Shraga Hocherman

Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS?

BACKGROUND Administration of novel, versus classic, antipsychotic agents to patients suffering from psychosis is associated both with moderately better scores on cognitive tests, and with fewer extrapyramidal symptoms (EPS). Because improved motor functioning may enable better performance on some components of cognitive test batteries, and because the advantages of the novel antipsychotics on cognitive performance are not very large, it is sometimes difficult to discern if improvement in a given cognitive task is due to a direct effect of the novel antipsychotic drug, or is secondary to the novel drugs decreased propensity to induce EPS. In an attempt to distinguish between these two possibilities, the present study examined the ability of patients suffering from schizophrenia receiving classic, versus novel antipsychotics, to perform a computerized visuo-motor test (VMT). VMT assesses planning capabilities, attention and executive functions known to be impaired in schizophrenia, which are suggested to be affected by novel antipsychotics. METHODS Seventy-six patients suffering from schizophrenia or schizophreniform disorder, receiving haloperidol (23 patients, mean dose 10.01+/-6.1mg/day), olanzapine (26 patients, mean dose 10.56 +/- 4.9 mg/day) or risperidone (27 patients, mean dose 4.35 +/- 1.7 mg/day) were assessed for EPS using the parkinsonian subscale of the Extrapyramidal Symptom Rating Subscale (ESRS), and with the VMT. RESULTS Cognitive functioning as measured by the VMT was better for patients receiving risperidone or olanzapine, compared with those receiving haloperidol (F=6.636, df=2,67, P=0. 002), while the patients receiving haloperidol or risperidone suffered from more severe EPS compared with the patients receiving olanzapine (F=3.996, df=2,71, P=0.023). DISCUSSION Although the patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol, their performance on a task involving visuo-motor and attentional skills was similar to that of the patients receiving olanzapine. This finding implies that there is a dissociation between the antipsychotic drugs ability to affect cognitive functioning, and EPS. This dissociation indirectly suggests that the advantages offered by novel antipsychotics on cognitive performance are a direct effect, rather than being entirely mediated by improved movement abilities.

Antipsychotic-Induced Rabbit Syndrome Epidemiology, Management and Pathophysiology

Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth/lips, resembling the chewing movements of a rabbit. The movement consists of a vertical-only motion, at about 5Hz, with no involvement of the tongue. Usually, the involuntary movements associated with rabbit syndrome appear after a long period (in most cases months or years) of antipsychotic treatment; however, a few patients with the syndrome have had treatment histories with no antipsychotic involvement. The reported prevalence of rabbit syndrome ranges from 2.3 to 4.4% of patients treated with typical antipsychotics. There have been isolated reports of rabbit syndrome in patients treated with the atypical agents risperidone and clozapine.Patients with rabbit syndrome are most often misdiagnosed as having oral tardive dyskinesia. In such cases the key for correct diagnosis is the involvement of tardive tongue movements, which does not occur in rabbit syndrome.The treatment of rabbit syndrome is empirical, reflecting poor understanding of its neuropathology. The first step is to reduce the amount of antipsychotic treatment as much as possible. However, since, in most cases, full withdrawal of antipsychotic treatment is impossible, the syndrome cannot be completely abolished without additional measures. The next stage of treatment involves specific drugs that aim to control the syndrome. Anticholinergic drugs are the best known treatment. Rabbit syndrome does not respond to treatment with levodopa or dopamine agonists.The most striking aspect of this syndrome is its specificity. Rabbit syndrome affects only the buccal region, and within this area it involves a highly stereotyped involuntary movement. This immediately focuses attention on the basal ganglia, in particular the substantia nigra pars reticulata, which is also implicated in oral dyskinesia. Continuing neurophysiological and pharmacological research of the basal ganglia holds the key to better understanding and treatment of this syndrome in the coming years.

Visuomotor Performance in Patients With Essential Tremor

Essential tremor (ET) is the most prevalent extrapyramidal disorder, yet its diagnosis is still controversial. This article introduces new findings that pertain to this diagnostic problem. Twenty‐three patients with ET were studied. Patients with parkinsonism, cerebellar signs, severe head injury, or those under neuroleptic medication were excluded. Twenty‐five normal subjects served as control subjects. Visuomotor tests involving tracking and tracing along three different paths with both the right and left hands, were used. Performance was assessed by measuring test duration, directional error, the proportion of the cumulative test time during which directional error exceeded half the maximal possible level (PT50%), the mean distance from the model path, the velocity of the hand movement, and the number of tracking interruptions. In 15 of 23 patients performance was the same as in the control subjects. These patients were defined as having a “simple condition” of ET (ETs). Considerable visuomotor impairment was found in eight patients who were regarded as having a “complex condition” of ET (ETc). Patients with ETc had significantly lower tracking speed, more tracking interruptions, longer test duration, greater directional error, greater PT50%, and greater distance from path than patients with ETs or control subjects. Most patients with ET appear to have normal visuomotor capabilities (ETs) but some display significant visuomotor disturbances (ETc). Considering the presence of similar impairments in patients with early Parkinsons disease and the increased prevalence of parkinsonism in patients with ET, it is possible that preclinical parkinsonism exists in patients with ETc. Further follow up of patients with ETc is necessary to verify this possibility.

Visuo-motor coordination deficits and motor impairments in Parkinson's disease.

Background Visuo-motor coordination (VMC) requires normal cognitive executive functionality, an ability to transform visual inputs into movement plans and motor-execution skills, all of which are known to be impaired in Parkinsons disease (PD). Not surprisingly, a VMC deficit in PD is well documented. Still, it is not known how this deficit relates to motor symptoms that are assessed routinely in the neurological clinic. Such relationship should reveal how particular motor dysfunctions combine with cognitive and sensory–motor impairments to produce a complex behavioral disability. Methods and Findings Thirty nine early/moderate PD patients were routinely evaluated, including motor Unified Parkinsons Disease Rating Scale (UPDRS) based assessment, A VMC testing battery in which the subjects had to track a target moving on screen along 3 different paths, and to freely trace these paths followed. Detailed kinematic analysis of tracking/tracing performance was done. Statistical analysis of the correlations between measures depicting various aspects of VMC control and UPDRS items was performed. The VMC measures which correlated most strongly with clinical symptoms represent the ability to organize tracking movements and program their direction, rather than measures representing motor-execution skills of the hand. The strong correlations of these VMC measures with total UPDRS score were weakened when the UPDRS hand-motor part was considered specifically, and were insignificant in relation to tremor of the hand. In contrast, all correlations of VMC measures with the gait/posture part of the UPDRS were found to be strongest. Conclusions Our apparently counterintuitive findings suggest that the VMC deficit pertains more strongly to a PD related change in cognitive-executive control, than to a reduction in motor capabilities. The recently demonstrated relationship between gait/posture impairment and a cognitive decline, as found in PD, concords with this suggestion and may explain the strong correlation between VMC dysfunction and gait/posture impairment. Accordingly, we propose that what appears to reflect a motor deficit in fact represents a multisystem failure, dominated by a cognitive decline.

The response of single units in the auditory cortex of rhesus monkeys to predicted and to unpredicted sound stimuli.

Rhesus monkeys were trained to predict the nature of short auditory signals of two different types, to which they responded differentially. Prediction was based on visual signals that preceded the auditory ones. The monkeys use of the visual signals as predictors was assessed through two behavioural criteria. (1) performance in trials in which the visual signals was followed by the correct auditory signal (true conditioning) vs performance in trials in which the visual signal was followed by the wrong auditory signal (false conditioning). (2) Reaction time in trials with different types of conditioning. The response of single auditory cortex units to correctly and to incorrectly predicted auditory signals was recorded. The unconditioned response of every unit to each type of auditory stimulus was also obtained. Of 92 units that were analysed in detail, the response of about half was affected by the predictability of the stimulus. Units were affected in two different ways. One involved facilitation of the response to correctly predicted signals and inhibition of the response to incorrectly predicted signals. The other involved facilitation of the response to incorrectly predicted signals and base line response to correctly predicted signals. These findings were discussed in terms of neural mechanisms that relate to prediction.

The role of feedback in manual tracking of visual targets.

The role of visual feedback in manual tracking was investigated in 24 subjects who tracked 5-, 10-, and 40-mm/diameter targets, moving on a screen at 18 to 25 mm/sec., along various paths, by moving an unseen handle over a digitizing tablet. A cursor indicating instantaneous handle position was visible at all times on half the trials and hidden within a circle coaxial with the target but double its diameter in the other half. The handle had to be within the instantaneous targets digitizer-defined boundaries for the latter to keep moving. All tracking movements were segmented into small movement steps. A tendency to outrun the target was seen, indicating predictive control. Absence of visual feedback had negligible effect on movement velocity. Movement direction appeared to involve open-loop programming but improved significantly when subjects could see the cursor. Occasional corrective movements occurred only when visual feedback was given. Otherwise, a large positional error accumulates despite reasonable ability to control tracking direction.

Visual and kinesthetic control of goal-directed movements to visually and kinesthetically presented targets.

The study investigated the contribution of kinesthetic and visual input to the performance of reaching movements and identified rules governing the transformation of information between these two sensory modalities. The study examined the accuracy by which 39 subjects reproduced locations of five targets in a horizontal plane. Mode of target presentation and feedback during reproduction of a targets location was either visual, kinesthetic or a combination of both modalities. Thus, it was possible to examine performance when target presentation and reproduction involved feedback from the same sensory modality (intramodal) as well as from different sensory modalities (intermodal). Errors in target reproduction were calculated in terms of distance and systematic biases in movement extent. The major findings of the study are (1) Intramodal reproduction of a targets location on the basis of kinesthetic feedback is somewhat less accurate than intramodal reproduction on the basis of visual feedback. (2) Intermodal performance is significantly less accurate than intramodal performance. (3) Accuracy of performance does not depend on the direction of information transfer between sensory modalities. (4) Intermodal performance is characterized by systematic biases in extent of movement which are dependent on the direction of information transfer between modalities. (5) When presentation of the targets location is bimodal, reproduction is adversely affected by the conflicting input. The results suggest that transformation rules, used to combine input from various sensory modalities, depend on environmental conditions and attention.

MODALITY-SPECIFIC EFFECTS ON DISCRIMINATION OF SHORT EMPTY TIME INTERVALS

The ability of human subjects to judge the duration of short empty time intervals was studied in relation to the modality composition of the marker signals. Ac each trial, a pair of empty intervals was presented by a series of three successive stimuli, and the subject was asked to point out the longer interval of the two. Tone pips and flashes of light were used as the bounding signals. All the possible combinations of auditory and visual stimuli were used, in random order, to delimit pairs of intervals. Performance was found modality-independent when the first two stimuli were of the same modality. Strong response biases were introduced by varying the modality of the first or the second stimulus. Analysis of these biases indicates that memorization of the empty time intervals is affected by the modality of the binding signals.

Perception of the immediate extrapersonal space through proprioceptive inputs

SummaryIn the present work we sought to examine the idea that an internalized representation of space can be formed and used in the absence of visual information. To this end human subjects were trained to locate 5 points within a horizontal plane at shoulder level, under guidance of an acoustic signal. Next, reaching accuracy was determined for both the trained and the untrained hands without external cues. This allowed comparison of hand positioning that could be based upon a memory trace of proprioceptive inputs (trained hand) to hand positioning that must be based upon a more abstract internal representation than proprioceptive memory (untrained hand). The effect of training on reach accuracy of the two hands and the effect of prolongation the time interval between guided and recall (unguided) trials were studied. Finally, subjects were asked to interpolate between already learned target positions, a procedure which tested their ability to utilize an abstract construct of space. The relative contribution of the elbow and shoulder joints to reaching errors was determined. This analysis served to evaluate whether representation of spatial locations was based on joint angle coordinates, or on a more abstract extracorporeal reference system. Our results indicate that a memorized sensory image of the limb, which corresponds to the hand being at the target position, is used whenever possible. An abstract representation of position is used whenever comparison of the actual sensory input to a memorized sensory trace is made impossible, costing an approximately 25% reduction in accuracy. The interpolation procedure indicates that the same abstraction is used when target positions are determined mentally, as when the untrained limb performs the task. Finally, it appears that this abstract spatial representation is based on extrapersonal coordinates rather than on joint angles.

Subthalamic Nucleus Deep Brain Stimulation Does Not Improve Visuo-Motor Impairment in Parkinson’s Disease

Objective To evaluate how bilateral subthalamic nucleus deep brain stimulation (STN-DBS) affects visuo-motor coordination (VMC) in patients with Parkinson’s disease (PD). Background VMC involves multi-sensory integration, motor planning, executive function and attention. VMC deficits are well-described in PD. STN-DBS conveys marked motor benefit in PD, but pyscho-cognitive complications are recognized and the effect on VMC is not known. Methods Thirteen PD patients with bilateral STN-DBS underwent neurological, cognitive, and mood assessment before VMC testing with optimal DBS stimulation parameters (‘on-stimulation’) and then, on the same day without any medication changes, after DBS silencing and establishing motor function deterioration (‘off-stimulation’). Twelve age-matched healthy controls performed 2 successive VMC testing sessions, with a break of similar duration to that of the PD group. The computer cursor was controlled with a dome-shaped ‘mouse’ hidden from view that minimized tremor effects. Movement duration, hand velocity, tracking continuity, directional control variables, and feedback utilization variables were measured. MANOVA was performed on (1) clinically measured motor function, (2) VMC performance and (3) mood and attention, looking for main and interaction effects of: (1) group (controls/PD), (2) test-order (controls: first/second, PD: on-stimulation/off-stimulation), (3) path (sine/square/circle) and (4) hand (dominant/non-dominant). Results Unified PD Rating Scale (UPDRS) Part III worsened off-stimulation versus on-stimulation (mean: 42.3 versus 21.6, p = 0.02), as did finger tapping (p = 0.02), posture-gait (p = 0.01), upper limb function (p<0.001) and backwards digit span (p = 0.02). Stimulation state did not affect mood. PD patients performed worse in non-velocity related VMC variables than controls (F(5,18) = 8.5, p<0.001). In the control group there were significant main effects of hand (dominant/non-dominant), path (sine/square/circle) and test-order (Test_1/Test_2). In the PD group, hand and path effects, but no test-order (on-stimulation/off-stimulation), were found. Conclusions ‘Low-level’ clinically-measured motor function responds to STN-DBS but ‘high-level’ motor and cognitive functions relating to VMC may be unresponsive to STN-DBS.