Marjorie E. Anderson

Monosynaptic inhibition of thalamic neurons produced by stimulation of the substantia nigra

Electrical stimulation to the substantia nigra (Pars reticulata) produced a monosynaptic inhibition of the neurons of the ventromedial necleus of the thalamus in anesthetized cats.

A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease

More than 80 years after iron accumulation was initially described in the substantia nigra (SN) of Parkinsons disease (PD) patients, the mechanisms responsible for this phenomenon are still unknown. Similarly, how iron is delivered to its major recipients in the cell - mitochondria and the respiratory complexes - has yet to be elucidated. Here, we report a novel transferrin/transferrin receptor 2 (Tf/TfR2)-mediated iron transport pathway in mitochondria of SN dopamine neurons. We found that TfR2 has a previously uncharacterized mitochondrial targeting sequence that is sufficient to import the protein into these organelles. Importantly, the Tf/TfR2 pathway can deliver Tf bound iron to mitochondria and to the respiratory complex I as well. The pathway is redox-sensitive and oxidation of Tf thiols to disulfides induces release from Tf of highly reactive ferrous iron, which contributes to free radical production. In the rotenone model of PD, Tf accumulates in dopamine neurons, with much of it accumulating in the mitochondria. This is associated with iron deposition in SN, similar to what occurs in PD. In the human SN, TfR2 is also found in mitochondria of dopamine neurons, and in PD there is a dramatic increase of oxidized Tf in SN. Thus, we have discovered a novel mitochondrial iron transport system that goes awry in PD, and which may provide a new target for therapeutic intervention.

Discharge patterns of basal ganglia neurons during active maintenance of postural stability and adjustment to chair tilt.

Neurons in the putamen and globus pallidus were studied in awake monkeys making active postural adjustments during static and dynamic chair tilt. When the chair was held horizontal and the monkey actively maintained a restricted head position, neurons had tonic firing rats similar to those described previously, with low frequency patterns in the putamen and low frequency-burst or intermediate (IFD) to high frequency (HFD) tonic patterns in neurons in the pallidal segments. Over half of the neurons with IFD or HFD discharge rates and a smaller proportion of those with slow discharge rates showed changes in firing that were temporally correlated with chair tilt. Phase shifts of firing frequency relative to sinusoidally vaired chair position varied in units with different tonic discharge frequencies. Maximum and minimum discharge rates in IFD neurons occurred near maximum chair velocities, whereas the phase shift decreased in HFD neurons, which had higher discharge rates during the horizontal chair position. Neurons with changes in discharge during chair tilt were found in all portions of the putamen and globus pallidus studied.

High frequency deep brain stimulation: what are the therapeutic mechanisms?

High frequency deep brain stimulation (HFS) used to treat the symptoms of Parkinsons disease (PD) was first assumed to act by reducing an excessive tonic GABAergic inhibitory output from the internal globus pallidus (GPi). Stimulation in GPi might produce this directly by mechanisms such as depolarization block or activation of presynaptic inhibitory fibers, and the same mechanisms evoked by HFS in the subthalamic nucleus (STN) could reduce the excitatory action of STN on GPi neurons. Although somatic recordings from neurons near the stimulation site may appear to support this potential mechanism, the action downstream from the site of stimulation often is not consistent with this interpretation. A more parsimonious explanation for the similar effects of HFS in STN or GPi and a lesion of either of these structures is that both HFS and pallidotomy interrupt an abnormal pattern of firing in cortico-basal ganglia-thalamocortical loops that is responsible for the symptoms of PD.

SACCADIC EYE MOVEMENTS AND EYE-HEAD COORDINATION IN CHILDREN

The eye and head movements of nine children, ages 6 through 10, were measured in order to establish quantitative characteristics of eye movements and eye-head coordination patterns of children with normal vision and reading levels. The relationship between saccade amplitude and duration was linear, but the slope of this relationship indicated that saccades in children may have higher velocities than they do in adults. One of three temporal patterns of head and saccadic eye movement occurred during shifts of gaze to visual targets, depending on the temporal and spatial predictability of the target. It is suggested that quantitative measurements such as these could be used to examine developmental characteristics of eye and eye-head movement control.

Features of targeted arm movement after unilateral excisions that included the supplementary motor area in humans

The strategies used to make rapid targeted flexion movements at the elbow were assessed for the right and left arms of ten neurologically normal subjects and seven patients who had unilateral cortical resections that included all or part of one supplementary motor area (SMA). Visual targets were displaced either a constant distance (fixed step task) or a variable distance (variable step task). The reaction time (RT) for SMA patients as a group did not differ significantly from normal, although for some patients, RT exceeded the normal range bilaterally. Total movement time (TMT) was longer than normal for the SMA group, and again, increased TMTs tended to occur bilaterally. Both groups of subjects used a combination of duration and velocity scaling to adjust movement amplitude. In normal subjects, however, velocity scaling predominated, whereas in SMA patients, duration scaling was increased bilaterally. Our data indicate that the initiation of rapid elbow movement to a target presented visually is not consistently delayed after lesions that include part of the SMA, but the movement speed and strategy used to adjust movement amplitude may be changed bilaterally.

The Basal Ganglia and Movement

Early clinical reports, such as James Parkinson’s “An Essay on the Shaking Palsy” (Parkinson, 1817), gave vivid descriptions of the complex motor symptoms that now are associated with pathological changes in the basal ganglia, and it is primarily from the subsequent clinical literature that information has originated regarding possible roles of the basal ganglia in the coordination of movement. Degeneration of neurons in various nuclei of the basal ganglia has been found in the brains of individuals who had marked slowness or apparent absence of voluntary movement under certain conditions (bradykinesia or akinesia), but these same individuals also may have had an involuntary phasic activity of motor units that produced an incessant resting tremor. Other individuals with pathological changes in the basal ganglia exhibit the more dramatic involuntary movements of athetosis, chorea, or ballismus. As experimental studies were added to clinical-pathological correlations, a common theme appeared, and the basal ganglia were referred to as “centers for the automatic or subvoluntary integration of the various motor centers” (Ferrier, 1876), “supravestibular systems” (Muskens, 1922), “a group... concerned with posture other than the support of the body against gravity” (Martin, 1967). Denny-Brown (1962) even referred to the globus pallidus, from which many of the basal ganglia output fibers originate, as “the ‘head ganglion’ of the motor system of primates, forming the essential link between the environment and the reflex organization.”

Pallidal and Cortical Determinants of Thalamic Activity

Output from the basal ganglia reaches the cerebral cortex via the thalamus. In the primate, GABAergic axons from the internal pallidal segment (GPi) and the substantia nigra, pars reticulata (SNr) provide an inhibitory input to the ventral anterior (VA), oral, and some of the caudal portions of the ventrolateral (VLo and VLc), the ventromedial (VM), and to some extent, the dorsomedial (MD) thalamic nuclei (Sakai et al., 1996; Kultas-Ilinsky et al., 1997; Ilinsky et al., 1993; DeVito and Anderson, 1982). Changes in this inhibition are presumed to be major contributors to the symptoms of Parkinson’s disease (Hutchison et al., 1994; Wichmann et al., 1999), and several therapeutic interventions, such as pallidotomy or deep brain stimulation, are directly targeted at modification of pallidal output.

Motor Effects Produced by Disruption of Basal Ganglia Output to the Thalamus

When a limb movement is made to a target, information relevant to a series of decisions or parametric values must be carried in the eventual neural output to muscles. One way to examine the role(s) of the basal ganglia in controlling movement, then, is to examine the influence of basal ganglia output on these movement-related decisions or parameters, several of which are shown diagrammatically in Figure 1.

Pallidal Output Circuits in the Thalamus

The activity of electrophysiologically-identified pallidalreceiving (PR) neurons in the thalamus has been examined during a task that required arm movements to visible or remembered target locations. As is the case for pallidal neurons and cells in many cortical areas, PR cells with movement-related changes in discharge may also show changes in activity immediately following a visual cue (cue activity), or they may show prolonged changes in activity during the precue-trigger interval (preparatory activity). Movement-related changes in discharge were directionally tuned for half of the PR neurons studied. Directional tuning was broad and often fit well by a cosine model. Directional tuning of cue- or preparatory activity was consistent with that measured during the perimovement epoch. When muscimol was injected into the arm area of the internal pallidal segment, arm position became unstable, movements were slowed, and the tonic discharge rate of PR neurons was increased. The task-related phasic changes in neuronal activity were not abolished, however. We conclude that sources other than the basal ganglia, and especially the corticothalamic neurons, may contribute important phasic task-related signals to the PR thalamus.