Neither simple nor sequential arm movements are bradykinetic in parkinsonian patients with peak-dose dyskinesias.

OBJECTIVE: To find out whether parkinsonian patients with levodopa-induced peak-dose dyskinesias are bradykinetic. METHODS: The performance of a sequential internally determined arm movement and a simple externally triggered arm movement was studied in a group of dyskinetic parkinsonian patients during their best clinical condition and when they were OFF treatment. Patients' performance was compared with that of an age-matched control group. Movements in the three-dimensional space were recorded by the ELITE motion analysis system. Kinematic variables analysed for the sequential motor task were total movement duration and total pause duration; for the simple motor task, movement duration and reaction time; and for both tasks, movement inaccuracy. RESULTS: When patients were OFF therapy they performed sequential and simple movement tasks slower than healthy subjects whereas when they were dyskinetic they did not. During the sequential task, when the patients were dyskinetic total pause duration shortened and movement inaccuracy increased. CONCLUSIONS: Our kinematic finding indicates that parkinsonian patients' with peak-dose dyskinesias are not bradykinetic. SIGNIFICANCE: Parkinsonian patients with peak-dose dyskinesias are not bradykinetic, probably because dopamine at peak doses functionally normalizes the mechanisms controlling movement speed.     

Sensory Processing in Schizophrenia: Neither Simple nor Intact

This special issue focuses on the theme of sensory processing dysfunction in schizophrenia. For more than 50 years, from approximately the time of Bleuler until the early 1960s, sensory function was considered one of the few preserved functions in schizophrenia (Javitt¹). Fortunately, the last several decades have brought a renewed and accelerating interest in this topic. The articles included in the issue range from those addressing fundamental bases of sensory dysfunction (Brenner, Yoon, and Turetsky) to those that examine how elementary deficits in sensory processing affect the sensory experience of individuals with schizophrenia (Butler, Kantrowitz, and Coleman) to the question of how sensory-based treatments may lead to improvement in remediation strategies (Adcock). Although addressing only a small portion of the current complex and burgeoning literature on sensory impairments across modalities, the present articles provide a cross-section of the issues currently under investigation. These studies also underscore the severe challenges that individuals with schizophrenia face when trying to decode the complex world around them.     

Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus

In major depression, decreased hippocampal volume has been attributed to hypercortisolemia, a frequent sign of the disorder, because in animals an excess of corticosteroids has led to dendritic atrophy, astrogliosis and loss of neurons in this brain region. The present study is the first to investigate the structural integrity of the human hippocampus in major depression and following glucocorticoid treatment. Post-mortem hippocampal tissue from 15 patients who had had major depression or bipolar affective disorder, 10 patients who had been treated with glucocorticoids and 16 controls was assessed using haematoxylin-eosin, Nissl and Bodian staining. The patterns of reactive astrogliosis (glial fibrillary acidic protein, GFAP), synaptic density (synaptophysin), synaptic reorganization (growth-associated protein B-50) and early signs of Alzheimer's disease (Alz-50) were examined immunocytochemically. Multivariate analysis, with the patients' age, tissue fixation time and postmortem delay as covariates, was performed. There was no evidence of neuronal cell loss or other major morphological alterations in any of the groups, nor was there a significant change in the distribution pattern of synaptophysin or Alz-50. Changes in B-50 and GFAP staining were observed in the steroid-treated and depressed patients in areas CA1 and CA2 only. The human hippocampus in major depression and after glucocorticoid treatment does not reveal any major morphological changes or signs of neuronal cell death, but does show subtle alterations in B-50 and GFAP expression in selected parts of the pyramidal cell layer.     

Neither short-term nor long-term administration of oral choline alters metabolite concentrations in human brain.

BACKGROUND: This study reexamined conflicting proton magnetic resonance spectroscopy (MRS) reports of increased or unaffected choline-containing compounds (Cho) in human brain in response to a single dose of 50 mg/kg choline bitartrate. METHODS: The present work was based on a well-established strategy for quantitative proton MRS (2.0 T, STEAM localization sequence, TR/TE/TM = 6000/20/10 ms, LCModel automated spectral evaluation) that allows the determination of cerebral metabolite concentrations rather than T1-weighted resonance intensity ratios. Moreover, the investigations were extended to a possible long-term effect of oral choline by monitoring the continuous ingestion of 2 x 16 g of lecithin per day for 4 weeks. Six young healthy volunteers participated in each study and metabolite concentrations were determined in standardized locations in gray matter, white matter, cerebellum, and thalamus. RESULTS: Neither for short-term nor for long-term administration of choline do the data reveal statistically significant deviations from the basal concentrations of Cho, total N-acetyl-containing compounds (neuronal markers), total creatine, and myo-inositol (glial marker) in any of the investigated brain regions. CONCLUSIONS: Previous reports of increased Cho are not confirmed.     

Neither ibotenic acid nor volkensin lesions of the nucleus accumbens shell affect the expression of cocaine sensitization

Studies have shown that the nucleus accumbens shell plays an integral role in the expression of psychostimulant-induced behavioural sensitization. Dopaminergic regulation of excitatory amino acid inputs in this region of the brain could be a key factor in the neural influence of this phenomenon. Alterations in the dopaminergic innervation patterns in the shell have been demonstrated in rats that received repeated cocaine injections. Furthermore, lesions of brain regions that send projections to the shell alter psychostimulant-induced locomotion, both acutely and in sensitization paradigms. A previous study from our laboratory demonstrated that lesions of the shell before repeated cocaine treatment decrease the locomotor response to cocaine during the induction phase of behavioural sensitization. To better understand the role of this brain region during the expression phase of behavioural sensitization, the present study examined the effects of two forms of cytotoxic lesions of the shell. Rats received a sensitization-inducing regimen of cocaine (bi-daily injections of 15 mg/kg i.p. for 5 consecutive days). Two days after the last injection, rats demonstrating behavioural sensitization received one of three bilateral microinjections into the shell: (i) 0.5 micro L 0.9% saline; (ii) 2.5 micro g/0.5 micro L ibotenic acid (which lesions the cell bodies at the injection site); or (iii), 0.5 ng/0.2 micro L of volkensin (a retrograde suicide transport lectin). Upon challenge with cocaine (15 mg/kg) 12 days after surgery, neither ibotenic acid- nor volkensin-lesioned rats showed any difference in their locomotor response compared with sham controls. These data indicate that bilateral shell lesions do not affect the long-term expression of behavioural sensitization in cocaine-sensitized rats.     

Neither environmental enrichment nor voluntary wheel running enhances recovery from incomplete spinal cord injury in rats

Environmental enrichment and exercise may be neuroprotective or promote recovery after different forms of CNS injury. Here, we tested the possible effects of moderate environmental enrichment and voluntary exercise on the outcome of incomplete spinal cord injury in rats. We provided rats in standard cages with basic environmental enrichment (carton house, nesting material, tube, gnawing sticks). We also analyzed the effect of increased activity by housing spinal-cord-injured rats in cages with or without access to running wheels. In a third experiment, we looked at the possible effect of pre-injury training. In all experiments, a battery of behavior tests were used. Enriched environment provided before, after or both before and after injury did not alter the outcome on any of these tests. Similarly, despite excessive running after injury, no differences in terms of recovery and behavior were found in the running experiment. Similarly, running prior to injury did not significantly decrease the degree of functional deficit caused by the injury. Since there were no effects of further enrichment, above the possible effects of being socially housed, and since exercise did not improve the outcome, we conclude that these forms of increased activity do not render the animals significantly less sensitive to spinal cord injury and do not cause robust improvement when initiated after injury. While these results pose a limit to how helpful environmental and physical training programs may be in rodent impact injury models, they do not contradict the fact that voluntary and guided training can be effective tools in human spinal cord rehabilitation.     

Diazepam reduces stress-induced analgesia in humans

The analgesic effects of a repetitive stress induced by anticipation of pain (noxious footshock) were studied on both the threshold of a nociceptive flexion reflex and the corresponding pain sensation after a 4-day-treatment of diazepam vs placebo (cross-over and double-blind study) in normal volunteers. During diazepam, the stressor stimulus produced a weaker depression on both nociceptive reflex and pain sensation than that observed during placebo. Furthermore, the reversal effect by naloxone was much more marked during placebo than during diazepam. These data clearly suggest a possible moderating action of benzodiazepine brain type receptors upon the endogenous opiate systems involved in the phenomenon of stress-induced analgesia in humans.     

Neither the butyrylcholinesterase K variant nor transferrin C2 variant confers a risk for Alzheimer's disease in Koreans

Summary. To investigate the possible involvement of the butyrylcholinesterase (BCHE) K variant and transferrin (TF) C2 variant in the manifestation of Alzheimer's disease (AD), we analyzed the BCHE, TF and apolipoprotein E (APOE) genotypes of 164 sporadic AD patients and 239 normal elderly controls. The frequencies of the BCHE K and TF C2 did not differ between the AD patients and controls (P > 0.1). The occurrence of the APOE ε4 did not influence the distribution of the BCHE K and TF C2 variants (P > 0.1). No linkage disequilibrium between the BCHE K and TF C2 was observed either in both the AD patients and controls (P > 0.1). In conclusion, neither the BCHE K nor the TF C2 confers a risk for AD. Received February 9, 2001; accepted June 8, 2001     

Neither adrenergic nor cholinergic antagonists in the central nervous system affect 2-deoxy-D-glucose(2-DG)-induced hyperglycemia

To investigate whether the brain adrenergic and cholinergic neurotransmitter systems are involved in the regulation of 2-deoxy-D-glucose (2-DG)-induced hyperglycemia, we studied the effects of adrenergic and cholinergic antagonists on 2-DG-induced secretion of epinephrine and glucagon, and hyperglycemia, in anesthetized fed rats. When 2-DG (10 mg/10 microliters) was injected into the third cerebral ventricle, hepatic venous plasma glucose, glucagon, and epinephrine concentrations were significantly increased. Co-administration of phentolamine, propranolol, atropine and hexamethonium (1 X 10(-7) mol) with 2-DG did not modify the hyperglycemia and hormonal responses normally observed after the administration of 2-DG alone. From this evidence we concluded that neither brain adrenoceptive nor cholinoceptive neurons are involved in the regulation of 2-DG-induced hyperglycemia.     

Influence of arm movements on saccades in humans

When reaching for an object we usually look at it before we touch it with the hand. This often unconscious eye movement prior to the arm movement allows guiding of the final part of the hand trajectory by visual feedback. We examined the temporal and spatial coordination of this control system by psychophysical measurements of eye and arm movements of naive human subjects looking or looking and pointing as fast as possible to visual targets in physical and virtual-reality setups. The reaction times of saccades to a step-displaced target were reduced, and the number of corrective saccades decreased, when the subject had to produce a corresponding simultaneous hand movement to the same target. The saccadic reaction time was increased when saccade and hand movement went in opposite directions. In a double-step task the reaction time for the second saccade was longer than for the first. Co-use of the hand leads to an additional increase of saccadic reaction time. Taken together this study shows an improvement in initial saccades if they are accompanied by hand movements to the same target. This effect might ensure that the reach target is foveated early and accurately enough to support the visual feedback control of the hand near the target. Longer reaction times for the second saccade to double-step displaced targets might reflect a saccadic refractory time intensified by simultaneous arm movements. These results are discussed in the light of recent findings from our laboratory on saccade- and reach-related neurons in the superior colliculus of macaque monkeys.     

Neither triazolam nor activity phase advance circadian locomotor activity in SCN-lesioned hamsters bearing fetal SCN transplants.

Both triazolam (Tz) and exercise can phase advance free-running locomotor activity rhythms in intact hamsters. Furthermore, Tz increases activity at the time of injection, and this appears to be the mechanism whereby Tz produces phase shifts. This study tested the phase-shifting effect of Tz in SCN-lesioned (SCN-X) hamsters that had regained circadian rhythms of locomotor activity after transplantation of fetal SCN into the third ventricle. The results indicate that in both groups, increases in locomotor activity are seen at the time of Tz injection, and most intact animals, but no grafted animals show a phase advance in response to Tz administration. Given that hamsters bearing SCN grafts have limited neural connections between the host brain and transplanted SCN tissue, the results suggest that a site outside the SCN, with afferents to these nuclei, mediates the phase-shifting effect of Tz and of exercise.     

Low-level deficits in beat perception: Neither necessary nor sufficient for explaining developmental dyslexia in a consistent orthography

This article reports two different studies examining the theoretical account of low-level deficits in beat perception as an alternative explanation of developmental dyslexia in Greek, an orthographically consistent language. Study I examined the relationship of amplitude rise time and frequency discrimination with measures of phonological processing, working memory, and reading fluency in a large unselected sample of Grade 4 children. Study II examined the presence of beat perception deficits in groups of Grade 2, 4, and 6 children with dyslexia and their chronological age controls. The results provided no evidence to support meaningful associations between beat perception tasks and reading or the theoretical account of beat perception deficits as a sufficient explanation or contributing factor to dyslexia. Implications on the importance of auditory processing in reading in orthographically consistent languages are discussed.     

Acetazolamide reduces peripheral afferent transmission in humans

Carbonic anhydrase has been localized in skeletal muscle and nerve, thus, inhibition with acetazolamide (ACZ) may alter nerve and/or muscle function in healthy humans. ACZ (3 oral doses 14, 8, and 2 h prior to testing) reduced isometric force (37%) and peak to peak electromyographic (EMG) amplitude (1.38 mV to 0.83 mV), while increasing EMG latency associated with a unilateral Achilles tendon-tap. Reflex recovery profiles, following a contralateral conditioning tap, were similar in both placebo and ACZ experiments. ACZ led to significant changes in H_max/M_max ratio (52.19/14.42 to 45.73/15.65) and H-reflex latency (34.18 ± 2.54 ms to 35.24 ± 2.74 ms). Motor nerve conduction velocity and maximal voluntary isometric torque (knee extensors) were unaltered by ACZ. These data suggest that inhibition of the tendon-tap reflex and associated isometric force, following ACZ, is related to impairment of synaptic integrity between Ia fibers of the muscle spindle and the alpha motor neuron and not impairment of the muscle spindle or force-generating capacity. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20: 1541–1548, 1997     

Transcranial magnetic stimulation reduces nociceptive threshold in rats

Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate or inhibit nerve cells in the brain noninvasively. TMS induces an electromagnetic current in the underlying cortical neurons. Varying frequencies and intensities of TMS increase or decrease excitability in the cortical area directly targeted. It has been suggested that TMS has potential in the treatment of some neurological disorders such as Parkinson's disease, stroke, and depression. Initial case reports and open label trials reported by several groups support the use of TMS in pain treatment. In the present study, we evaluated the effect of TMS on the nociceptive threshold in the rat. The parameters used were a frequency of 60 Hz and an intensity of 2 and 6 mT for 2 hr twice per day. After 5 days of TMS treatment, rats were evaluated for mechanical, chemical, and cold stimulation. We observed a significant reduction in the nociceptive threshold in TMS-treated rats but not in sham-treated rats in all behavioral tests evaluated. When TMS treatment was stopped, a slow recovery to normal mechanic threshold was observed. Interestingly, i.c.v. MK-801 or CNQX administration reverted the TMS-induced pronociception. The results suggest that high-frequency TMS can alter the nociceptive threshold and produce allodynia in the rats; results suggest the involvement of NMDA and AMPA/KA receptors on TMS-induced allodynia in the rat.     

Prediction of arm movement trajectories from ECoG-recordings in humans

Electrocorticographic (ECoG) signals have been shown to contain reliable information about the direction of arm movements and can be used for on-line cursor control. These findings indicate that the ECoG is a potential basis for a brain-machine interface (BMI) for application in paralyzed patients. However, previous approaches to ECoG-BMIs were either based on classification of different movement patterns or on a voluntary modulation of spectral features. For a continuous multi-dimensional BMI control, the prediction of complete movement trajectories, as it has already been shown for spike data and local field potentials (LFPs), would be a desirable addition for the ECoG, too. Here, we examined ECoG signals from six subjects with subdurally implanted ECoG-electrodes during continuous two-dimensional arm movements between random target positions. Our results show that continuous trajectories of 2D hand position can be approximately predicted from the ECoG recorded from hand/arm motor cortex. This indicates that ECoG signals, related to body movements, can directly be transferred to equivalent controls of an external effector for continuous BMI control.     

Neither B cells nor T cells are required for CNS demyelination in mice persistently infected with MHV-A59

Murine hepatitis virus A59 infection of the central nervous system (CNS) results in CNS demyelination in susceptible strains of mice. In infected B-cell-deficient mice, demyelination not only occurred but was also more severe than in parental C57BL/6 animals. This increase may be due to the persistence of virus in the CNS in the absence of B cells. In mice lacking antibody receptors or complement pathway activity, virus did not persist yet demyelination was similar to parental mice. In infected RAG1(-/-) mice, moderately sized, typical demyelinating lesions were identified. Therefore, demyelination can occur in the absence of B and T cells.     

Neither L-NAME nor L-arginine changes extracellular glutamate elevation and anoxic depolarization during global ischemia and reperfusion in rat

Both the rise in extracellular glutamate concentration and anoxic depolarization in the rat striatum during 15 min of global ischemia and reperfusion were monitored using glutamate biosensor and direct current potential electrodes, respectively. Cerebral blood flow (CBF) was simultaneously monitored with a glutamate biosensor or a direct current potential electrode. Before the onset of ischemia, treatment with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) decreased CBF, while L-arginine increased CBF. However, neither L-NAME nor L-arginine significantly changed CBF during ischemia and reperfusion compared with vehicle-treated animals. The time-course and extracellular glutamate concentration increase during ischemia and reperfusion among L-NAME-, L-arginine- and vehicle-treated animals were very similar. These results were strengthened by the time-course and amplitude of anoxic depolarization. The study suggests that NO is not an important mediator of glutamate release during ischemia and reperfusion.