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Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[(18)F]FMeNER-D(2). (S,S)-[(18)F]FMeNER-D(2) appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[(18)F]FMeNER-D(2) in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[(18)F]FMeNER-D(2) as a molecular imaging biomarker in AD.

A postural control system in the lamprey is driven by vestibular input and maintains the dorsal-side-up orientation of the animal during swimming. After a unilateral labyrinthectomy (UL), the lamprey continuously rolls toward the damaged side. Normally, a recovery of postural equilibrium ("vestibular compensation") takes about 1 mo. However, illumination of the eye contralateral to UL results in an immediate and reversible restoration of equilibrium. Here we used eye illumination as a tool to examine a functional recovery of the postural network. Important elements of this network are the reticulospinal (RS) neurons, which are driven by vestibular input and transmit commands for postural corrections to the spinal cord. In this study, we characterized modifications of the vestibular responses in individual RS neurons caused by UL and the effect exerted on these responses by eye illumination. The activity of RS neurons was recorded from their axons in the spinal cord by chronically implanted electrodes, and spikes in individual axons were extracted from the population activity signals. The same neurons were recorded both before and after UL. Vestibular stimulation (rotation in the roll plane through 360 degrees ) and eye illumination were performed in quiescent animals. It was found that the vestibular responses on the UL-side changed only slightly, whereas the responses on the opposite side disappeared almost completely. This asymmetry in the bilateral activity of RS neurons is the most likely cause for the loss of equilibrium in UL animals. Illumination of the eye contralateral to UL resulted, first, in a restoration of vestibular responses in the neurons inactivated by UL and in an appearance of vestibular responses in some other neurons that did not respond to vestibular input before UL. These responses had directional sensitivity and zones of spatial sensitivity similar to those observed before UL. However, their magnitude was smaller than before UL. Second, the eye illumination caused a reduction of the magnitude of vestibular responses on the UL side. These two factors tend to restore symmetry in bilateral activity of RS neurons, which is the most likely cause for the recovery of equilibrium in the swimming UL lamprey. Results of this study are discussed in relation to the model of the roll control system proposed in our previous studies as well as in relation to the vestibular compensation.

In the swimming lamprey, a postural control system maintains a definite orientation of the animal's longitudinal axis in relation to the horizon (pitch angle). Operation of this system is based on vestibular reflexes. Important elements of the postural network are the reticulospinal (RS) neurons, which are driven by vestibular input and transmit commands for postural corrections from the brain stem to the spinal cord. Here we describe responses to vestibular stimulation (rotation of the animal in the pitch plane) in RS neurons of intact lampreys. The activity of neurons was recorded from their axons in the spinal cord by chronically implanted arrays of macroelectrodes. From the multielectrode recordings of mass activity, discharges in individual axons were extracted by means of a spike-sorting program, and the axon position in the spinal cord and its conduction velocity were determined. Vestibular stimulation was performed by rotating the animal in steps of 45 degrees throughout 360 degrees or by periodical "trapezoid" tilts between the nose-up and -down positions. Typically, the RS neurons exhibited both dynamic responses (activity during movement) and static responses (activity in a new sustained position). The neurons were classified into two groups according to their pattern of response. Group UP neurons responded preferentially to nose-up rotation with maximal activity at 0-135 degrees up. Group DOWN neurons responded preferentially to nose-down rotation with maximal activity at 0-135 degrees down. Neurons of the two groups also differed in the position of their axons in the spinal cord and axonal conduction velocity. An increase in water temperature, which presumably causes a downward turn in swimming lampreys, affected the activity in the UP and DOWN groups differently, so that the ratio UP responses to DOWN responses increased. We suggest that the UP and DOWN groups mediate the opposing vestibular reflexes and cause the downward and upward turns of the animal, respectively. The lamprey will stabilize the orientation in the pitch plane at which the effects of UP and DOWN groups are equal to each other. In addition to the main test (rotation in the pitch plane), the animals were also tested by rotation in the transverse (roll) plane. It was found that 22% of RS neurons responding to pitch tilts also responded to roll tilts. The overlap between the pitch and roll populations suggests that the RS pathways are partly shared by the pitch and roll control systems.

Background and Purpose— Dexterous object manipulation, requiring generation and control of finger forces, is often impaired after stroke. This study aimed to describe recovery of precision grip force control after stroke and to determine clinical and imaging predictors of 6-month performance. Methods— Eighty first-ever stroke patients with varying degrees of upper limb weakness were evaluated at 3 weeks, 3 months, and 6 months after stroke. Twenty-three healthy individuals of comparable age were also studied. The Strength-Dexterity test was used to quantify index finger and thumb forces during compression of springs of varying length in a precision grip. The coordination between finger forces (CorrForce), along with Dexterity-score and Repeatability-score, was calculated. Anatomical magnetic resonance imaging was used to calculate weighted corticospinal tract lesion load (wCST-LL). Results— CorrForce, Dexterity-score, and Repeatability-score in the affected hand were dramatically lower at each time point compared with the less-affected hand and the control group, even in patients with mild motor impairment according to Fugl-Meyer assessment. Improved performance over time occurred in CorrForce and Dexterity-score but not in Repeatability-score. The Fugl-Meyer assessment hand subscale, sensory function, and wCST-LL best predicted CorrForce and Dexterity-score status at 6 months (R 2 =0.56 and 0.87, respectively). wCST-LL explained substantial variance in CorrForce (R 2 =0.34) and Dexterity-score (R 2 =0.50) at 6 months; two-point discrimination and Fugl-Meyer score accounted for considerable additional variance. Absence of recovery in CorrForce was predicted by wCST-LL >4 cc and in Dexterity-score by wCST-LL >6 cc. Conclusions— Findings highlight persisting deficits in the ability to grasp and control finger forces after stroke. wCST-LL was the strongest predictor of performance at 6 months, but early two-point discrimination and Fugl-Meyer score had substantial additional predictive value. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02878304.

pathways. The axons of larger RS neurons reach the most caudal of approximately 100 spinal segments, whereas the VS pathway does not descend below the 15th segment. This study was carried out to compare functional projections of RS and VS neurons in the rostral spinal segments that the neurons innervate together. To reveal these projections, individual RS or VS neurons were stimulated, and the responses of different groups of spinal motoneurons were recorded in ventral root branches to dorsal and ventral parts of myotomes. The responses were detected using a spike-triggered averaging technique on the background of ongoing motoneuronal activity. Individual RS and VS neurons exerted uniform effects on segmental motor output within this rostral part of the spinal cord. The effects of VS neurons on different groups of motoneurons were weaker and less diverse than those of RS neurons. The results indicate that VS neurons are able to elicit a flexion of the rostral part of the body and to turn the head in different planes without affecting more caudal parts. By contrast, larger RS neurons can elicit head movement only together with movement of a considerable part of the body and thus seem to be responsible for formation of gross motor synergies.

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