Efficacy of digital cognitive behavioural therapy for symptoms of generalised anxiety disorder: a study protocol for a randomised controlled trial.

BACKGROUND: Generalised anxiety disorder (GAD) is a chronic and disabling condition with considerable personal and economic impact. Cognitive behavioural therapy (CBT) is a recommended psychological therapy for GAD; however, there are substantial barriers to accessing treatment. Digital CBT, in particular smartphone-delivered CBT, has the potential to improve accessibility and increase dissemination of CBT. Despite the emerging evidence of smartphone-based psychological interventions for reducing anxiety, effect size scores are typically smaller than in-person interventions, and there is a lack of research assessing the efficacy of smartphone-delivered digital interventions specifically for GAD. METHODS: In the DeLTA trial (DigitaL Therapy for Anxiety), we plan to conduct a parallel-group superiority randomised controlled trial examining the efficacy of a novel smartphone-based digital CBT intervention for GAD compared to a waitlist control. We aim to recruit 242 adults (aged 18 years or above) with moderate-to-severe symptoms of GAD. This trial will be conducted entirely online and will involve assessments at baseline (week 0; immediately preceding randomisation), mid-intervention (week 3), post-intervention (week 6; primary end point) and follow-up (week 10). The primary objective is to evaluate the efficacy of the intervention on GAD symptom severity compared to a waitlist control at post-intervention. Secondary objectives are to examine between-group effects on GAD at follow-up, and to examine the following secondary outcomes at both post-intervention and follow-up: 1) worry; 2) depressive symptoms; 3) wellbeing; 4) quality of life; and 5) sleep difficulty. DISCUSSION: This trial will report findings on the initial efficacy of a novel digital CBT intervention for GAD. Results have the potential to contribute towards the evidence base for digital CBT for GAD and increase the dissemination of CBT. TRIAL REGISTRATION: ISRCTN, ISRCTN12765810. Registered on 11 January 2019.

Eye tracking abnormalities in schizophrenia: evidence for dysfunction in the frontal eye fields.

BACKGROUND: Eye tracking deficits are robust abnormalities in schizophrenia, but the neurobiological disturbance underlying these deficits is not known. METHODS: To clarify the pathophysiology of eye tracking disturbances in schizophrenia, we tested 12 first-episode treatment-naive schizophrenic patients and 10 matched healthy individuals on foveofugal and foveopetal step-ramp pursuit tasks. RESULTS: On foveopetal tasks, the initiation of pursuit eye movements was delayed in schizophrenic patients, and their steady-state pursuit gain was reduced particularly at slower target speeds (8 and 16 deg/sec). In foveofugal step-ramp tasks, their primary catch-up saccades were normal in latency and accuracy, but their postsaccadic pursuit in the first 100 msec after the primary catch-up saccade was significantly reduced even relative to their slow steady-state pursuit, especially during and immediately after an acute episode of illness. CONCLUSIONS: These observations indicate that motion-sensitive areas in posterior temporal cortex provide sufficiently intact information about moving targets to guide accurate catch-up saccades, but that the sensory processing of motion information is not being used effectively for pursuit eye movements. Low-gain pursuit after the early stage of pursuit initiation suggests that the use of extraretinal signals about target motion (e.g., anticipatory prediction) only partially compensates for this deficit. The pattern of low-gain pursuit, impaired pursuit initiation, and intact processing of motion information for catch-up saccades but not pursuit eye movements, was consistent in the schizophrenic patients tested at five time points over a 2-year follow-up period, and implicates the frontal eye fields or their efferent or afferent pathways in the pathophysiology of eye tracking abnormalities in schizophrenia.

Microwave catheter design.

A microwave antenna system for transcatheter ablation of cardiac tissue is investigated. A numerical model based on the finite-difference time-domain method incorporating a Gaussian pulse excitation has been constructed and frequency domain electric and magnetic fields are obtained through Fourier transformation. Results are presented for a coaxial line fed monopole catheter which is modified by the successive inclusion of a Teflon sheath outer coating, a terminating disk at the tip of the antenna, a sleeve choke, and a high dielectric constant cylinder surrounding the monopole antenna. The effects of these design features are characterized in terms of specific absorption rate (SAR) and return loss (RL). Numerical calculations are confirmed by comparing with the RL measurement of a Teflon-coated monopole containing a disk and choke.

Positron emission tomography study of voluntary saccadic eye movements and spatial working memory.

1. The purpose of this study is to define the cortical regions that subserve voluntary saccadic eye movements and spatial working memory in humans. 2. Regional cerebral blood flow (rCBF) during performance of oculomotor tasks was measured with [15O]-H2O positron emission tomography (PET). Eleven well-trained, healthy young adults performed the following tasks: visual fixation, visually guided saccades, antisaccades (a task in which subjects made saccades away from rather than toward peripheral targets), and either an oculomotor delayed response (ODR, a task requiring memory-guided saccades after a delay period) or a conditional antisaccade task (a task in which the color of the peripheral target determined whether a saccade toward or away from the target was required). An additional six subjects performed a sequential hand movement task to compare localization of hand-related motor cortex and the frontal eye fields (FEFs) and of the hand- and eye-movement-related regions of the supplementary motor area (SMA). 3. Friston's statistical parametric mapping (SPM) method was used to identify significant changes in rCBF associated with task performance. Because SPM does not take advantage of the anatomic information available in magnetic resonance (MR) scans, each subject's PET scan was registered to that individual's MR scan, after which all PET and MR studies were transformed to conform to a standard reference MR image set. Subtraction images were visually inspected while overlayed on the reference MR scan to which PET images had been aligned, in order to confirm anatomic localization of significant rCBF changes. 4. Compared with visual fixation, performing visually guided saccades led to a significant bilateral activation in FEF, cerebellum, striate cortex, and posterior temporal cortex. Right posterior thalamus activation was also observed. 5. The visually guided saccade task served as the comparison task for the ODR, antisaccade, and conditional antisaccade tasks for identification of task-related changes in rCBF beyond those associated with saccade execution. Performance on the ODR task was associated with a bilateral increase of rCBF in FEFs, SMA, dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex. The cortical regions of increased regional blood flow during the ODR task also showed increased rCBF during the antisaccade task; however, FEF and SMA activations were significant only in the right hemisphere. These findings closely parallel those of single-cell recording studies with behaving monkeys in indicating that FEF, DLPFC, SMA, and posterior parietal cortex perform computational activity for voluntary purposive saccades. 6. Comparison of PET scans obtained during performance of eye movement and hand movement tasks indicated that peak activations in FEF were located approximately 2 cm lateral and 1 cm anterior to those of hand-related motor cortex. The oculomotor area of SMA, the supplementary eye field (SEF), was located approximately 7-8 mm anterior and superior to the hand-related area of SMA. 7. During performance of antisaccade and ODR tasks, rCBF was significantly lower in ventromedial prefrontal cortex (PFC), along the rectus gyrus, and in ventral anterior cingulate cortex than during the visually guided saccade and fixation tasks. During the antisaccade task, the ventral region of lower rCBF involved medial structures including left ventral striatum and bilateral medial temporal-limbic cortex. During the ODR task, the ventral aspect of the region of lower rCBF extended laterally, rather than medially, to include the temporal poles. The lower blood flow observed in ventromedial PFC during both the antisaccade and ODR tasks, relative to the visually guided saccade and fixation tasks, suggests that modulation of output from ventromedial PFC to limbic cortex and the striatum may play a role in the voluntary control of saccadic eye movements, possibly in the suppression of responses that would interrupt

Human ocular responses to translation of the observer and of the scene: dependence on viewing distance.

Recent experiments on monkeys have indicated that the eye movements induced by brief translation of either the observer or the visual scene are a linear function of the inverse of the viewing distance. For the movements of the observer, the room was dark and responses were attributed to a translational vestibulo-ocular reflex (TVOR) that senses the motion through the otolith organs; for the movements of the scene, which elicit ocular following, the scene was projected and adjusted in size and speed so that the retinal stimulation was the same at all distances. The shared dependence on viewing distance was consistent with the hypothesis that the TVOR and ocular following are synergistic and share central pathways. The present experiments looked for such dependencies on viewing distance in human subjects. When briefly accelerated along the interaural axis in the dark, human subjects generated compensatory eye movements that were also a linear function of the inverse of the viewing distance to a previously fixated target. These responses, which were attributed to the TVOR, were somewhat weaker than those previously recorded from monkeys using similar methods. When human subjects faced a tangent screen onto which patterned images were projected, brief motion of those images evoked ocular following responses that showed statistically significant dependence on viewing distance only with low-speed stimuli (10 degrees/s). This dependence was at best weak and in the reverse direction of that seen with the TVOR, i.e., responses increased as viewing distance increased. We suggest that in generating an internal estimate of viewing distance subjects may have used a confounding cue in the ocular-following paradigm--the size of the projected scene--which was varied directly with the viewing distance in these experiments (in order to preserve the size of the retinal image). When movements of the subject were randomly interleaved with the movements of the scene--to encourage the expectation of ego-motion--the dependence of ocular following on viewing distance altered significantly: with higher speed stimuli (40 degrees/s) many responses (63%) now increased significantly as viewing distance decreased, though less vigorously than the TVOR. We suggest that the expectation of motion results in the subject placing greater weight on cues such as vergence and accommodation that provide veridical distance information in our experimental situation: cue selection is context specific.

Neurological disease in xeroderma pigmentosum. Documentation of a late onset type of the juvenile onset form.

Xeroderma pigmentosum (XP) is an autosomal recessive, neurocutaneous disorder characterized by sunlight-induced skin cancers and defective DNA repair. Many XP children develop a primary neuronal degeneration. We describe 2 unusual XP patients who had a delayed onset of XP neurological disease. Somatic cell genetic studies indicated that they have the same defective DNA repair gene and are both in XP complementation group A. These 2 patients, together with a group A patient previously reported from London, establish as a distinct clinical entity the late onset type of the juvenile onset form of XP neurological disease. The functional capacity of these patients' cultured fibroblast strains to survive after treatment with ultraviolet radiation indicates that their DNA repair defect is less severe than that of typical group A patients who have a more severe neurodegeneration with an earlier symptomatic onset. The premature death of nerve cells in XP patients (which is presumably due to their inherited defects in DNA repair mechanisms) suggests that normal repair of damaged DNA in neurons is required to maintain integrity of the human nervous system.

Motion processing for saccadic eye movements in humans.

1. We studied the latencies and amplitudes of saccades to moving targets in normal human subjects. Targets underwent ramp or step-ramp motions. The goal was to determine how the saccadic system uses information about target velocity. 2. For simple ramp motion saccadic latency decreased as target speed increased. A threshold distance model, which assumes that the target has to move a minimum distance before saccadic processing starts, provided a good fit to the responses of all four subjects and explains discrepancies between previously published findings. 3. A double step experiment showed that target position may have some effect on saccadic amplitude when sampled approximately 70 ms before saccade onset, but it must be sampled at least 140 ms before onset for an accurate saccade to occur. 4. Saccades to simple ramp targets approximated the target position 55 ms before saccade onset. Based on our double step results, this is more compensation than possible by a simple position estimate and implies extrapolation of target motion by the saccadic system. The lack of complete compensation may be due to an underestimate of the target speed and/or of the saccadic latency. 5. A delayed-saccade paradigm resulted in saccades with a longer, constant latency and allowed longer viewing of target motion. These saccades accounted for all but approximately 20 ms of target motion, suggesting that with more processing time of target motion a better extrapolation may be generated. 6. In a step-ramp paradigm the target stepped in one direction, then moved smoothly in the opposite direction. Saccades in this paradigm could be made in either the direction of the step or in the direction of target motion: the direction and latency were determined solely by the time at which the target crossed the fixation point. This time must be calculated from target speed and position, implying that the saccadic system must use speed information to adjust latency or to cancel unnecessary saccades.

Early responses to double-step targets are independent of step amplitude.

We used a double-step paradigm to examine saccadic responses occurring at short intervals (50-150 ms) after the presentation of a 2-8 degrees step. Saccades occurring 60-110 ms after the second step had amplitudes independent of the step size. The amplitudes scaled to step size for intervals greater than 110 ms. These findings suggest that there is an early period of saccadic goal processing during which only information about the hemispheric location, but not the amplitude, of the target motion is available.

Short latency ocular-following responses in man.

The ocular-following responses elicited by brief unexpected movements of the visual scene were studied in human subjects. Response latencies varied with the type of stimulus and decreased systematically with increasing stimulus speed but, unlike those of monkeys, were not solely determined by the temporal frequency generated by sine-wave stimuli. Minimum latencies (70-75 ms) were considerably shorter than those reported for other visually driven eye movements. The magnitude of the responses to sine-wave stimuli changed markedly with stimulus speed and only slightly with spatial frequency over the ranges used. When normalized with respect to spatial frequency, all responses shared the same dependence on temporal frequency (band-pass characteristics with a peak at 16 Hz), indicating that temporal frequency, rather than speed per se, was the limiting factor over the entire range examined. This suggests that the underlying motion detectors respond to the local changes in luminance associated with the motion of the scene. Movements of the scene in the immediate wake of a saccadic eye movement were on average twice as effective as movements 600 ms later: post-saccadic enhancement. Less enhancement was seen in the wake of saccade-like shifts of the scene, which themselves elicited weak ocular following, something not seen in the wake of real saccades. We suggest that there are central mechanisms that, on the one hand, prevent the ocular-following system from tracking the visual disturbances created by saccades but, on the other, promote tracking of any subsequent disturbance and thereby help to suppress post-saccadic drift. Partitioning the visual scene into central and peripheral regions revealed that motion in the periphery can exert a weak modulatory influence on ocular-following responses resulting from motion at the center. We suggest that this may help the moving observer to stabilize his/her eyes on nearby stationary objects.

Human smooth pursuit: stimulus-dependent responses.

We studied pursuit eye movements in seven normal human subjects with the scleral search-coil technique. The initial eye movements in response to unpredictable changes in target motion were analyzed to determine the effect of target velocity and position on the latency and acceleration of the response. By restricting our analysis to the presaccadic portion of the response we were able to eliminate any saccadic interactions, and the randomized stimulus presentation minimized anticipatory responses. This approach has allowed us to characterize a part of the smooth-pursuit system that is dependent primarily on retinal image properties. The latency of the smooth-pursuit response was very consistent, with a mean of 100 +/- 5 ms to targets moving 5 degrees/s or faster. The responses were the same whether the velocity step was presented when the target was initially stationary or after tracking was established. The latency did increase for lower velocity targets; this increase was well described by a latency model requiring a minimum target movement of 0.028 degrees, in addition to a fixed processing time of 98 ms. The presaccadic accelerations were fairly low, and increased with target velocity until an acceleration of about 50 degrees/s2 was reached for target velocities of 10 degrees/s. Higher velocities produced only a slight increase in eye acceleration. When the target motion was adjusted so that the retinal image slip occurred at increasing distances from the fovea, the accelerations declined until no presaccadic response was measurable when the image slip started 15 degrees from the fovea. The smooth-pursuit response to a step of target position was a brief acceleration; this response occurred even when an oppositely directed velocity stimulus was present. The latency of the pursuit response to such a step was also approximately 100 ms. This result seems consistent with the idea that sensory pathways act as a low-pass spatiotemporal filter of the retinal input, effectively converting position steps into briefly moving stimuli. There was a large asymmetry in the responses to position steps: the accelerations were much greater when the position step of the target was away from the direction of tracking, compared with steps in the direction of tracking. The asymmetry may be due to the addition of a fixed slowing of the eyes whenever the target image disappears from the foveal region. When saccades were delayed by step-ramp stimuli, eye accelerations increased markedly approximately 200 ms after stimulus onset.(ABSTRACT TRUNCATED AT 400 WORDS)

Abduction nystagmus in internuclear ophthalmoplegia.

We tested the hypothesis that abnormalities of the abducting eye in internuclear ophthalmoplegia reflect an adaptive process that helps overcome the adduction weakness of the opposite eye. This response operates under the constraints of Hering's law of equal innervation: any attempt to increase the innervation to a weak muscle in one eye must be accompanied by a commensurate increase in innervation to the yoke muscle in the other eye. In 4 patients with internuclear ophthalmoplegia, we patched one eye for 1 to 5 days to allow time for the central nervous system to optimize innervation for the habitually viewing eye. We predicted that there would be a conjugate adjustment of innervation that would diminish the abduction overshoot and backward postsaccadic drift made by the habitually viewing eye. This was the case in 3 of our 4 patients. Our findings show that the abduction nystagmus is a manifestation of a normal adaptive response in some patients with INO.

Head shaking and vestibulo-ocular reflex in congenital nystagmus.

The authors investigated the mechanisms underlying the head shaking shown by some patients with congenital nystagmus (CN). In order to improve visual function by head shaking, a patient with CN must have some visual acuity loss due to retinal image motion created by the nystagmus; an abnormal vestibulo-ocular reflex (VOR); and the head shaking must be correlated with the nystagmus. The authors measured the VOR gain (eye velocity/head velocity) and examined eye-head coordination in five patients with CN with various combinations of these three factors. One patient met all three criteria and was able to increase his acuity by shaking his head. Other patients who shook their heads either had no loss of visual acuity due to the nystagmus or had a normal VOR. In either case, head shaking was of no apparent visual benefit and may represent, instead, an associated pathologic tremor in the cephalomotor control system.

Graphic analysis of paralytic strabismus with the Lancaster red-green test.

We used the Lancaster red-green test to monitor changes in ocular alignment in patients with paralytic strabismus. By inferring the position of the right eye and that of the left eye at many different positions of gaze and then plotting the data on a graph, one can derive a static eye position curve. The location of the curve relative to the line depicting normal ocular alignment ( orthophoria ) indicates whether there is an esodeviation or an exodeviation . The slope of a line drawn tangent to the curve indicates, for that particular point, whether the deviation is concomitant or not and which eye is relatively weak or restricted and by how much. This graphic technique provides a simple, sensitive, and quantitative measure of ocular alignment that may be especially useful for detecting subtle changes in the relative positions of the two eyes. This method may be a useful adjunct in the planning and evaluation of therapy for patients with paralytic strabismus.

Thrombosis of Björk-Shiley aortic valve prostheses.

Though thromboembolic complications are reportedly minimal in patients with Björk-Shiley aortic valve prostheses, massive thrombosis remains a major and often fatal problem. The authors observed massive thrombosis in 3 patients, only one of whom survived. In all three instances, the disk of the prosthesis was relatively radiolucent. With valves manufactured after late 1975, which contain a tantalum foil hoop, cineradiography is the most rapid and accurate method of showing the disk. A simple method of calculating the valve opening angle from the cineradiograph is described. It is suggested that serial cineradiographs might be useful in detecting lesser degrees of thrombosis and partial immobilization of the disk.

The Björk-Shiley aortic prosthesis: flow characteristics, thrombus formation and tissue overgrowth.

Thrombus formation and tissue overgrowth were observed in nine Björk-Shiley aortic prostheses recovered six months or longer after implantation. These pathologic findings may be attributed to the flow characteristics of the prosthesis. The open disc of the valve separates the flow into two unequal regions. Varying degrees of thrombus formation were observed in the minor outflow region, including the depression in the aortic face of the disc and the metal strut bridging this area. Tissue overgrowth was noted along the perimeter of the prosthesis adjacent to the minor outflow region. That overgrowth further reduced the available cross section for flow in this already constrained area. In vitro velocity measurements with a laser-Doppler anemometer identified a zone of stagnation about 20 mm wide near the aortic face of the disc. The average velocities in the major and minor outflow regions were around 100 and 25 cm/sec, respectively, and the corresponding peak-shear stresses were approximately 700 and 150 dynes/cm2. There is reason, then, to attribute the thrombus formation and tissue overgrowth to the stagnation zone and the low shear in the minor outflow region.