Cognitive processing speed deficits in multiple sclerosis: Dissociating sensorial and motor processing changes from cognitive processing speed.

BACKGROUND: The assessment of cognitive information processing speed (IPS) is complicated in MS, with altered performance on tests such as the Symbol Digit Modalities Test (SDMT) potentially representing changes not only within cognitive networks but in the initial sensorial transmission of information to cognitive networks, and/or efferent transmission of the motor response. OBJECTIVE: We aimed to isolate and characterise cognitive IPS deficits in MS using ocular motor tasks; a prosaccade task (used to assess and control for sensorial and motor IPS) which was then used to adjust performance on the Simon task (cognitive IPS). METHODS: All participants (22 MS patients with early disease, 22 healthy controls) completed the ocular motor tasks and the SDMT. The Simon task assessed cognitive IPS by manipulating the relationship between a stimulus location and its associated response direction. Two trial types were interleaved: (1) congruent, where stimulus location = response direction; or (2) incongruent, where stimulus location ≠ response direction. RESULTS MS patients did not perform differently to controls on the SDMT. For OM tasks, when sensorial and motor IPS was controlled, MS patients had significantly slower cognitive IPS (incongruent trials only) and poorer conflict resolution. SDMT performance did not correlate with slower cognitive IPS in MS patients, highlighting the limitation of using SDMT performance to interpret cognitive IPS changes in patients with MS. CONCLUSION: Cognitive IPS deficits in MS patients are dissociable from changes in other processing stages, manifesting as impaired conflict resolution between automatic and non-automatic processes. Importantly, these results raise concerns about the SDMT as an accurate measure of cognitive IPS in MS.

Multiple sclerosis: Executive dysfunction, task switching and the role of attention.

BACKGROUND: It has been suggested that switching ability might not be affected in multiple sclerosis (MS) as previously thought; however, whether this is true under more 'real-world' conditions when asymmetry in task difficulty is present has not been ascertained. OBJECTIVE: The objective of this paper is to examine the impact of task difficulty asymmetry on task switching ability in MS. METHOD: An ocular motor (OM) paradigm that interleaves the simple task of looking towards a target (prosaccade, PS) with the cognitively more difficult task of looking away from a target (antisaccade, PS) was used. Two switching conditions: (1) PS switch cost, switching to a simple task from a difficult task (PS switch), relative to performing two simple tasks concurrently (PS repeat); (2) AS switch cost, switching to a difficult task from a simple task (AS switch) relative to performing two difficult tasks concurrently (AS repeat). Forty-five relapsing-remitting MS patients and 30 control individuals were compared. RESULTS: Controls and patients produced a similar magnitude PS switch cost, suggesting that task difficulty asymmetry does not detrimentally impact MS patients when transitioning from a more difficult task to a simpler task. However, MS patients alone found switching from the simpler PS trial to the more difficult AS trial easier (shorter latency and reduced error) than performing two AS trials consecutively (AS switch benefit). Further, MS patients performed significantly more errors than controls when required to repeat the same trial consecutively. CONCLUSION: MS patients appear to find the maintenance of task-relevant processes difficult not switching per se, with deficits exacerbated under increased attentional demands.

Urocortin protects chondrocytes from NO-induced apoptosis: a future therapy for osteoarthritis?

Osteoarthritis (OA) is characterized by a loss of joint mobility and pain resulting from progressive destruction and loss of articular cartilage secondary to chondrocyte death and/ or senescence. Certain stimuli including nitric oxide (NO) and the pro-inflammatory cytokine tumor necrosis factor α (TNF-α have been implicated in this chondrocyte death and the subsequent accelerated damage to cartilage. In this study, we demonstrate that a corticotrophin releasing factor (CRF) family peptide, urocortin (Ucn), is produced by a human chondrocyte cell line, C-20/A4, and acts both as an endogenous survival signal and as a cytoprotective agent reducing the induction of apoptosis by NO but not TNF-α when added exogenously. Furthermore, treatment with the NO donor S-nitroso-N-acetyl-D-L-penicillamine upregulates chondrocyte Ucn expression, whereas treatment with TNF-α does not. The chondroprotective effects of Ucn are abolished by both specific ligand depletion (with an anti-Ucn antibody) and by CRF receptor blockade with the pan-CRFR antagonist α-helical CRH(9-41). CRFR expression was confirmed by reverse transcription-PCR with subsequent amplicon sequence analysis and demonstrates that C-20/A4 cells express both CRFR1 and CRFR2, specifically CRFR1α and CRFR2ß. Protein expression of these receptors was confirmed by western blotting. The presence of both Ucn and its receptors in these cells, coupled with the induction of Ucn by NO, suggests the existence of an endogenous autocrine/paracrine chondroprotective mechanism against stimuli inducing chondrocyte apoptosis via the intrinsic/mitochondrial pathway.

Negative symptoms: A review of schizophrenia, melancholic depression and Parkinson's disease.

Negative symptoms generally refer to a reduction in normal functioning. In schizophrenia they encompass apathy, anhedonia, flat affect, avolition, social withdrawal and, on some accounts, psychomotor retardation. Negative symptoms have been identified in other psychiatric disorders, including melancholic depression, and also in neurological disorders, such Parkinson's disease. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms represent an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on families, carers and the patients themselves. Identifying and understanding subgroups within disorders may also contribute to the clinical care and scientific understanding of the pathophysiology of these disorders. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms may play an important role not only in other psychiatric disorders such as melancholic depression, but also in neurological disorders, such as Parkinson's disease. In each disorder negative symptoms manifest with similar motor and cognitive impairments and are associated with comparable neuropathological and biochemical findings, possibly reflecting analogous impairments in the functioning of frontostriatal-limbic circuits.

Self-paced saccades and saccades to oddball targets in Parkinson's disease.

Patients with Parkinson's disease (PD) manifest difficulty in initiation and execution of movements, particularly when movements are sequential, simultaneous or repetitive. Eye movements are particularly effective in evaluating motor impairments. We utilized a series of saccadic eye movement paradigms to explore the ability of 13 patients with mild-moderate PD and 13 age-matched healthy controls to self-pace saccades between two continuously illuminated targets, before and after an externally cued tracking period, and respond to unexpected changes in task demand. The latter was explored by measuring saccadic responses to unexpected "oddball" targets that appeared during a well-learned reciprocating sequence of saccades, in either the opposite direction to that expected or at twice the anticipated extent. Results indicated that all participants demonstrated a marked increase in saccade amplitudes from the externally cued saccade tracking to the self-paced saccades. Unexpectedly, this difference was magnified in PD patients. Self-paced saccades before externally cueing were also more frequent than requested in the PD group, but timing improved following external cueing. The second key finding was that while patients were able to respond to unexpected changes in target amplitude, performance was more variable (in terms of latency and accuracy) when responding to unexpected changes in target direction. Hence, beneficial effects of external cueing on the timing of self-paced saccades may be mediated through cortical regions, placing less emphasis on striatal regions known to be compromised in PD. Additionally, responding to changes in saccade direction (but not amplitude) may rely on basal ganglia circuitry.

Ocular motor differences between melancholic and non-melancholic depression.

BACKGROUND: Major depressive disorder may be a heterogeneous disorder, yet melancholic depression is the most consistently described subtype, regarded as qualitatively different to non-melancholic depression in terms of cognitive and motor impairments. Eye movement studies in depression are infrequent and findings are inconclusive. METHODS: This study employed a battery of saccadic eye movement tasks to explore reflexive saccades, as well as higher order cognitive aspects of saccades including inhibitory control and spatial working memory. Nineteen patients with major depressive disorder (9 melancholic; 10 non-melancholic) and 15 healthy controls participated. RESULTS: Differences were revealed between melancholic and non-melancholic patients. Melancholia was associated with longer latencies, difficulty increasing peak velocities as target amplitudes increased, and hypometric primary saccades during the predictable protocol. In contrast, the non-melancholic depression group performed similarly to controls on most tasks, but saccadic peak velocity was increased for reflexive saccades at larger amplitudes. LIMITATIONS: Most patients were taking antidepressant medication. CONCLUSIONS: The latency increases, reduced peak velocity and primary saccade hypometria with more severe melancholia may be explained by functional changes in the fronto-striatal-collicular networks, related to dopamine dysfunction. In contrast, the serotonergic system plays a greater role in non-melancholic symptoms and this may underpin the observed increases in saccadic peak velocity. These findings provide neurophysiological support for functional differences between depression subgroups that are consistent with previous motor and cognitive findings.

Hypometric primary saccades and increased variability in visually-guided saccades in Huntington's disease.

Eye movement abnormalities can be distinctive and suggestive of a specific pathophysiology. To further investigate the deficits in the control of saccades in patients with Huntington's disease (HD), we investigated the ability of 11 HD patients and 11 matched controls to perform visually-guided saccades. We adopted reflexive saccade tasks involving predictable and unpredictable sequences, at different amplitudes of target step (10 degrees, 20 degrees, 30 degrees, 40 degrees ), as well as voluntary self-paced saccades. Prolongation of initiation was observed in the HD group as the target amplitude of predictable saccades increased. During the self-paced saccade task, the HD patients had increased intersaccadic intervals, performed fewer saccades in the allocated time and displayed an increased temporal variability in comparison to the controls. Furthermore, hypometric primary saccades, and an increased number of corrective saccades, were observed during both reflexive and voluntary saccades in the HD group. The delayed initiation of large saccades, deficits in voluntary, self-paced saccades, impaired saccadic accuracy and increased corrective saccades in HD, were interpreted in light of other ocular motor and limb studies, and appear to be due to damage to the fronto-striatal loop, including the supplementary eye fields, as well as possible brainstem and cerebellar involvement.

Saccades to remembered targets: the effects of saccades and illusory stimulus motion.

In 10 human subjects, we measured the accuracy of saccades to remembered locations of targets that were flashed on a 20 x 30 deg random dot display, while they tracked a spot of light that stepped between three vertical locations. The background was either stationary or stepping horizontally in synchrony with vertical motion of the spot of light, a condition that induced a strong illusion of diagonal target motion. Memory-guided saccades were less accurate horizontally, but not vertically, when the background moved compared with when it was stationary. The horizontal component of memory-guided saccades correlated better with the position of the background when the target was flashed than with the position of the background at the end of the memory period. We conclude that the visual illusion corrupted the working memory of target-location, but had a lesser effect on the estimate of gaze at the end of the memory period, which seemed to depend more on extraretinal signals.

Subdural haematoma presenting with transient neurological deficits.

OBJECTIVE: To stress that transient neurological deficits do not always imply transient cerebral ischaemia, and may be produced by subdural haematoma. CLINICAL FEATURES: An 80-year-old man was seen for intermittent gait disturbance, with normal findings on initial examination. He was then admitted after the onset of a fixed neurological deficit which worsened. Subdural haematoma was diagnosed by computed tomography (CT). An 80-year-old woman was seen after she had experienced left hemisphere transient neurological deficits. A CT scan showed a left-sided subdural haematoma. INTERVENTION AND OUTCOME: Both patients underwent successful surgery with complete resolution of their symptoms and signs. CONCLUSION: Subdural haematoma is relatively common and must be considered in those with unexplained transient neurological deficits. Magnetic resonance imaging or CT are the diagnostic procedures of choice. Antiplatelet or anticoagulant therapy must not be instituted until subdural haematoma is excluded.

Responses of monkey precentral neurones to passive movements and phasic muscle stretch: relevance to man.

Single cell recordings were made from movement-related neurones from the precentral cortex of two monkeys, trained to perform a simple lever-pulling task. They were also trained to remain relaxed while the arm was explored with passive movements at different joints, cutaneous stimuli and during the application of two types of phasic muscle stretch: percutaneous vibration and percussion of muscle tendons. Recordings were made of the responses of cortical neurones both to the 'natural' stimuli and to vibration of specific muscle tendons or percussion of the triceps tendon. Both tendon percussion and vibration excited neurones within area 4 with an average latency for tendon percussion of 21.0 msec. There was a high degree of consistency in the effects on single neurones of tendon percussion and vibration at the same site. Although long-term facilitation was not seen. vibration-induced discharge in the motor cortex should be considered as a potential mechanism of its effects in intact man. In contrast to the similarity of the effect of the two forms of phasic stretch, the relationship between a single neurone's response to either tendon percussion or vibration and to passive movement was complex. The dissociation seen between the effects of phasic muscle stretch and that of passive movement may underlie the failure, in man, to find uniformly increased long-latency stretch reflexes in clinical states of extrapyramidal rigidity.

Ocular motor deficits in Parkinson's disease. III. Coordination of eye and head movements.

Eye-head coordination was measured in patients with Parkinson's disease as they made horizontal gaze shifts in response to predictable and unpredictable target steps and to targets moving smoothly with either constant or sinusoidally varying velocity. Patients preferred not to move their heads for both large and small amplitude gaze shifts. Both eye and head movement reaction times were prolonged. Saccades were hypometric and, frequently, slow. Head movements were also slow, hypometric, and varied in amplitude for target shifts of a given amplitude. Compensatory eye movements (CEMs) that normally stabilize gaze direction during head movement varied in gain from zero to greater than unity, and often drove the eyes off target. CEM abnormalities occurred most commonly in patients with abnormal vestibulo-ocular reflex (VOR) gain in darkness. We attribute these abnormalities of programming combined eye-head saccades to dysfunction of striatonigralcollicular circuits. Smooth gaze pursuit gain, the ratio of gaze velocity to target velocity, was lowered in patients while tracking sinusoidal targets at 0.3, 0.5 and 1.0 Hz. Some patients could track these targets with the head fixed but not with the head free. We attribute this to abnormal suppression of the vestibuloocular reflex. The results indicate that Parkinson's disease impairs motor programming of coordinated eye-head gaze saccades and disrupts normal interaction between head movement and the VOR.

Ocular motor deficits in Parkinson's disease. I. The horizontal vestibulo-ocular reflex and its regulation.

Horizontal vestibulo-ocular reflex (VOR) function was quantified in 14 parkinsonian patients and compared with that of 10 age-matched normals. Eight patients had mild and 6 had advanced rigidity and akinesia. In advanced disease VOR gains were subnormal in darkness during sinusoidal wholebody rotation at frequencies from 0.3 to 3.0 Hz. When fixating a stationary target, patients enhanced VOR gains to near unity, but gains of patients with advanced disease were significantly lower than controls. Visual suppression of the VOR by fixating a target moving with the head was defective in all stages of the disease. Advanced patients also exhibited defective voluntary control of the reflex in darkness: both voluntary enhancement, by imagining a stationary target, and voluntary suppression, by imagining a target moving with the head, were abnormal. This disordered voluntary control of the VOR was independent of defective visually mediated smooth pursuit. Attempted visual and voluntary suppression of the reflex produced a rise in VOR gain, above the hypoactive values recorded in darkness in advanced disease. This inappropriate activation of the VOR implied structural integrity of brainstem smooth eye movement pathways, despite vestibulo-ocular hyporeflexia. Unrecognized degeneration in brainstem VOR circuits, or defective cerebral hemisphere control of the reflex caused by the nigrostriatal or cerebral cortical dysfunction of Parkinson's disease, may explain subnormal ocular responses to passive head motion. We attribute the abnormal visual and voluntary modulation of smooth eye movements to disordered long-loop cerebral control of the VOR and suggest that it is analogous to the defective long-loop cerebral regulation of spinal reflexes that occurs in Parkinson's disease.

Ocular motor deficits in Parkinson's disease. II. Control of the saccadic and smooth pursuit systems.

We quantified the horizontal pursuit and saccadic function of 14 parkinsonian patients and 10 normal subjects matched for age. Eight patients had mild, and 6 advanced disease. Ocular motor deficits were more marked in patients with advanced disease. Saccadic reaction times and postsaccadic refractory periods were prolonged. Peak saccadic velocities were significantly reduced. Slow saccades may be caused by inappropriate coactivation of opposing ocular muscles. Multiple step, hypometric saccades were abnormally frequent. Correct final eye position towards a brief target flash was attained without visual feedback. Brief corrective intervals occurred after hypometric saccades. They are attributed to internal (nonvisual) efference copy feedback of eye position errors. Frequent square wave jerks were also a feature of Parkinson's disease. Smooth pursuit gain was lowered in all patients while tracking sinusoidal targets at frequencies from 0.25 to 1 Hz. Pursuit gain was uniformly reduced at all target velocities at each frequency. This decrease in gain indicates that dysfunction of the gain element, rather than abnormal drop acceleration saturation is responsible for impaired smooth pursuit. The results indicate that Parkinson's disease damages structures involved in the regulation of the saccadic and pursuit systems. We infer that nigrostriatal pathways, known to be damaged in Parkinson's disease, control the latency, velocity and amplitude of saccades, and the gain element of smooth pursuit.

Cerebral square wave jerks.

Abnormal saccadic intrusions consisting of frequent sporadic horizontal saccades followed, after an interval, by corrective saccades occurred in 70% of 17 patients with acute or chronic focal cerebral lesions. These square wave jerks were significantly lower in amplitude than those in cerebellar system disease. The metrics of these jerks were uniform regardless of the site of cerebral damage. Mean durations approximated the reaction time for saccadic refixations triggered by visual feedback. Very short-latency corrective saccades in some patients are attributed to internal (nonretinal) feedback of eye position errors. Low-amplitude cerebral square wave jerks can be detected clinically by funduscopy.