systems.

Exploratory structural equation modeling of resting-state fMRI: Applicability of group models to individual subjects

The extension of group-level connectivity methods to individual subjects remains a hurdle for statistical analyses of neuroimaging data. Previous group analyses of positron emission tomography data in clinically depressed patients, for example, have shown that resting-state connectivity prior to therapy predicts how patients eventually respond to pharmacological and cognitive–behavioral therapy. Such applications would be considerably more informative for clinical decision making if these connectivity methods could be extended into the individual subject domain. To test such an extension, 46 treatment-naïve depressed patients were enrolled in an fMRI study to model baseline resting-state functional connectivity. Resting-state fMRI scans were acquired and submitted to exploratory structural equation modeling (SEM) to derive the optimal group connectivity model. Jackknife and split sample tests confirm that group model was highly reproducible, and path weights were consistent across the best five group models. When this model was applied to data from individual subjects, 85% of patients fit the group model. Histogram analysis of individual subjects' paths indicate that some paths are better representative of group membership. These results suggest that exploratory SEM is a viable technique for neuroimaging connectivity analyses of individual subjects' resting-state fMRI data.

Ultrafast bold fMRI using single-shot spin-echo echo planar imaging

The choice of imaging parameters for functional MRI can have an impact on the accuracy of functional localization by affecting the image quality and the degree of blood oxygenation-dependent (BOLD) contrast achieved. By improving sampling efficiency, parallel acquisition techniques such as sensitivity encoding (SENSE) have been used to shorten readout trains in single-shot (SS) echo planar imaging (EPI). This has been applied to susceptibility artifact reduction and improving spatial resolution. SENSE together with single-shot spin-echo (SS-SE) imaging may also reduce off-resonance artifacts. The goal of this work was to investigate the BOLD response of a SENSE-adapted SE-EPI on a three Tesla scanner. Whole-brain fMRI studies of seven healthy right hand-dominant volunteers were carried out in a three Tesla scanner. fMRI was performed using an SS-SE EPI sequence with SENSE. The data was processed using statistical parametric mapping. Both, group and individual subject data analyses were performed. Individual average percentage and maximal percentage signal changes attributed to the BOLD effect in M1 were calculated for all the subjects as a function of echo time. Corresponding activation maps and the sizes of the activated clusters were also calculated. Our results show that susceptibility artifacts were reduced with the use of SENSE; and the acquired BOLD images were free of the typical quadrature artifacts of SS-EPI. Such measures are crucial at high field strengths. SS SE-EPI with SENSE offers further benefits in this regard and is more specific for oxygenation changes in the microvasculature bed. Functional brain activity can be investigated with the help of single-shot spin echo EPI using SENSE at high magnetic fields.

Prior information and oculomotor initiation: the effect of cues in gaps

Eye movements reflect not only an important output of various neural control systems, but also often reflect cognitive processing. For example, saccades are frequently used as a behavioural index of attentional processing. A second important eye movement type, smooth pursuit (SP), has received much less attention in this regard. These two types of eye movement were classically thought of as being separate, but recent results have suggested a closer linkage of their control mechanisms and perhaps their interactions with cognitive processes. Prior information, in the form of cues, alters saccade latency leading to characteristic cueing effects. When the period between the appearance of the cue and the appearance of the saccade target is sufficiently long, the latency of saccades to targets appearing at cued locations is increased. This "inhibition of return" is enhanced by a second type of stimulus manipulation, the early removal of the fixation target a few hundred milliseconds before the target appears (the gap paradigm). In the current experiments, the effect of cues, and interactions between cues and long gaps were investigated. In the main pursuit experiment, and in a separate saccade experiment, subjects were presented with interleaved runs of tasks with and without long gaps (gap duration = 1 s), and with and without cues. In tasks without cues, SP latency was reduced by long gaps (mean reduction 8 ms); unexpectedly, saccade latency for non-cue tasks was increased by long gaps (mean increase 41 ms). In a control experiment with only non-cue tasks, in which SP and saccade gap and non-gap tasks were run together, SP latency was again reduced in gap tasks, while saccade latency was increased, but by much less than in the first experiment. Analysis of individual subjects' data showed that while gaps increased saccade latency in two subjects who had participated in the main experiment (in which cues and gaps had been combined), in two naive subjects long gaps did not affect saccade latency. In the main pursuit experiment, cues had both spatially specific and non-spatially specific (warning) effects on pursuit latency. In non-gap conditions, latency was greater when contralateral cues were presented 250 ms prior to the appearance of the pursuit target, compared to ipsilateral cues, a pattern of effect consistent with inhibition of return. However, this was reversed when cues appeared during a gap--contralateral cues increased while ipsilateral cues decreased latency. For saccades, as expected, in both gap and non-gap conditions, cue effects were consistent with inhibition of return (latency was lower with contralateral cues), and the inhibition of return effect was larger in gap, compared to non-gap conditions. The results suggest that, in appropriate contexts (or as a result of appropriate training), there are distinct inhibitory mechanisms that operate on saccades but not pursuit. What appears to be an inhibition of return effect on pursuit latency when static cues are presented in pursuit tasks, may be better understood as the product of a modulation of mechanisms active in pursuit initiation, perhaps related to motion processing. In contrast to some recent evidence suggesting a close anatomical and functional linkage between pursuit and saccade initiation, the results are consistent with the involvement of a wider range of mechanisms, or a greater degree of flexibility, in programming the initiation of these two oculomotor behaviours.

Regional neocortical thinning in mesial temporal lobe epilepsy

To determine the nature and extent of regional cortical thinning in patients with mesial temporal lobe epilepsy (MTLE). High-resolution volumetric MRIs were obtained on 21 patients with MTLE and 21 controls. Mean cortical thickness was measured within regions of interest and point-by-point across the neocortex using cortical reconstruction and parcellation software. Bilateral thinning was observed within frontal and lateral temporal regions in MTLE patients relative to controls. The most striking finding was bilateral cortical thinning in the precentral gyrus and immediately adjacent paracentral region and pars opercularis of the inferior frontal gyrus, extending to the orbital region. Within the temporal lobe, bilateral thinning was observed in Heschl's gyrus only. Ipsilateral only thinning was observed in the superior and middle temporal gyri, as well as in the medial orbital cortex. Greater asymmetries in cortical thickness were observed in medial temporal cortex in patients relative to controls. Individual subject analyses revealed that this asymmetry reflected significant ipsilateral thinning of medial temporal cortex in 33% of patients, whereas it reflected ipsilateral thickening in 20% of MTLEs. Patients with MTLE show widespread, bilateral pathology in neocortical regions that is not appreciated on standard imaging. Future studies are needed that elucidate the clinical implications of neocortical thinning in MTLE.

Open‐label use of placebos in the treatment of ADHD: a pilot study

This study examined short-term efficacy, side effects and acceptability of a placebo treatment procedure designed to maintain children with attention deficit hyperactivity disorder (ADHD) on 50% of their usual stimulant dose. An open-label prospective crossover trial was conducted in 26 children with ADHD, ages 7-15 years, stable on stimulant therapy, followed at a community-based developmental paediatrics ADHD clinic. Subjects were randomly assigned to one of two orders of experimental conditions: (1) baseline (100%) dose (1 week), then 50% dose (1 week), then 50% dose + placebo (1 week), or (2) baseline (100%), then 50% dose + placebo, then 50% dose. The inert nature of the placebo was fully disclosed to parent and child. Treatment was open-label for child, parents and physician, but single blind for teachers. Main outcome measures included weekly IOWA Conners parent and teacher rating scales, the Pittsburgh side effects rating scale (PSERS) and the Clinical Global Impressions (CGI) scale. Parent IOWA showed ADHD behaviour tended to remain the same when the dose of stimulant medication was reduced with placebo but to deteriorate when the dose was reduced without placebo. There were no significant differences between conditions on the Teacher IOWA. PSERS scores were higher at baseline than on 50% dose. On the CGI, there was a significant difference (P = 0.004) between the 50% dose and the 50% + placebo conditions. Individual subject analysis showed that eight subjects met criteria for responder. Results indicate that the open-label placebo treatment was acceptable and efficacious in the short term for some children.

Bismuth Subgallate/Borneol (Suile) Is Superior to Bacitracin in the Human Forearm Biopsy Model for Acute Wound Healing

The human forearm biopsy model can evaluate the effect of novel agents on acute wounds. Bismuth subgallate/borneol (Suile) is a new product cleared by the Food and Drug Administration for treating partial-thickness wounds. Anecdotal reports suggest that Suile may be effective for full-thickness wounds because of its antimicrobial and hemostatic properties. In a randomized, investigator-blinded study, 20 normal healthy volunteers underwent 2 6-mm full-thickness skin punch biopsies on the flexor surface of each forearm (2 wounds per subject). Biopsies were randomly assigned to control (bacitracin) and test article (Suile). Wounds were examined, measured by digital planimetry, and photographed daily until healed. Adverse events and pain levels were monitored. Time-to-complete closure was determined. Direct quantitative and qualitative comparisons of wound healing were made. The Suile group trended strongly toward more rapid healing (log-rank analysis). Individual subject arm analysis identified which biopsies healed first. Suile-treated biopsies healed more rapidly (P = .03, paired t-test). Although this study was powered to demonstrate equivalence, convincing evidence indicates that Suile is superior to bacitracin in this model. Based on the results, future studies in full-thickness wounds with Suile are warranted. The biopsy model provides these advantages: direct comparison within subjects, rapid study completion, good patient compliance, and experience with products before embarking on larger clinical trials in wounds.