Ambulatory intracranial pressure in humans: ICP increases during movement between body positions.

Introduction: Positional changes in intracranial pressure (ICP) have been described in humans when measured over minutes or hours in a static posture, with ICP higher when lying supine than when sitting or standing upright. However, humans are often ambulant with frequent changes in position self-generated by active movement. Research question: We explored how ICP changes during movement between body positions. Material and methods: Sixty-two patients undergoing clinical ICP monitoring were recruited. Patients were relatively well, ambulatory and of mixed age, body habitus and pathology. We instructed patients to move back and forth between sitting and standing or lying and sitting positions at 20 s intervals after an initial 60s at rest. We simultaneously measured body position kinematics from inertial measurement units and ICP from an intraparenchymal probe at 100 Hz. Results: ICP increased transiently during movements beyond the level expected by body position alone. The amplitude of the increase varied between participants but was on average ∼5 mmHg during sit-to-stand, stand-to-sit and sit-to-lie movements and 10.8 mmHg [95%CI: 9.3,12.4] during lie-to-sit movements. The amplitude increased slightly with age, was greater in males, and increased with median 24-h ICP. For lie-to-sit and sit-to-lie movements, higher BMI was associated with greater mid-movement increase (ß = 0.99 [0.78,1.20]; ß = 0.49 [0.34,0.64], respectively). Discussion and conclusion: ICP increases during movement between body positions. The amplitude of the increase in ICP varies with type of movement, age, sex, and BMI. This could be a marker of disturbed ICP dynamics and may be particularly relevant for patients with CSF-diverting shunts in situ.

ICP during head movement: significance of the venous system.

BACKGROUND: It is thought that the internal jugular veins (IJV) are the primary route for cranial venous outflow in supine position and the vertebral venous plexus when upright. Previous studies have noted a greater increase in intracranial pressure (ICP) when subjects turn their head in one direction compared to the other, but no clear cause had been investigated. We hypothesised that in the supine position, head turning and consequently obstructing the IJV draining the dominant transverse sinus (TVS) would lead to a greater rise in ICP compared to turning to the non-dominant side. METHODS: A prospective study in a large-volume neurosurgical centre. Patients undergoing continuous ICP monitoring as part of their standard clinical management were recruited. Immediate ICP was measured in different head positions (neutral, rotated to the right and left) when supine, seated, and standing. TVS dominance was established by consultant radiologist report on venous imaging. RESULTS: Twenty patients were included in the study, with a median age of 44 years. Venous system measurements revealed 85% right-sided vs 15% left-sided dominance. Immediate ICP rose more when head turning from neutral to the dominant TVS (21.93mmHg ± 4.39) vs non-dominant side (16.66mmHg ± 2.71) (p= <0.0001). There was no significant relationship in the sitting (6.08mmHg ± 3.86 vs 4.79mmHg ± 3.81, p = 0.13) or standing positions (8.74mmHg ± 4.30 vs 6.76mmHg ± 4.14, p =0.07). CONCLUSION: This study has provided further evidence that the transverse venous sinus to internal jugular system pathway is the likely primary venous drainage when supine; and quantified its effect when head turning on ICP. It may guide patient-specific nursing care and advice.

Reflexive and volitional saccadic eye movements and their changes in age and progressive supranuclear palsy.

BACKGROUND AND OBJECTIVES: Saccades, rapid movements of the eyes towards a visual or remembered target, are useful in understanding the healthy brain and the pathology of neurological conditions such as progressive supranuclear palsy (PSP). We set out to investigate the parameters of horizontal reflexive and volitional saccades, both visually guided and memory-guided, over a 1 min epoch in healthy individuals and PSP patients. METHODS: An experimental paradigm tested reflexive, volitional visually guided, and volitional memory-guided saccades in young healthy controls (n = 14; 20-31 years), PSP patients (n = 11; 46-75 years) and older age-matched healthy controls (n = 6; 56-71 years). The accuracy and velocity of saccades was recorded using an EyeBrain T2® video eye tracker and analyses performed using the MyEyeAnalysis® software. Two-way analysis of variance (ANOVA) was used to identify significant effects (p < 0.01) between young and older controls to investigate the effects of ageing upon saccades, and between PSP patients and age-matched controls to study the effects of PSP upon saccades. RESULTS: In both healthy individuals and PSP patients, volitional saccades are slower and less accurate than reflexive saccades. In PSP patients, accuracy is lower across all saccade types compared to age-matched controls, but velocity is lower only for reflexive saccades. Crucially, there is no change in accuracy or velocity of consecutive saccades over short (one-minute) timescales in controls or PSP patients. CONCLUSIONS: Velocity and accuracy of saccades in PSP does not decrease over one-minute timescales, contrary to that previously observed in Parkinson's Disease (PD), suggesting a potential clinical biomarker for the distinction of PSP from PD.

Persistent Postural-Perceptual Dizziness (PPPD) from Brain Imaging to Behaviour and Perception.

Persistent postural-perceptual dizziness (PPPD) is a common cause of chronic dizziness associated with significant morbidity, and perhaps constitutes the commonest cause of chronic dizziness across outpatient neurology settings. Patients present with altered perception of balance control, resulting in measurable changes in balance function, such as stiffening of postural muscles and increased body sway. Observed risk factors include pre-morbid anxiety and neuroticism and increased visual dependence. Following a balance-perturbing insult (such as vestibular dysfunction), patients with PPPD adopt adaptive strategies that become chronically maladaptive and impair longer-term postural behaviour. In this article, we explore the relationship between behavioural postural changes, perceptual abnormalities, and imaging correlates of such dysfunction. We argue that understanding the pathophysiological mechanisms of PPPD necessitates an integrated methodological approach that is able to concurrently measure behaviour, perception, and cortical and subcortical brain function.

Altered visual and haptic verticality perception in posterior cortical atrophy and Alzheimer's disease.

There is increasing theoretical and empirical support for the brain combining multisensory information to determine the direction of gravity and hence uprightness. A fundamental part of the process is the spatial transformation of sensory signals between reference frames: eye-centred, head-centred, body-centred, etc. The question 'Am I the right way up?' posed by a patient with posterior cortical atrophy (PCA) suggests disturbances in upright perception, subsequently investigated in PCA and typical Alzheimer's disease (tAD) based on what looks or feels upright. Participants repeatedly aligned to vertical a rod presented either visually (visual-vertical) or haptically (haptic-vertical). Visual-vertical involved orienting a projected rod presented without or with a visual orientation cue (circle, tilted square (±18°)). Haptic-vertical involved orientating a grasped rod with eyes closed using a combination of side (left, right) and hand (unimanual, bimanual) configurations. Intraindividual uncertainty and bias defined verticality perception. Uncertainty was consistently greater in both patient groups than in control groups, and greater in PCA than tAD. Bias in the frontal plane was strongly directionally affected by visual cue tilt (visual-vertical) and grip side (haptic-vertical). A model was developed that assumed verticality information from multiple sources is combined in a statistically optimal way to produce observed uncertainties and biases. Model results suggest the mechanism that spatially transforms graviceptive information between body parts is disturbed in both patient groups. Despite visual dysfunction being typically considered the primary feature of PCA, disturbances were greater in PCA than tAD particularly for haptic-vertical, and are considered in light of posterior parietal vulnerability. KEY POINTS: The perception of upright requires accurate and precise estimates of orientation based on multiple noisy sensory signals. The question 'Am I the right way up?' posed by a patient with posterior cortical atrophy (PCA; purported 'visual variant Alzheimer's') suggests disturbances in the perception of upright. What looks or feels upright in PCA and typical Alzheimer's disease (tAD) was investigated by asking participants to repeatedly align to vertical a rod presented visually (visual-vertical) or haptically (haptic-vertical). PCA and tAD groups exhibited not only greater perceptual uncertainty than controls, but also exaggerated bias induced by tilted visual orientation cues (visual-vertical) and grip side (haptic-vertical). When modelled, these abnormalities, which were particularly evident in PCA haptic-vertical performance, were compatible with disruption of a mechanism that spatially transforms verticality information between body parts. The findings suggest an important role of posterior parietal cortex in verticality perception, and have implications for understanding spatial disorientation in dementia.

Ocular myasthenia gravis saccades as a measure of extraocular muscle function.

Background: It is important to understand the pathophysiology of ocular myasthenia gravis (OMG) to improve treatment. Aim: To use modern video-oculography to characterise saccadic eye movements in patients with OMG, including anti-AChR, anti-MuSK, anti-LRP4, and seronegative OMG. Methods: In total, 21 patients with OMG and five age-matched healthy control subjects underwent video-oculography. Participants performed a sequence of horizontal saccades (3 minutes each) at ±5°, ± 10°, and ±20°, followed by 3 minutes of saccades directed at randomly presented targets at ±5°, ± 10°, and ±15°. We recorded the direction, amplitude, duration, peak, and average velocity of each saccade for each task for each participant. Results: Saccadic amplitude, duration, and average velocity were all lower in OMG patients than in control subjects (p < 0.021). Saccadic amplitude and velocity decreased over time, but this decrease was similar in OMG patients and control subjects. Fixation drift and ocular disparity tended to be greater in OMG patients than in control subjects. Saccadic intrusions occurred more frequently in OMG patients than in control subjects (p < 0.001). No significant effects of time or group by time on fixation drift or ocular disparity were found. Discussion: Saccadic velocities in OMG patients differed from those in normal control subjects, which suggests that OMG affects fast-twitch fibres, although fast-twitch fibres were still able to generate "twitch" or "quiver" movements in the presence of even severe ophthalmoplegia. Slow-twitch muscle fibres involved in gaze holding were also affected, accounting for increased fixation drift following saccades. Our objective finding of increased fixation drift and a larger number of saccadic intrusions mirror our anecdotal experience of patients with OMG who report significant diplopia despite minimal ophthalmoplegia on examination. Such microsaccades may be a surrogate for compensation of a gaze-holding deficit in MG.

Case Report: Acute Onset Fear of Falling and Treatment With "Cognitive Physical Therapy".

Fear of falling (FoF) is prevalent in older adults, especially those with previous falls, and typically starts insidiously. We present a 78-year-old woman with an abrupt onset FoF and no history of falls, balance problems, vertigo, oscillopsia, psychiatric or psychological issues to account for this. These cognitive changes led to a behavioural alteration of her gait that became slow and wide-based, with her gaze fixed on the floor. She began a tailored program of "Cognitive Physical Therapy (CPT)" combining cognitive behavioural therapy (CBT) and physical rehabilitation. 1 month later her 6 m walk time and steps were reduced by a 25 and 35%, respectively, and the stride length increased by 34%, with further improvement 2 months later. We postulate that the abrupt onset of symptoms triggered a central shift toward postural hypervigilance and anxiety, suppression of anticipatory (feed forward) postural adjustments (APA) leading to FoF. CPT improved objective gait parameters related to FoF and reduced postural anxiety suggesting that early diagnosis and prompt treatment may avoid chronic symptoms and social isolation.

Voluntary steps and gait initiation.

This chapter explores mechanisms that control goal-directed steps for the purpose of reorienting the body or initiating gait. A key issue concerns the control of balance. We argue that standing balance is relinquished while the stepping foot is in the air thus allowing the body to fall under gravity. The falling body's trajectory is largely controlled by motor activity that occurs before the stepping foot leaves the ground (the throw), and is finely tuned to where and when the foot is planned to land (the catch). This close coupling between the throw and catch is paramount for achieving the stepping goal while simultaneously ensuring balance is regained at the end of the step. Nonetheless, there is some scope for making midstep adjustments by modifying the body's trajectory and/or the stepping leg's movement. The magnitude of midstep adjustment is severely limited by mechanical and balance constraints, but can occur at remarkably short latency in response to new visual information, possibly controlled by subcortical neural networks. We conclude that taking a step is a highly predictive and coordinated action that is vulnerable to errors leading to falls, particularly in the face of neural and muscular degeneration associated with aging or neurologic disease.

The Throw-and-Catch Model of Human Gait: Evidence from Coupling of Pre-Step Postural Activity and Step Location.

Postural activity normally precedes the lift of a foot from the ground when taking a step, but its function is unclear. The throw-and-catch hypothesis of human gait proposes that the pre-step activity is organized to generate momentum for the body to fall ballistically along a specific trajectory during the step. The trajectory is appropriate for the stepping foot to land at its intended location while at the same time being optimally placed to catch the body and regain balance. The hypothesis therefore predicts a strong coupling between the pre-step activity and step location. Here we examine this coupling when stepping to visually-presented targets at different locations. Ten healthy, young subjects were instructed to step as accurately as possible onto targets placed in five locations that required either different step directions or different step lengths. In 75% of trials, the target location remained constant throughout the step. In the remaining 25% of trials, the intended step location was changed by making the target jump to a new location 96 ms ± 43 ms after initiation of the pre-step activity, long before foot lift. As predicted by the throw-and-catch hypothesis, when the target location remained constant, the pre-step activity led to body momentum at foot lift that was coupled to the intended step location. When the target location jumped, the pre-step activity was adjusted (median latency 223 ms) and prolonged (on average by 69 ms), which altered the body's momentum at foot lift according to where the target had moved. We conclude that whenever possible the coupling between the pre-step activity and the step location is maintained. This provides further support for the throw-and-catch hypothesis of human gait.

Sequential construction of one, two, or three dithiolene ligands from alkynes and sulfur in dinuclear cyclopentadienyl molybdenum complexes.

This paper describes the sequential assembly of up to three dithiolene ligands from alkynes and elemental sulfur at a dimetal center. The dimolybdenum mu-alkyne complexes [Mo(2)(mu-R(1)C[triple bond]CR(2))(CO)(4)Cp(2)] (1a-c; Cp = eta-C(5)H(5), R(1) = R(2) = H, CO(2)Me; R(1) = H, R(2) = CO(2)Me) undergo oxidative decarbonylation on reaction with elemental sulfur in refluxing toluene to give good to excellent yields of the terminal dithiolene complexes [Mo(2)(S)(mu-S)(2)(SCR(1)=CR(2)S)Cp(2)] (2a-c). Further reaction of these complexes with 1 equiv of an alkyne R(3)C[triple bond]CR(4) (R(3) = R(4) = H, CO(2)Me; R(3) = H, R(4) = CO(2)Me) followed by oxidation with elemental sulfur produces the bis(dithiolene) complexes [Mo(2)(mu-S)(2)(SCR(1)=CR(2)S)(SCR(3)=CR(4)S)Cp(2)] (4a-d). Two examples, [Mo(2)(mu-S)(2)(S(2)C(2)H(2))(2)Cp(2)] and [Mo(2)(mu-S)(2){S(2)C(2)(CO(2)Me)(2)}(2)Cp(2)], have been structurally characterized. Reaction of 2 with an excess of an activated alkyne R(5)C[triple bond]CR(6) (R(5) = R(6) = CO(2)Me) and sulfur, or of 4 with the alkyne alone, affords good yields of the tris(dithiolene) complexes [Mo(2)(SCR(1)=CR(2)S)(SCR(3)=CR(4)S)(SCR(5)=CR(6)S)Cp(2)] (6a-e). The degree of control over the substituents in these complexes is demonstrated by the synthesis of [Mo(2)(S(2)C(2)H(2)){mu-S(2)C(2)(CO(2)Me)(2)}{mu-S(2)C(2)(CO(2)Et)(2)}Cp(2)] (6e), which contains three different dithiolene ligands, as a single isomer.