Brain white matter microstructure is associated with susceptibility to motion-induced nausea.

Nausea is associated with significant morbidity, and there is a wide range in the propensity of individuals to experience nausea. The neural basis of the heterogeneity in nausea susceptibility is poorly understood. Our previous functional magnetic resonance imaging (fMRI) study in healthy adults showed that a visual motion stimulus caused activation in the right MT+/V5 area, and that increased sensation of nausea due to this stimulus was associated with increased activation in the right anterior insula. For the current study, we hypothesized that individual differences in visual motion-induced nausea are due to microstructural differences in the inferior fronto-occipital fasciculus (IFOF), the white matter tract connecting the right visual motion processing area (MT+/V5) and right anterior insula. To test this hypothesis, we acquired diffusion tensor imaging data from 30 healthy adults who were subsequently dichotomized into high and low nausea susceptibility groups based on the Motion Sickness Susceptibility Scale. We quantified diffusion along the IFOF for each subject based on axial diffusivity (AD); radial diffusivity (RD), mean diffusivity (MD) and fractional anisotropy (FA), and evaluated between-group differences in these diffusion metrics. Subjects with high susceptibility to nausea rated significantly (P < 0.001) higher nausea intensity to visual motion stimuli and had significantly (P < 0.05) lower AD and MD along the right IFOF compared to subjects with low susceptibility to nausea. This result suggests that differences in white matter microstructure within tracts connecting visual motion and nausea-processing brain areas may contribute to nausea susceptibility or may have resulted from an increased history of nausea episodes.

A functional MRI study of three motor tasks in the evaluation of stroke recovery.

Functional brain imaging studies have provided insights into the processes related to motor recovery after stroke. The comparative value of different motor activation tasks for probing these processes has received limited study. We hypothesized that different hand motor tasks would activate the brain differently in controls, and that this would affect control-patient comparisons. Functional magnetic resonance imaging (MRI) was used to evaluate nine control subjects and seven patients with good recovery after a left hemisphere hemiparetic stroke. The volume of activated brain in bilateral sensorimotor cortex and four other motor regions was compared during each of three tasks performed by the right hand: index-finger tapping, four-finger tapping, and squeezing. In control subjects, activation in left sensorimotor cortex was found to be significantly larger during squeezing as compared with index-finger tapping. When comparing control subjects with stroke patients, patients showed a larger volume of activation in right sensorimotor cortex during index-finger tapping but not with four-finger tapping or squeezing. In addition, patients also showed a trend toward larger activation volume than controls within left supplementary motor area during index-finger tapping but not during the other tasks. Motion artifact was more common with squeezing than with the tapping tasks. The choice of hand motor tasks used during brain mapping can influence findings in control subjects as well as the differences identified between controls and stroke patients. The results may be useful for future studies of motor recovery after stroke.

Activation of distinct motor cortex regions during ipsilateral and contralateral finger movements.

Previous studies have shown that unilateral finger movements are normally accompanied by a small activation in ipsilateral motor cortex. The magnitude of this activation has been shown to be altered in a number of conditions, particularly in association with stroke recovery. The site of this activation, however, has received limited attention. To address this question, functional magnetic resonance imaging (MRI) was used to study precentral gyrus activation in six control and three stroke patients during right index finger tapping, then during left index finger tapping. In each hemisphere, the most significantly activated site (P < 0.001 required) was identified during ipsilateral and during contralateral finger tapping. In the motor cortex of each hemisphere, the site activated during use of the ipsilateral hand differed from that found during use of the contralateral hand. Among the 11 control hemispheres showing significant activation during both motor tasks, the site for ipsilateral hand representation (relative to contralateral hand site in the same hemisphere) was significantly shifted ventrally in all 11 hemispheres (mean, 11 mm), laterally in 10/11 hemispheres (mean, 12 mm), and anteriorly in 8/11 hemispheres (mean, 10 mm). In 6 of 11 hemispheres, tapping of the contralateral finger simultaneously activated both the ipsilateral and the contralateral finger sites, suggesting bilateral motor control by the ipsilateral finger site. The sites activated during ipsilateral and contralateral hand movement showed similar differences in the unaffected hemisphere of stroke patients. The region of motor cortex activated during ipsilateral hand movements is spatially distinct from that identified during contralateral hand movements.

Quantitative assessment of mirror movements after stroke.

BACKGROUND AND PURPOSE: Mirror movements (MM) are involuntary synchronous movements of one limb during voluntary unilateral movements of the opposite limb. We measured MM in stroke and control subjects and evaluated whether MM after stroke are related to motor function. METHODS: Twenty-three patients and 16 control subjects were studied. A computerized dynamometer was used during two squeezing tasks to measure intended movements from the active hand as well as MM from the opposite hand. Motor deficits were measured with the arm motor component of the Fugl-Meyer scale. RESULTS: During paretic hand squeezing, MM in the unaffected hand were detected in 70% (repetitive squeeze) to 78% (sustained squeeze) of stroke patients. For both tasks, this was significantly (P < 0.05) greater than the incidence of MM in the paretic hand or in either hand of control subjects (17% to 44%), except when compared with the incidence of MM in the dominant hand of control subjects (56%; P = 0.17). The incidence of MM in the paretic hand was not significantly different from that seen in either hand of control subjects. Patients with MM in the unaffected hand had significantly greater motor deficit than patients without MM. Patients with MM in the paretic hand had significantly better motor function than patients without MM. CONCLUSIONS: Simultaneously recording motor performances of both hands provides precise information to characterize MM. MM in the unaffected hand and in the paretic hand are associated with different degrees of motor deficit after stroke. Evaluation of MM may be useful for studying mechanisms of stroke recovery.

Computerized measurement of motor performance after stroke.

BACKGROUND AND PURPOSE: Stroke scales usually convert motor status to a score along an ordinal scale and do not provide a permanent recording of motor performance. Computerized methods sensitive to small changes in neurological status may be of value for studying and measuring stroke recovery. METHODS: We developed a computerized dynamometer and tested 23 stroke subjects and 12 elderly control subjects on three motor tasks: sustained squeezing, repetitive squeezing, and index finger tapping. For each subject, scores on the Fugl-Meyer and National Institutes of Health stroke scales were also obtained. RESULTS: Sustained squeezing by the paretic hand of stroke subjects was weaker (9.2 kg) than the unaffected hand (20.2 kg; P < .0005), as well as control dominant (23.1 kg; P < .0005) and nondominant (19.9 kg; P < .005) hands. Paretic index finger tapping was slower (2.5 Hz) than the unaffected hand (4.2 Hz; P < .01), as well as control dominant (4.7 Hz; P < .0005) and nondominant (4.9 Hz; P < .0005) hands. Many features of dynamometer data correlated significantly with stroke subjects' Fugl-Meyer scores, including sustained squeeze maximum force (rho = .91) and integral of force over 5 seconds (rho = .91); repetitive squeeze mean force (rho = .92) and mean frequency (rho = .73); and index finger tap mean frequency (rho = .83). Correlation of these motor parameters with National Institutes of Health stroke scale score was weaker in all cases, a consequence of the scoring of nonmotor deficits on this scale. Dynamometer measurements showed excellent interrater (r = .99) and intrarater (r = .97) reliability. CONCLUSIONS: The degree of motor deficit quantitated with the dynamometer is strongly associated with the extent of neurological abnormality measured with the use of two standardized stroke scales. The computerized dynamometer rapidly measures motor function along a continuous, linear scale and produces a permanent recording of hand motor performance accessible for subsequent analyses.

Activation of protein kinase C by arachidonic acid selectively enhances the phosphorylation of GAP-43 in nerve terminal membranes.

Arachidonic acid (AA), a cis-unsaturated fatty acid that activates certain subspecies of protein kinase C (PKC), has been proposed to act as a retrograde messenger in modifying the efficacy of synapses during long-term potentiation (LTP). One prominent PKC substrate of the nerve terminal membrane, GAP-43 (F1, B-50, neuromodulin), shows an increase in phosphorylation that correlates with the persistence of LTP. The present study investigated whether AA might exert its effects on presynaptic endings by modulating the phosphorylation of GAP-43 and other membrane-bound proteins. Using synaptosomal membranes from the rat cerebrocortex, in which in vivo relationships between protein kinases and their native substrates are likely to be preserved, we found that in the absence of Ca2+, AA exerted a modest effect on the phosphorylation of GAP-43 and several other proteins; however, when AA was applied in conjunction with Ca2+, GAP-43 showed a particularly striking response: at Ca2+ levels likely to exist at the nerve terminal membrane during synaptic activity (10(-7) to 10(-5) M), AA (50 microM) increased the sensitivity of GAP-43 phosphorylation to Ca2+ by an order of magnitude, and increased its maximal level of phosphorylation by 50%. At resting Ca2+ levels, AA potentiated the stimulation in GAP-43 phosphorylation produced by 4 beta-phorbol 12,13-dibutyrate, a diacylglycerol (DAG) analog. The stimulatory effect of AA and its synergistic interaction with Ca2+ were found to be mediated by PKC, since they were blocked by a specific peptide inhibitor of PKC, [Ala25]PKC(19-31), but were unaffected by an inhibitor of protein phosphatase activity or by scavengers of free radicals. Since GAP-43 has been implicated in the development and plasticity of synaptic relationships, the synergistic effects of AA and the intracellular signals Ca2+ and DAG on the phosphorylation of GAP-43 may serve as an AND gate to modify presynaptic function and/or structure in response to coincident pre- and postsynaptic activity.

Serotonin release varies with brain tryptophan levels.

This study examines directly the effects on serotonin release of varying brain tryptophan levels within the physiologic range. It also addresses possible interactions between tryptophan availability and frequency of membrane depolarization in controlling serotonin release. We demonstrate that reducing tryptophan levels in rat hypothalamic slices (by superfusing them with medium supplemented with 100 microM leucine) decreases tissue serotonin levels as well as both spontaneous and electrically-evoked serotonin release. Conversely, elevating tissue tryptophan levels (by superfusing slices with medium supplemented with 2 microM tryptophan) increases both tissue serotonin levels and serotonin release. Serotonin release was found to be affected independently by tryptophan availability and frequency of electrical field-stimulation (1-5 Hz), since increasing both variables produced nearly additive increases in release. These observations demonstrate for the first time that both precursor-dependent elevations and reductions in brain serotonin levels produce proportionate changes in serotonin release, and that the magnitude of the tryptophan effect is unrelated to neuronal firing frequency. The data support the hypothesis that serotonin release is proportionate to intracellular serotonin levels.

Tryptophan availability modulates serotonin release from rat hypothalamic slices.

Application of a novel in vitro experimental system has allowed us to describe the relationship between tryptophan availability and serotonin release from rat hypothalamic slices. Superfusing hypothalamic slices with a physiologic medium containing l-tryptophan (1, 2, 5, or 10 microM) caused dose-dependent elevations in tissue tryptophan levels; the magnitude of the elevations produced by supplementing the medium with less than 5 microM tryptophan was within the physiologic range for rat brain tryptophan levels. Slice serotonin levels rose biphasically as the tryptophan concentration in the medium was increased. Superfusing the slices with medium supplemented with a low tryptophan concentration (1 or 2 microM) caused proportionally greater incremental changes in serotonin levels than the increases caused by further elevating the tryptophan concentration (5 or 10 microM). The spontaneous release of serotonin from the slices exhibited a dose-dependent relationship with the tryptophan concentration of the superfusion medium. Electrically evoked serotonin release, which was calcium-dependent and tetrodotoxin-sensitive, also increased in proportion to the medium tryptophan concentration. These data suggest that the rate at which serotonin is released from hypothalamic nerve terminals is coupled to brain tryptophan levels. Accelerations in hypothalamic serotonin synthesis, caused by elevating brain tryptophan levels, result in proportionate increases in the rates of serotonin release during rest and with membrane depolarization.

Effect of chronic D-fenfluramine administration on rat hypothalamic serotonin levels and release.

D-fenfluramine, an anorectic agent in rats and man, was administered daily at doses 1.25, 2.5, 5 or 10 mg/kg/day for 10 days, and sacrificed 6 days later. Hypothalamic serotonin (5-HT) levels were unchanged in rats receiving 1.25-5 mg/kg/day of d-fenfluramine but reduced by 22% (p less than 0.01) at the highest drug dose (10 mg/kg/day); hypothalamic 5-hydroxyindole acetic acid (5-HIAA) levels were reduced by 15% (p less than 0.05) or 28% (p less than 0.01) in rats receiving 5 or 10 mg/kg/day of the drug, respectively. Hypothalamic slices prepared from rats which were previously treated with any of the drug doses spontaneously released endogenous 5-HT at rates that did not differ from those of vehicle-treated rats. 5-HT released with electrical field-stimulation was unaffected by prior d-fenfluramine treatment at doses of 1.25-5 mg/kg/day, and was reduced by 20% (p less than 0.05) from slices prepared from rats which received 10 mg/kg/day. 5-HIAA efflux was also attenuated by the highest drug dose. These data indicate that chronic administration to rats of customary anorectic doses of d-fenfluramine (i.e. 0.06-1.25 mg/kg) fail to cause long-lasting reductions in brain 5-HT release.

A second hypothalamic nucleus receiving retinal input in man: the paraventricular nucleus.

A retinofugal projection to the suprachiasmatic nucleus of the hypothalamus has been described in man by means of a newly developed staining technique (PPD) for tracing degenerated fibers in the human brain. We applied the PPD method to the chiasmal/hypothalamic area of human autopsy brains from patients who had incurred prior optic nerve damage. We followed degenerated fibers from the optic nerve through the optic chiasm and the optic tract. At the optic chiasm/tract junction, some fibers were seen to diverge and to form an optic fascicle which traversed the lateral preoptic-anterior hypothalamic area towards the third ventricle. These degenerated fibers terminated in the paraventricular nucleus of the hypothalamus. We suggest that there are at least two retinohypothalamic pathways in man. Some of the neuroendocrine imbalances in blind persons may be attributed to the disruption of the retinal input to the paraventricular and suprachiasmatic nuclei of the hypothalamus. These retinohypothalamic pathways may be the anatomical substrates for light/dark entrainment of human neuroendocrine and autonomic regulatory processes.

Optic neuritis or ophthalmic artery aneurysm? Case presentation with histopathologic documentation utilizing a new staining method.

An elderly woman was admitted to the hospital with a presumptive diagnosis of optic neuritis following abrupt loss of vision in her left eye. Noninvasive studies were unrevealing, and she was put on a course of prednisone. Further visual loss 2 weeks later prompted a second course of prednisone therapy. Six years later the patient died from cardiac arrest. The autopsy revealed an aneurysm arising from the origin of the left ophthalmic artery. Selected brain specimens were histologically examined by application of a newly developed staining technique capable of identifying degenerated axons in human brain tissue even after long survival periods. We traced degeneration from the site of compression at the left optic nerve to five primary visual nuclei. Furthermore, transsynaptic cellular changes were observed in the lateral geniculate nucleus.

A retinohypothalamic pathway in man: light mediation of circadian rhythms.

It has been proposed that, in animals, a retinohypothalamic pathway exists which mediates the synchronization of the diurnal light-dark cycle with the central neural components regulating endogenous rhythms. There have been numerous anatomic, physiologic and behavioral investigations to substantiate this proposed connection in experimental animals. Morphologic investigation of a retinohypothalamic tract in man has awaited the development of a technique capable of axonal tracing in the human brain. The paraphenylenediamine method was applied to 7 post-mortem human brains. Degenerated axons were found in the suprachiasmatic nuclei of the hypothalamus in each of the 4 patients who had incurred prior optic nerve damage. The retinosuprachiasmatic pathway may be the anatomical substrate for the integration of retinal light information with endogenous rhythms in man.