Basal Ganglia, Tremor, Vim-DBS, and the Excitability of Spinal Motor Neuron Pooya Pakarian Presentation based on: Pakarian P, Rayegani SM, and Shahzadi S. (2004) Effect of Vim thalamic DBS in Parkinson's disease on F wave duration. Neurosci Lett. Sep 9;367(3):323-6.

Basal Ganglia Straitum: Pallidum: Other nuclei: 1- Putamen 2- Caudate 3- Nucleus Accumbens (ventral striatum) Pallidum: 1- Globus Pallidus internus 2- GP externus 3- Substantia Innominata (ventral pallidum) Other nuclei: 1- Substantia Nigra pars reticulata 2- SN pars compacta 3- SubThalamic Nucleus (STN)

Caudate Putamen GPe GPi

STN SN (r & c)

Basal Ganglia: 3 circuits Sensoriomotor: Putamen to GPi Associative: Caudate to SNr Limbic: Ventral striatum to ventral pallidum

somatosensory cortices Sensorimotor circuit somatosensory cortices Thalamus Putamen GPe GPi STN SNc motor cortices D1 D2 direct indirect excitation inhibition D1 & D2 Dopamine receptors

Medical Remarks Hypokinetic disorders result from overactivity in the indirect pathway. example: Decreased level of dopamine supply in nigrostriatal pathway results in akinesia, bradykinesia, and rigidity in Parkinson’s dieseas (PD). Hyperkinetic disorders result from underactivity in the indirect pathway. example: Lesions of STN result in Ballism. Damage to the pathway from Putamen to GPe results in Chorea, both of them are involuntary limb movements. Lesion-making in STN or GPi are successful therapeutic procedures of PD.

Cognitive Remarks Putamen, GPi, and GPe are organized somatotopically. Their neurons are selectively responsive to the direction of limb movement. A considerable convergence is also evident along the cortico-basal ganglio- thalamo- cortical pathway. GPi cells have a baseline firing rate of 60-80Hz. During a voluntary hand movement, the firing rates of 70% of the cells in the hand area of GPi increase, while those of the remaining 30% decrease. Focusing theory vs. Scaling theory ( result of emphasis on somatotopy vs. convergence)

New findings inconsistent with the old model Most striatal cells have both D1 and D2 receptors. GPe neurons send some axons back to striatum. Although the projections from GPe to GPi are inhibitory, the pattern of activity in GPe replicates that of GPi (the 70-30 distribution of increase/decrease in firing rate). STN neurons project strongly back to GPe. SNc send dopaminergic projections to GPe, GPi, and STN. Intralaminar group of thalamic nuclei, receive projections from GPi and send projections to Putamen. This is some sort of feedback.

Mechanisms of Tremor in PD peripheral tremor Cerebellum central Cellular oscil. BG-thal network oscil.

Peripheral vs. Central 1- Deafferentation does change the frequency of tremor, but does not cease it. 2- Novacaine infiltration in a muscle can cancel stretch reflexes. Rigidity will be alleviated in this situation but not tremor. 3- Induction of Tonic Vibration Reflex whose signals are exclusively conveyed in Ia fibres (which are the afferent fibers of stretch reflexes) results in tremor cessation.

Cerebellum vs. BG-Thal 1- Vim is a nucleus of thalamus that connects cerebellum to motor cortices. Lesion-making, as well as High Frequency Deep Brain Stimulation (reversible analogous of lesion-making) in Vim are very successful strategies for alleviation of tremor in PD, but not in cerebellar tremors. 2- PD patients previously undergone hemicerebellectomy are not tremor-free in the corresponding side of their bodies.

Cellular vs. Network Oscillators 1- Both hyperpolarization-induced low threshold calcium spike and other kinds of bursts have been seen in tremor-locked activity of thalamic cells. 2- Not only thalamic cells, but also cells seated in STN and GP can demonstrate synchronous oscillatory activity.

Mechanism of rigidity in PD 1- Non- paralyzing doses of novacaine, concurrently alleviate rigidity and cancel stretch reflexes. 2- Deafferentation alleviates rigidity. 3- Spinal stretch reflex is normal in rigidity (confirmed by H-reflex). 4- Supraspinal stretch reflexes are hyperexcitable in rigidity. 5- The peripheral theory of tremor claims that tremor shares these mechanisms with rigidity.

F-Wave F-wave is elicited by antidromic activation of spinal motoneurons and their consequent backfiring. The duration of F-wave is an index for motoneuron excitability. Excitability of spinal motoneuron serves as an index for excitability of long loop reflex pathway.

Tremor or Rigidity? Milanov 2001: F wave duration was most prolonged in Parkinsonian tremor patients followed by PD patients with rigidity. In conclusion increased motoneuron activity participates in generation of both Parkinsonian tremor and rigidity. Abbruzzese et al. 1985 ,Naito et al. 1988: excitability of the spinal motor neurons was enhanced in rigid Parkinsonian patients. It thus seemed reasonable to assume that the main underlying cause of rigidity is an excessive supraspinal drive to the spinal motor neurons, including an increase in motoneuron excitability. No evidence for contribution of these mechanisms to cause tremor was observed.

Functional Anatomy Anteriorly located lesions in Vim nucleus tend to be more effective in reducing rigidity, whereas the lesions more effective in tremor cessation tend to lie more posteriorly. The location of DBS electrodes also varies in various patients.

Methods F-waves where recorded from abductor hallucis muscle by stimulation of tibial nerve. Twenty F-waves were recorded in two DBS conditions of On & Off from each of the 8 PD patients who participated in our study. The Implantable Pulse Generator (IPG) attached to the DBS electrode can be easily turned on and off by using the proper electronic device whose probe is put on the skin surface. Medtronic Model 7432 Physician Programmer

Guiot’s method of electrode localization

Analysis Based on their electrode location, participants where grouped in two 4-member groups of more anteriorly or more posteriorly electrode located. Independent variables: 1- two levels group of electrode location (anterior & posterior), 2- two levels of DBS status (On & Off). Dependent variable: F wave duration. Analysis: 2x2 ANOVA on pooled data Group of electrode location had a significant main effect. F(1,316)= 6.499, P=0.01 DBS status had a significant main effect: F(1,316)= 23.445, P=0.000 They had a significant interaction: F(1,316)= 11.204, P=0.001

Our results does not confirm the idea that tremor and rigidity have common mechanisms and contradicts the peripheral theory of tremor