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ref: -0 tags: implicit motor sequence learning basal ganglia parkinson's disease date: 03-06-2012 22:47 gmt revision:2 [1] [0] [head]

PMID-19744484 What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease.

  • Unilateral lesion of both STN and GPi in one patient. Hence, the patient was his own control.
    • DRastically reduced the need for medication, indicating that it had a profound effect on BG output.
  • Arm contralateral lesion showed faster reaction times and normal movement speeds; ipsilateral arm parkinsonian.
  • Implicit sequence learning in a task was absent.
  • In a go / no-go task when the percent of no-go trials increased, the RT speriority of contralateral hand was lost.
  • " THe risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producting deficits that impair daily life.
  • Subthalamotomy incurs persistent hemiballismus / chorea in 8% of patients; in many others chorea spontaneously disappears.
    • This can be treated by a subsequent pallidotomy.
  • Patient had Parkinsonian symptoms largely restricted to right side.
  • Measured TMS ability to stimulate motor cortex -- which appears to be a common treatment. STN / GPi lesion appears to have limited effect on motor cortex exitability 9other things redulate it?).
  • conclusion: interrupting BG output removes such abnormal signaling and allows the motor system to operate more normally.
    • Bath DA presumably calms hyperactive SNr neurons.
    • Yuo cannot distrupt output of the BG with compete imuntiy; the associated abnormalities may be too subtle to be detected in normal behaviors, explaniing the overall clinical improbement seen in PD patients after surgery and the scarcity fo clinical manifestations in people with focal BG lesions (Bhatia and Marsden, 1994; Marsden and Obeso 1994).
      • Our results support the prediction that surgical lesions of the BG in PD would be associated with inflexibility or reduced capability for motor learning. (Marsden and Obeso, 1994).
  • It is better to dispense with faulty BG output than to have a faulty one.

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ref: Steigerwald-2008.11 tags: parkinsons disease essential tremor DBS STN VIM date: 02-22-2012 18:40 gmt revision:4 [3] [2] [1] [0] [head]

PMID-18701754[0] Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state

  • Recorded from the STN in both PD and ET patients -- with the ET patients acting as a control (sorta; as good as we'll get).
  • ET is common neuromotor condition that involves intention tremor and movement overshoot; progresses over many years.
    • Malfunction of the olivocerebellar pathways.
    • no involvement of Dopamine-dependent pathways.
  • 65 PD patients!
  • Classified single units based on ISI & the asymmetry index, the ratio of the mode to the mean of the ISI histogram.
    • bursting or burstlike firing, intermitten grouped firing separated by periods of pauses.
      • Further analyzed for burstlike features via 'burst surprise method' Salcman 1985).
    • irregular, broad ISI CV > 85.
    • Regular tonic firing, bell shaped ISI, CV < 90.
  • PD patients had more burst-like neurons; ET patients had more irregular neurons.
  • Neurons with theta and beta characteristics predominated in bursting neurons (71/81); gamma oscillationgs were commonly found in nonbursting cells (8/11).
  • Only found synchronized beta activity in SUAs recorded from PD patients.
  • Levy: emphasized the importance of tremor for beta-band oscillations because the majority of synchronous cells were recorded from five patients with resting tremor in the operating room, whereas no synchronous pairs were found in nontremulous patients.
  • aha! a limitation of our study, however, is the lack of tremor recordings during surgeries // we were therefore not able to determine the amount of tremor-locked activity within the 3-10 Hz or transient changes in response to intermittent tremor.
    • Another limitation: no movements, attention could have wandered.
  • Still, STN firing rate increased, as per MPTP model.
  • Shift toward bursting type activity in PD.
  • Did not find differences in the proportion of neurons exhibiting intrinsic oscillatory activity or interneuronal synchronization.
  • Large proportion of neurons exhibiting theta-band activity around 4Hz in PD patients; c.f. monkeys, 10 Hz activity dominates.
    • Tremor is not an accurate reporter of pathology.

____References____

[0] Steigerwald F, Pötter M, Herzog J, Pinsker M, Kopper F, Mehdorn H, Deuschl G, Volkmann J, Neuronal activity of the human subthalamic nucleus in the parkinsonian and nonparkinsonian state.J Neurophysiol 100:5, 2515-24 (2008 Nov)

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ref: RodriguezOroz-2001.09 tags: STN SNr parkinsons disease single unit recording spain 2001 tremor oscillations DBS somatotopy organization date: 02-22-2012 18:24 gmt revision:12 [11] [10] [9] [8] [7] [6] [head]

PMID-11522580[0] The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics

  • Looks like they discovered exactly what we have discovered ... only in 2001. This is both good and bad.
    • From the abstract: "Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded."
  • Again, from the abstract: "The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys."
  • It may be that we want to test differential modulation / oscillation: look for differences between rest and activity, if there is sufficient support for both these in the files we have.
  • These people were much, much more careful about localization of their single-electrode tracks. E.g. they calculated electrode location relative the DBS electrode stereotatically, and referenced this to the postoperative MRI location of the treatment electrode.
  • Many more (32% of 350 neurons) responded to active or passive movement.
  • Of this same set, 15% (31 neurons) had a firing rate with rhythmical activity; 38 neurons had rhythmic activity associated with oscillatory EMG, but most of these were responsive to passive stimulation.
  • Autocorrelation of the neuronal bursting and tremor peaked at mean 7Hz, while autocorr. of EMG peaked at mean 5Hz.
  • This whole paragraph is highly interesting: ''The neuronal response associated with active movements was studied by simultaneous recording of neuronal EMG activity of the limbs. Five tremor-related neurons, recorded while a voluntary movement was performed, were available for analysis. Voluntary activation of a particular limb segment arrested the tremor. This was associated with a change in the discharges of the recorded neuron, which fired at a slower rate and in synchrony with the voluntary movement. On occasions, freezing of the voluntary movement ensued and tremor reappeared, changing the neuronal activity back to the typical 4-5Hz tremor-related activity. The cross-correlation analysis of two such neurons showed a peak frequency of 4.63 and 4.88 Hz for tremor-related activity, and 1.5 to 1.38 Hz during voluntary movement. Whether neuronal discharges in the STN preceded or followed EMG activity of the limbs could not be precisely established under the present conditions.
  • Somatotopic representation in the STN is expected from normal and MTPT-treated monkeys. Indeed, somatotopy is enhanced int he GPm of MTPT-treated monkeys.
    • This somatotopy is likely to result from organized afferent from the primary motor cortex (M1) to dorsolateral STN; this is the target of DBS treatment. Ventral and medial STN seems to project to associative and limbic cortical regions.
    • It seems they think the STN is generally not diseased, it is just a useful target for stimulating without evoked movement as in M1. This is consistent with optogenetic studies by Deisseroth [1].
    • Supporting this: "DBS of STN in Parkinson's disease improves executive motor functions, but aggravates conditional associative learning.
  • Interesting: In Parkinson's disease patients with tremor, Levy and colleagues found synchronization and a high firing rate (>10Hz) while recording pairs of neurons >600um apart.
  • Recordings of cortical activity through EEG and STN LFP showed significant coherence in the beta and gamma frequency bands during movement - consistent with corticosubthalamic motor projection. ... and suggest that the STN neurons involved in parkinsonian tremor are the same as the ones ativated during the performance of a voluntary movement. (! -- I agree with this.)
  • More: The reciprocal inhibitory-excitatory connections tightly linking the GPe and the STN may generate self-perpetuating oscillations.

Old notes:

  • this paper concentrates on STN electrophysiology in PD.
    • has a rather excellent list of references.
  • found a somatotopic organization in the STN, with most motor-related units more irregular and in the dorsolateral STN.
  • found a substantial fraction of tremor-synchronized neurons.
  • conclude that the somatotopic organization is about the same as in monkeys (?) (!)
  • M1 projects to STN, as verified through anterograde tracing studies. [1] These neurons increase their firing rate in response to passive movements.
  • there appears to be a relatively-complete representation of the body in the dorsolateral STN.

____References____

[0] Rodriguez-Oroz MC, Rodriguez M, Guridi J, Mewes K, Chockkman V, Vitek J, DeLong MR, Obeso JA, The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.Brain 124:Pt 9, 1777-90 (2001 Sep)
[1] Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K, Optical deconstruction of parkinsonian neural circuitry.Science 324:5925, 354-9 (2009 Apr 17)

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ref: -0 tags: stem cell therapy parkinsons disease DBS date: 02-21-2012 19:04 gmt revision:1 [0] [head]

PMID-15272269 Stem cell therapy for human neurodegenerative disorders-how to make it work.

  • Before clinical trials are initiated, we need to know how to control stem cell proliferation and differentiation into specific phenotypes, induce integration into existing circuits and optimize functional recovery in animal models. (from abstract)
  • It may seem untralistic, though, to induce functional recovery by replacing cells lost through disease, considering the complexity of human brain structure and function.
    • Animal models have shown at least that it is possible.
  • Intrastriatal transplantation of human fetal mesencephatic tissue have provided a proof of principle that neuronal replacement can work in humans; neurons survive, even as the patients own SN neurons die, for up to 10 years [1,2]. Seems they can become functionally integrated into the brain, and releive symptoms of akinesia [3].
  • Sham-controlled surgieries showed modest benefit, showing that the transplantation techniques are suboptimal.
  • Dyskinesias are a common side-effect in 7-15% of patients, likely due to patchy reinervation or inflammatory response to the grafted cells.
  • Unlikely that this will be a common treatment, due to unavailabiltiy of the fetal tissue.
    • Better bet: culture the cells in vitro.
  • Requirements for graft:
    • Cells should release a regulated amount of DA
    • Cells must reverse PD in animal models
    • at least 1e5 cells must survive in humans
    • grafted cells should establish a dense terminal network throughout the striatum
    • and cells should become functionally integrated into the BG.
      • Debilitating symptoms in PD and related disorders are caused by pathological canges in non-dopaminergic systems (neuroplasticity hypothesis).
      • For more complete reversal of Parkinson's symptoms, it may be necessary to stimulate regrowth of axons from grafts in the SNpc to the striatum, which would require modification of host migration markers / growth inhibitory mechanisms [33].
  • Only embryonic stem cells have been shown to work; stem cells from the adult brain don't.
    • Human ESC may have chromosomal instability.
  • Only 5-10% of cells in fetal mesencelphatic grafts are dopaminergic neurons. It is not yet known whether it is favorable to implant pure DA cells or if the grant should contain other cells, like glia, specifically atrocytes, which control cell fate [18,19].
  • Many different pathways to dopmaninergic ESC.
    • FACS = fluorescence-assisted cell sorting.
  • To date, improvements after fetal grafts have not exceeded those found with deep brain stimulation [4,6,7], and there is no convincing evidence for the reversal of drug-resistant symptoms [4]
    • Even in animals with good reinnervation improvements are only partial [27].
  • Some evidence for the generation of striatal neurons in mice after a stroke -- figure 3.
  • Implantation of mouse ESCs into rat striatum caused teratomas in 20% of the animals [36].
    • ESCs are more likely to generate tumors when implanted in the same species that they were derived from.

Stroke:

  • No notable regeneration int eh cerebral cortex.
  • Targeted apoptosis of neurons in mice, leaving tissue intact, leads to reformation of cortical neurons which extend axons into the thalamus. Therefore restricted self-repair is probably due to lack of cues to trigger neurogenesis from SC.

ALS:

  • Several promising lines of research, but much more basic science needs to be done regarding differentiation and delivery before treatment can be attempted.
  • Protecting existing neurons from degeneration seems like a better strategy.

Synthesis:

  • Much more work is required, especially the basic science of differentiation / cell survival, but it's undoubtedly worth it.

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ref: OSuilleabhain-1998.11 tags: analysis tremor parkinsons disease date: 07-19-2010 19:22 gmt revision:2 [1] [0] [head]

PMID-9827772[0] Time-frequency analysis of tremor

  • Frequency of tremor in non-attended, non-tapping leg and arm changed frequency and synchronized:
    • For example, arm and leg tremors at 5.2 and 3.8 Hz, respectively, shifted to a common frequency of 4.6 Hz in one Parkinsons disease patient while using the contralateral arm to perform a tapping movement in time with a metronome at 2 Hz.
    • Psychogneic tremor was sychronized to the metronome in normal volunteers (e.g. 2Hz or 4Hz).
  • PSD was estimated via the welch method of averaging periodograms (FFT length 128, kaiser window segments overlapping 50%)
  • Also used the wigner method for tracking frequency changes in the tremor; this yeilded estimates every 0.5s with 0.1Hz resolution.

____References____

[0] O'Suilleabhain PE, Matsumoto JY, Time-frequency analysis of tremors.Brain 121 ( Pt 11)no Issue 2127-34 (1998 Nov)