Tremorgenesis: a new conceptual scheme using reciprocally innervated circuit of neurons
© Manto; licensee BioMed Central Ltd. 2008
Received: 24 November 2008
Accepted: 26 November 2008
Published: 26 November 2008
Neural circuits controlling fast movements are inherently unsteady as a result of their reciprocal innervation. This instability is enhanced by increased membrane excitability. Recent studies indicate that the loss of external inhibition is an important factor in the pathogenesis of several tremor disorders such as essential tremor, cerebellar kinetic tremor or parkinsonian tremor. Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders. Oscillations are simulated by changing the intrinsic membrane properties of burst neurons. The authors use a model neuron of Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih), low threshold calcium current (It), and GABA/glycine mediated chloride currents. Post-inhibitory rebound is taken into account. The model includes a reciprocally innervated circuit of neurons projecting to pairs of agonist and antagonist muscles. A set of four burst neurons has been simulated: inhibitory agonist, inhibitory antagonist, excitatory agonist, and excitatory antagonist. The model fits well with the known anatomical organization of neural circuits for limb movements in premotor/motor areas, and, interestingly, this model does not require any structural modification in the anatomical organization or connectivity of the constituent neurons. The authors simulate essential tremor when Ih is increased. Membrane excitability is augmented by up-regulating Ih and It. A high level of congruence with the recordings made in patients exhibiting essential tremor is reached. These simulations support the hypothesis that increased membrane excitability in potentially unsteady circuits generate oscillations mimicking tremor disorders encountered in daily practice. This new approach opens new perspectives for both the understanding and the treatment of neurological tremor. It provides the rationale for decreasing membrane excitability by acting on a normal ion channel in a context of impaired external inhibition.
Main neurological disorders associated with tremor
Type of tremor
Enhanced Physiological tremor
Drug-induced postural tremor
Kinetic tremor ("intention tremor")
Primary writing tremor
Primary and secondary orthostatic tremor*
Current theories suggest that tremor is driven by complex combinations of mechanical reflex and central neurogenic oscillations. These oscillations are superimposed on a background of irregular fluctuations in muscle force and limb displacements . In tremors originating in the central nervous system, generators are relatively insensitive to peripheral perturbations in most cases. The mechanical reflex component is dependent upon the inertial and elastic properties of the body . The frequency of passive mechanical oscillations ω depends upon the stiffness K and is inversely related to the inertia I, according to the following equation:
ω = (K/I)1/2
-the loop between motor cortex and basal ganglia
-the loop between the cerebellum and the brainstem, especially the Guillain-Mollaret triangle, which links dentate nucleus of the cerebellum with the contralateral red nucleus and the inferior olive (this loop is also called the dentate-rubro-olivary tract)
-the loop between the cerebellum, the thalamic nuclei and the motor cortex (cerebello-thalamo-cortical pathway and cortico-ponto-cerebellar tracts)
-the peripheral loops, including the afferences from the muscle spindles to the alpha-motoneurons (spinal loop) and from the peripheral sensors to the motor cortex (transcortical loop). The stretch reflex depends on monosynaptic connections between primary afferent fibers and motor neurons. Spindles also inhibit motor neurons to antagonist muscles through Ia inhibitory interneurons. Afferent fibers from Golgi tendon organs provide a negative feedback for regulating tension via Ib inhibitory interneurons.
Clinical and experimental techniques to evaluate tremor
Clinical scores of disability
Clinical characterization of tremor
Quantification of drawings
Evaluation of tremor in 2 dimensions
Surface and needle EMG studies
Assessment of muscle discharges and motor units
Changes in magnetic field
Position in 3 dimensions
Textiles integrating position sensors
Simulation of neural circuits
It is currently assumed that most kinds of tremor are associated with an overexcitability of neurons, rendering the neurons prone to discharge in a rhythmic way. Therefore the initial events leading to an increase of excitability deserve attention. Several drugs reducing neuronal membrane excitability improve tremor. This is typically the case with propranolol, GABA-mimetic inhibitory agents such as gabapentin or topiramate, or ethanol. These drugs affect the balance between GABA and glutamate.
In this issue, Shaikh and colleagues propose a new conceptual scheme to analyze tremor disorders . They propose a scheme based on the Sherrington's principle for reciprocal innervation and the phenomenon of post-inhibitory rebound (PIR), which is the rebound increase in firing rates of neurons when the inhibition is removed. These 2 properties render some networks prone to oscillations [12, 13]. The authors point out that oscillations in reciprocally innervated circuits appear if the relative effect of intact external inhibition is reduced by an increased excitability within the reciprocally innervated neurons themselves. In other words, increased neural excitability can overcome the effects of normal external inhibition. Increased excitability could result from an increase in either the hyperpolarization activated cation current (Ih, related to HCN1–HCN4) or the low threshold calcium current (It, related to CaV3 channels) [14, 15], or alterations in the intracellular levels of second messengers and the regulators modulating the activation kinetics of these ion channels. Shaikh et al. have tested their hypothesis by simulating a Hodgkin-Huxley type, conductance-based model of pre-motor burst neurons responsible for ballistic limb movements. The authors hypothesize that increased membrane excitability in pre-motor neurons has a key role in pathogenesis of disorders like essential tremor. The circuit consists of reciprocally innervating excitatory neurons and reciprocally inhibiting inhibitory neurons, and includes physiologically-realistic membrane kinetics of the premotor neurons determined by subsets of membrane ion channels. The latter also determines the excitability of the membrane. By increasing specific membrane conductances that are known to increase PIR and neural excitability, such as Ih and It, they could simulate the range of frequencies of tremor recorded from patients. The increase in these currents resulted in alternating bursts of action potentials in the neurons innervating the sets of agonist and antagonist muscles. The frequency of the simulated tremor was very close to the actual tremor frequency recorded in human.
One of the consequences of this model is the following: interfering with the function of a normal ion channel to decrease membrane excitability in case of impaired external inhibition might reduce the oscillatory behaviour. This might have a special interest for circuits in the thalamus, inferior olive, cerebrum and cerebellum, given their electrophysiological properties and their patterns of innervation. Indeed, these structures are particularly prone to spontaneous or triggered oscillations. Thalamo-cortical firing patterns vary with their membrane potential, and thalamic neurons might behave as oscillators or even resonators . The interaction between cation currents and calcium conductance may generate oscillations from 0.5 to 4 Hz. Animal studies in models of Parkinson's disease suggest that neuronal oscillations are spontaneously generated within the basal ganglia system, especially the pallidum and the subthalamic nucleus, but are mainly synchronized by cortical activity via the striatal inputs. There is an abnormal coupling between the EMG of forearm muscles and the activity in the contralateral primary motor cortex at tremor frequency in this common neurodegenerative disorder . In essential tremor, a bilateral overactivity of cerebellar connections is strongly suspected, with increased synchronous discharges in the olivocerebellar tracts and overall disinhibition of cerebellar nuclei. These latter receive their inputs from the Purkinje cells and are the sole output of the cerebellar circuitry. Predictive computations and rhythmicity in sensorimotor networks are impaired in case of cerebellar lesion . Rhythmicity includes the regular recurrence of events within the information flow, as one can expect in tremor disorders. It is interesting to underline that cerebellar patients present errors in the tuning and timing of activation of agonist and antagonist muscle, as well as motor learning deficits [19, 20].
Tremor is attracting the attention of scientists from various disciplines, because of the high prevalence of neurological disorders associated with tremor and thanks to the progress made these last years in terms of better characterization of neurological disorders, mainly with brain imaging (Magnetic Resonance Imaging, Positron Emission Tomography) and molecular biology techniques. The model presented here brings new insights into mechanisms of tremor disorders and also opens direct and short-term perspectives in terms of treatment evaluation. The similarities with the recordings made in patients are outstanding. Furthermore, this model might serve in the future for the deciphering of motor commands and neural representations of movement, the so-called 'internal models' which now encompass not only motor but also cognitive operations . In this sense, this approach would have broader applications in translational medicine.
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