No abstract

Gait impairment in PSP is especially associated with dysfunction of the indirect, modulatory prefrontal-subthalamic-pedunculopontine loop of locomotor control. The direct, stereotyped locomotor loop from the primary motor cortex to the spinal cord with rhythmic cerebellar drive shows increased activity in PSP. The latter can be interpreted as an attempt of compensation, but may also contribute to a stereotyped gait pattern in PSP.

Primary orthostatic tremor is a rare neurological disease characterized mainly by a high frequency tremor of the legs while standing. The aim of this study was to identify the common core structures of the oscillatory circuit in orthostatic tremor and how it is modulated by changes of body position. Ten patients with orthostatic tremor and 10 healthy age-matched control subjects underwent a standardized neurological and neuro-ophthalmological examination including electromyographic and posturographic recordings. Task-dependent changes of cerebral glucose metabolism during lying and standing were measured in all subjects by sequential F-fluorodeoxyglucose-positron emission tomography on separate days. Results were compared between groups and conditions. All the orthostatic tremor patients, but no control subject, showed the characteristic 13-18 Hz tremor in coherent muscles during standing, which ceased in the supine position. While lying, patients had a significantly increased regional cerebral glucose metabolism in the pontine tegmentum, the posterior cerebellum (including the dentate nuclei), the ventral intermediate and ventral posterolateral nucleus of the thalamus, and the primary motor cortex bilaterally compared to controls. Similar glucose metabolism changes occurred with clinical manifestation of the tremor during standing. The glucose metabolism was relatively decreased in mesiofrontal cortical areas (i.e. the medial prefrontal cortex, supplementary motor area and anterior cingulate cortex) and the bilateral anterior insula in orthostatic tremor patients while lying and standing. The mesiofrontal hypometabolism correlated with increased body sway in posturography. This study confirms and further elucidates ponto-cerebello-thalamo-primary motor cortical activations underlying primary orthostatic tremor, which presented consistently in a group of patients. Compared to other tremor disorders one characteristic feature in orthostatic tremor seems to be the involvement of the pontine tegmentum in the pathophysiology of tremor generation. High frequency oscillatory properties of pontine tegmental neurons have been reported in pathological oscillatory eye movements. It is remarkable that the characteristic activation and deactivation pattern in orthostatic tremor is already present in the supine position without tremor presentation. Multilevel changes of neuronal excitability during upright stance may trigger activation of the orthostatic tremor network. Based on the functional imaging data described in this study, it is hypothesized that a mesiofrontal deactivation is another characteristic feature of orthostatic tremor and plays a pivotal role in development of postural unsteadiness during prolonged standing.

Spatial orientation was tested during a horizontal and vertical real navigation task in humans. Video tracking of eye movements was used to analyse the behavioral strategy and combined with simultaneous measurements of brain activation and metabolism ([18F]-FDG-PET). Spatial navigation performance was significantly better during horizontal navigation. Horizontal navigation was predominantly visually and landmark-guided. PET measurements indicated that glucose metabolism increased in the right hippocampus, bilateral retrosplenial cortex, and pontine tegmentum during horizontal navigation. In contrast, vertical navigation was less reliant on visual and landmark information. In PET, vertical navigation activated the bilateral hippocampus and insula. Direct comparison revealed a relative activation in the pontine tegmentum and visual cortical areas during horizontal navigation and in the flocculus, insula, and anterior cingulate cortex during vertical navigation. In conclusion, these data indicate a functional anisotropy of human 3D-navigation in favor of the horizontal plane. There are common brain areas for both forms of navigation (hippocampus) as well as unique areas such as the retrosplenial cortex, visual cortex (horizontal navigation), flocculus, and vestibular multisensory cortex (vertical navigation). Visually guided landmark recognition seems to be more important for horizontal navigation, while distance estimation based on vestibular input might be more relevant for vertical navigation.

Long-term potentiation (LTP) of inputs relaying sensory information from cortical and thalamic neurons to principal neurons in the lateral amygdala (LA) is thought to serve as a cellular mechanism for associative fear learning. Nitric oxide (NO), a messenger molecule widely implicated in synaptic plasticity and behavior, has been shown to enhance LTP in the LA as well as consolidation of associative fear memory. Additional evidence suggests that NO-induced enhancement of LTP and amygdala-dependent learning requires signaling through soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (cGK). Mammals possess two genes for cGK: the prkg1 gene gives rise to the cGK type I isoforms, cGKI␣ and cGKI␤, and the prkg2 gene encodes the cGK type II. Reportedly, both cGKI and cGKII are expressed in the amygdala, and cGKII is involved in controlling anxiety-like behavior. Because selective pharmacological tools for individual cGK isoforms are lacking, we used different knock-out mouse models to examine the function of cGKI and cGKII for LTP in the LA and pavlovian fear conditioning. We found robust expression of the cGKI specifically in the LA with cGKI␤ as the prevailing isoform. We further show a marked reduction of LTP at both thalamic and cortical inputs to the LA and a selective impairment of auditory-cued fear memory in cGKI-deficient mutants. In contrast, cGKII null mutants lack these phenotypes. Our data suggest a function of cGKI, likely the ␤ isoform, in the LA, supporting synaptic plasticity and consolidation of fear memory.