More on Basal Ganglia & Cerebellum

The themes concerning basal ganglia and cerebellum have been summarized in my previous blog post. Both structures have been traditionally known to play dominant roles in voluntary movements. However, as time goes by, such roles have developed into a wider perspective related to non-motor functions such as general learning, executive functions, and emotion.

Functional topography of Basal Ganglia
There is a convergence of cortical information in the striatum from the cortex. This means that axons of cortical neurons terminate on a far smaller number of striatal neurons, Similarly, the number of neurons in the pallidum and substantia nigra is smaller than that in the striatum, allowing further convergence along the direct and indirect pathways. There also seems to be a somatotopic organization with the cortico-striatal-thalamic pathways. Evidence mainly comes from animal studies using tracers systematically injected into the monkey brain. This includes projections from GPi to the M1, SMA, and premotor cortex (Hoover & Strick, 1993; Akkal, Dum, & Strick, 2007), to Area 7b in the parietal lobe (Clower, Dum, and Strick, 2007).

Important evidence showing how BG is involved in cognitive processes has been shown anatomically through the work of Middleton and Strick (2002). The authors injected a few different prefrontal areas such as Area 9m /9l, Area 46v/46d, and Area 12l ['m' and 'l', 'v' and 'd', 'l' stands for medial/lateral, ventral/dorsal, and lateral respectively]. They found that labels associated with these areas comprised almost 1/3 of the GPi, indicating the importance of BG for executive tasks.

Non-motor Aspects of Basal Ganglia
Although in the early days, scientists thought that BG is important only for sensorimotor functions, there has been considerable acceptance of the four parallel divisions or systems in BG. They include circuits responsible for the skeletal/sensorimotor system, oculomotor system, executive functions, and limbic functions (Alexander et al, 1990). The oculomotor system engages the frontal eye field (FEF) and the supplementary eye field (SEF) anterior to the dorsal premotor cortex (PMd). From these two areas, projections go into the caudate area of the striatum and in turn controlling the SNpr/GPi via the direct pathway before going out to the superior colliculus (brain stem). The oculomotor system is very important for saccadic eye movements and memory-guided saccades.  Refer to the figure below.

Fig-1:  Four different basal ganglia functional divisions (adapted from Kandel, 5e)

The prefrontal cortex subserves higher-order behavior such as cognitive control, reasoning, problem-solving, general attention, working memory, which are collectively known as the executive functions. Two areas, the dorsolateral prefrontal cortex (DLPFC) and lateral orbitofrontal cortex (LOFC), project to the dorsal caudate of the striatum. DLPFC is important for organizing behavioral responses to complex problems and using verbal skills in problem-solving. LOFC, on the other hand, controls empathy and socially-appropriate behavior. The limbic circuit [Nauta, 1986 for review] begins with projections from the anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (MPFC) to the ventral striatum, which also receives input from the memory structures: hippocampus, amygdala, and entorhinal cortices. The ACC/MPFC complex is important for motivating behavior and reinforcement learning.

Patients with cerebellar damage
When a person performs skilled and goal-directed movements, the cerebellum maintains accurate and timely limb movements. One influential idea says that the cerebellum is crucial for error-based motor adaptation. Prior evidence that point to this idea comes from studies involving visuomotor and force-field adaptation (e.g. the works from Amy Bastian or Reza Shadmehr). In 1970s, Marr and Albus independently suggested that the cerebellum may be involved in motor learning. This is associated with the concept of plasticity between the Purkinje cells and parallel fibers inside the cerebellar cortex. Ito later proposed the role of complex spikes from the climbing fibers as the learning signal. Experiments using motor adaptation have shown that people with cerebellar damage impacting climbing fibers aren't able to adapt to both force-field and visuomotor perturbation.

The output gates of the cerebellum are located in the deep cerebellar nuclei in the white matter. These nuclei send projections back to the cortex via the thalamus, and they are strongly excitatory necessary to maintain muscle tone. This, however, isn't related to strength but more on the timing. Lesions of the interposed nucleus reduce the accuracy of reaching movements because of errors in timing, in direction and extent, in straightness due to poor joint coordination. The hand oscillates irregularly around the target. Neurological examinations show that damage to cerebrocerebellar path delays movement timing (Holmes G., 1939). A complex movement can be decomposed into a sequence of movement components. In healthy people, this decomposition is not obvious as the movements are performed smoothly and timely.

Experiments with primates help to elucidate the role in the motor disruption. When a monkey is trying to keep its arm in a fixed position, the application of a force to extend the elbow triggers a stretch reflex in the biceps. This will pull the arm rapidly and precisely to its initial location. The contraction of the extensor triceps plays a dominant role in keeping this precision, preventing the elbow from overshooting after the biceps contract. This appears as an anticipatory mechanism, i.e. feed-forward control. When the two deep cerebellar nuclei, dentate and interposed nuclei are deactivated, the arm oscillates instead of firmly going back to the original position. There seems to be an excessive, yet inaccurate, feedback correction (Vilis, Hore, Flament, 1984 & 1986).

Different Cerebellar Lobules
Like the cerebral cortex, the cerebellar cortex can be divided into four functional divisions: the vermis, intermediate zone or paravermis, lateral hemispheres, and flocculonodular lobe. Animal studies, in particular, in rats and cats have been used as models for anatomical studies. Perhaps, the most popular and classic human cerebellar anatomy comes from the works by Larsell & Jansen (1970). Refer to the Fig-2 below. The lateral hemisphere is especially important because of its massive connections with the cerebral cortex. Both vermis and the lateral hemisphere ('H') are further divided into nine subdivisions or lobules, each assigned a Roman number I to IX.

The earlier attempts to localize cerebellar functional organization were done as a result of lesion studies in both higher-order mammals and humans. Like the sensorimotor cortex, the existence localization and cerebellar somatotopic map do not represent the bodily extent, but rather, the functional demand. A series of the different somatotopic maps were released by Bolk (1904), Adrian (1943), and Snider & Stowell (1944). The progress continued with the help of tracers and, more recently, neuroimaging. Using fMRI, Grodd et al. (2001) did an elegant study producing sensorimotor topography of the cerebellum. The study was based on 46 human subjects performing a series of motor tasks such as opening/closing of right/left fist, extending right/left arm and leg, and moving the lips. I also recommend another article by Manni & Petrosini (2004) in Nature Rev. Neurosci. for a more elaborated summary with historical contexts. The following diagrams are taken from their paper.

Fig-2: Gross anatomy of the cerebellum (right, after Larsell & Jansen) and functional map (left, after Grodd et al.). Both vermis and the lateral hemisphere ('H') are subdivided into lobules. Of utmost interest is the left somatotopic map. The arms are represented by Lobule V-VI. In particular, fine motor control of the hand and fingers are by Lobule VI and VIII of the lateral hemisphere. Note that the connections to bodily parts are ipsilateral.



The involvement of non-motor functions are shown by the neuroimaging work by Stoodley et al (2012), They found right-handed finger-tapping activated right cerebellar lobules IV–V and VIII. Verb generation engaged right cerebellar lobules VI and Crus I and a second cluster in lobules VIIB–VIIIA. Furthermore, mental rotation activated medial left cerebellar lobule VII (Crus II). Lastly, 2-back working memory task activated bilateral regions of lobules VI–VII.

Important Anatomical Connections
Studies elucidating specific connections between the cortex and cerebellum have been done using anatomical tracers in animals. For example, retrograde transneuronal transport with herpes simplex virus, HSV1, was injected into the cerebral cortex of Cebus monkeys to label neurons in the dentate nucleus (Dum & Strick, 2003, Akkal, Dum, & Strick, 2007). With sufficient survival time, it was enough to reveal a set of first-order neurons in the thalamus, and second-order neurons in the dentate nucleus. Dentate nucleus was targeted by researchers at the time as the shape is the largest and easily recognized. The study showed different dentate output channels to the motor areas (M1 and SMA) and non-motor regions in pre-SMA, Area 7b, Area 46, and Area 9L.

Another important study adopting both retrograde and anterograde tracers is by Kelly & Strick (2003) that reveals the existence of cortico-cerebellar loop in both motor and non-motor domains. In the motor loop, neurons in M1 project to cerebellar lobules V, VI, and HVIIB and HVIII, and project back to the same regions of cortex via dorsal parts of the dentate nucleus and the motor thalamus. In the prefrontal loop, however, Area 46 projects to lobule HVIIA/B (mainly to Crus II) via the pontine nuclei, and returns back to the same areas of the prefrontal cortex via ventral parts of the cerebellar dentate nucleus and prefrontal thalamus. This segregated domain also confirms the neuroimaging works mentioned above, separating motor and non-motor areas in the cerebellum. Lobules that are connected to prefrontal regions are considered non-motoric. Refer to Fig-3.

Fig-3:  Anatomical projections from the cerebral cortex and cerebellum forms loop (from Kelly & Strick, 2003)

Basal ganglia and cerebellum receive inputs from cortical motor areas and send projections back to the same areas. These multisynaptic links suggest the extent of influence of both structures to movement production. Most anatomical connectivity has been revealed by tracing studies done by Strick and his group. For example: injections of retrograde tracing to a specific area in M1 or SMA (e.g. arm) with right survival time have revealed how neurons in the dentate nucleus and internal segment of the globus pallidus are labeled. In fact, there seems to be clear functional segregation (e.g. arm, face, digits) in both dentate nucleus and GPi. This suggests that neurons in both the cerebellum and basal ganglia do project to the motor cortex. However, there is no direct connectivity between basal ganglia and cerebellum.