Pathophysiology of Cerebellar Tremor: The Forward Model-Related Tremor and the Inferior Olive Oscillation-Related Tremor

Abstract

Lesions in the Guillain–Mollaret (G–M) triangle frequently cause various types of tremors or tremor-like movements. Nevertheless, we know relatively little about their generation mechanisms. The deep cerebellar nuclei (DCN), which is a primary node of the triangle, has two main output paths: the primary excitatory path to the thalamus, the red nucleus (RN), and other brain stem nuclei, and the secondary inhibitory path to the inferior olive (IO). The inhibitory path contributes to the dentato-olivo-cerebellar loop (the short loop), while the excitatory path contributes to the cerebrocerebellar loop (the long loop). We propose a novel hypothesis: each loop contributes to physiologically distinct type of tremors or tremor-like movements. One type of irregular tremor-like movement is caused by a lesion in the cerebrocerebellar loop, which includes the primary path. A lesion in this loop affects the cerebellar forward model and deteriorates its accuracy of prediction and compensation of the feedback delay, resulting in irregular instability of voluntary motor control, i.e., cerebellar ataxia (CA). Therefore, this type of tremor, such as kinetic tremor, is usually associated with other symptoms of CA such as dysmetria. We call this type of tremor forward model-related tremor. The second type of regular tremor appears to be correlated with synchronized oscillation of IO neurons due, at least in animal models, to reduced degrees of freedom in IO activities. The regular burst activity of IO neurons is precisely transmitted along the cerebellocerebral path to the motor cortex before inducing rhythmical reciprocal activities of agonists and antagonists, i.e., tremor. We call this type of tremor IO-oscillation-related tremor. Although this type of regular tremor does not necessarily accompany ataxia, the aberrant IO activities (i.e., aberrant CS activities) may induce secondary maladaptation of cerebellar forward models through aberrant patterns of long-term depression (LTD) and/or long-term potentiation (LTP) of the cerebellar circuitry. Although our hypothesis does not cover all tremors or tremor-like movement disorders, our approach integrates the latest theories of cerebellar physiology and provides explanations how various lesions in or around the G–M triangle results in tremors or tremor-like movements. We propose that tremor results from errors in predictions carried out by the cerebellar circuitry.

Visuomotor Adaptation Deficits in Patients with Essential Tremor

“…Patients with ET in the present study could quickly return to the original routine, similar to healthy controls. Interestingly, when transcranial direct stimulation was applied to posterior cerebellar cortex, including lobules VI, crus I and crus II, healthy young and old subjects presented with enhanced adaptation but not de-adaptation [52,63,64]. These observations point to different mechanisms of adaptation and de-adaptation.…”

“…The first is a lesion to an excitatory cerebrocerebellar loop, which affects the cerebellar forward model leading to decreased accuracy of prediction and compensation by feedback delay. The second is a lesion to an inhibitory dentato-olivo-cerebellar loop leading to synchronized oscillations in inferior olive neurons [63]. The authors hypothesize that for ET, malfunction in various locations of the G-M triangle is reflected in heterogeneity of clinical ET characteristics including kinetic tremor, intention tremor, and in some cases also rest tremor and the optional appearance of additional "soft neurological signs" like mild cognitive impairment, gait and stance disturbance, or eye-hand-dyscoordination which could also affect visuomotor adaptation abilities [63].…”

Identifying the white matter pathways involved in multiple sclerosis-related tremor using diffusion tensor imaging

“…37 Therefore, two potential explanations exist for the strong correlation between tremor severity and the medial lemniscus diffusivity measures in our sample. One explanation could be the involvement of the dentato-rubro-olivary circuit 38 in MS-related tremor due to its intimate anatomical proximity. 33 The second explanation could be a reduction in sensory afferents modulating movement, 39,40 as the medial lemniscus is the main pathway for proprioception and conveys sensory information to various circuits to regulate smooth motor action by providing positional and gravitational information.…”

A structural magnetic resonance imaging review of clinical motor outcomes from deep brain stimulation in movement disorders

“… 178 , 179 Dysfunction of cortico-cerebellar circuitry has been proposed to result in excessive oscillatory feedback and the consequent tremor generation. 180 , 181 The neuromodulation of a ‘tremor network’ through cerebellar circuitry has been proposed to disrupt aberrant oscillatory activity, inducing corrective functioning and alleviating tremor activity. 76 Two cerebellar tracts that have been heavily implicated in tremor pathophysiology are ‘short’ and ‘long’ loops.…”