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    • Fig Right side shows that the percent habituation in stage

    2018-10-26

    Fig. 1 (Right side) shows that the percent habituation in stage 5 patients differed from controls at the 250ms and 500ms intervals, but was restored to control levels by bilateral pallidotomy. We speculated that the increased PPN output in PD was instantly re-inhibited or down regulated by the surgery to normalize sensory gating and hyperarousal to phasic inputs [33]. The importance of these results is that there is an immediate effect by the therapy in reinstituting a balance of activity. The damage to the SN apparently induces a disturbance that can be corrected by additional damage (pallidotomy) [33]. One conclusion is that the symptoms involved can be alleviated almost instantly by appropriate treatment, not requiring extended reorganization or regeneration, etc. Since lesion of a region provides little flexibility in the approach, a therapeutic strategy that can be modified with changes in status, for instance, as the disease progresses, would be more desirable. Prior to the use of l-DOPA for the treatment of PD, lesions of the thalamus and pallidum were being used, but pharmacological treatment became the preferred form of therapy [34]. While the use of l-DOPA has been effective for some of the symptoms of the disease, long-term use (>5 years) and increasing dosages can lead to dyskinesias. Other agents have been used but they provide less effective relief and can produce unwanted side effects. Surgical treatment includes the use of thalamotomy, pallidotomy, and subthalamic nucleus lesions. Nowadays, the most common therapeutic approach involves deep order Asiatic acid stimulation (DBS), with the most common site used being the subthalamic nucleus (STN). However, DBS of the PPN is now being used for the treatment of PD.
    Stimulation of the region of the pedunculopontine nucleus (PPN) The first investigators to stimulate the region of the PPN were Moruzzi and Magoun [35] to transform the electroencephalogram (EEG) from slow wave activity to fast activity. They used chloralose-anesthetized or midbrain-transected (decerebrate) cats and stimulated the region of the mesencephalic reticular formation. They also performed lesions immediately anterior to the PPN that eliminated the effects of such stimulation. These studies typically used stimulation frequencies of 300Hz, but established that 50Hz stimulation was close to the lowest effective frequency. Interestingly, the effects of stimulation had a latency, typically under 1s, that is, stimulation was not instantaneous, but effective in inducing high frequency EEG at short latency. Many years later, other investigators reported the presence of a region called the mesencephalic locomotor region (MLR), stimulation of which in the midbrain-transected (decebrate) cat, induced controlled locomotion on a moving treadmill [36]. By controlled locomotion, workers meant that increasing current levels order Asiatic acid elicited a walk, then a trot, then a gallop. Moreover, locomotion entailed alternation of antagonists in the same limb, and of agonizts in different limbs. These parameters are important because they establish a specific relation to stepping, rather than a general correlation with so-called “activity” or “exploration”. The parameters of stimulation were quite specific, requiring low current levels (<100μA), 40–60Hz stimulation, and localized to the lateral, but not the medial, cuneiform nucleus. We investigated this region and ultimately established that the MLR was not a locomotion-specific region, but actually a rhythmogenic area that overlapped with the histologically identified PPN, that basically drove descending projections to induce changes in posture and locomotion [37–39]. Stimulation at high frequency (300Hz) typically induced reduction in extensor muscle tone [40], while stimulation at 40–60Hz induced locomotion [37–39]. We concluded that the optimal site of stimulation was in the lateral cuneiform nucleus, and that stimulation “recruited”, rather than “induced” locomotion, since it required ~1s of stimulation to have the desired effect [37–39,41]. It was this line of research that led us to propose the use of PPN DBS for the treatment of PD.