FUNCTIONS OF THE BASAL GANGLIA

The basal ganglia are derived from basal grey matter areas in the telencephalon, which have become overgrown by the cerebral cortex, pushed inwards adjacent to the lateral ventricles, curved into a horizontally elongated comma as the cerebral hemispheres grow backwards over and around the diencephalon (and brain stem), then broken into a head and a curved tail, by fibres traversing to and from the neocortex of the cerebral hemispheres. The structures therefore are telencephalic, but are strongly connected to related diencephalic (subthalamic nuclei) and mid-brain structures (substantia nigra). The basal ganglia proper are the caudate nucleus and putamen (neostriatum), and globus pallidus (paleostriatum), usually grouped along with the sub-thalamic nuclei and substantia nigra. The caudate nucleus and putamen are histologically similar and fuse anteriorly. The putamen and globus pallidus make up the ovoid lentiform nucleus flanking the thalamus on either side, and separated from it by the internal capsule.

Similarly derived structures are the claustrum and amygdaloid bodies, which are functionally different (related more to visceral & emotional activity perhaps) and less well studied, and so are usually treated separately.

The globus pallidus is subdivided into the external lobe (GP_e) and the internal lobe (GP_i). From the internal lobe, the main output pathway from the basal ganglia, axons run (via the ansa lenticularis) to the ventral anterior/ventral lateral thalamus (VA/VL thalamus).

The substantia nigra also is divided into two parts, the pars compacta (SN_c) which houses 80% of the brain's dopaminergic neurones, and the pars reticulata (SN_r). Although anatomically separate, the GP_i and SN_r can be treated as one (GP_i/SN_r), since they are similar histologically, and in connectivity, and can be regarded as being derived from a single structure, divided (as with the caudato-putamen) by the fibres of the internal capsule. The cells in both structures show a high level of spontaneous activity; they project to, and inhibit thalamic cells in the VA/VL thalamus, suppressing movement (and emotional expression).

Input enters the neostriatum from widespread areas of the cerebral cortex, notably from the supplementary motor cortex, limbic cortex, prefrontal lobes, and frontal eye fields). The inputs to a large degree, and the outputs almost wholly, are somatotopically organised. Cortical inputs form excitatory glutamatergic synapses in the neostriatum. Within the neostriatum are excitatory cholinergic interneurones.

Three groups of output fibres leave the neostriatum:

(1) The first is a direct feed from the neostriatum to the GP_i/SN_r. This pathway uses GABA and Substance P as co-transmitters, and is inhibitory. The GP_i/SN_r - the main output pathway of the basal ganglia - projects via inhibitory GABAergic axons, to the VA/VL thalamus, and intralaminar nuclei, inhibiting cells (different cells than the cerebellar inputs), which project to the prefrontal cortex, limbic cortex, supplementary and pre-motor cortex primarily. Cortical inputs into this pathway inhibit the spontaneous activity of the GP_i/SN_r cells, release the thalamic cells from their inhibitory influence, and so PROMOTE movement.

(2) The second pathway projects indirectly: first to the GP_e , from here to the subthalamic nucleus, then to the GP_i/SN_r. The subthalamic nucleus excites the GP_i/SN_r via glutamatergic synapses, to inhibit thalamic activity. Activity in the GP_e promotes thalamic activity, by inhibiting the subthalamic nucleus (through GABAergic synapses). The axons from the neostriatum inhibit the GP_e using GABA and enkephalin as cotransmitters. Cortical inputs via this pathway will tend to INHIBIT movement. Disorders which promote activity in the subthalamic nucleusGP_i/SN_r pathway, will reduce movement; those which reduce activity, cause excessive movement.

(3) The third pathway is neurochemically similar to pathway (1), using GABA and Substance P as co-transmitters, but arises from different clusters of cells in the neostriatum, and projects somatotopically to the substantia nigra pars compacta (SN_c), which contains 80% of the brain's dopaminergic cells, and projects back to the striatum (nigrostriatal pathway) where it facilitates activity in pathway (1) - to promote movement, and inhibits activity in pathway (2) which is discussed above. (You should try to draw out these relationships using block diagrams as you read. Try to remember the overall relationships, but don't worry about rationalizing the fine details).

The basal ganglia then, appear to be able either to promote and facilitate motor activity or to inhibit it - and probably does both: suppressing unwanted actions which might interfere with a desired movement, whilst amplifying and facilitating those processes which contribute towards the genesis of the desired movement. This could give some insight into the physiological basis for the observation that disorders of the basal ganglia may give rise either to excessive, uncontrolled, involuntary movements, or to immobility and difficulty in initiating voluntary actions, or to combinations of both. The basal ganglia may act in conjunction with the supplementary motor cortex, to generate highly learned movement modules. They also seem to play a major role in controlling the proximal/axial musculature, via the "extra-pyramidal" (mainly ventro-medial) pathways. They may provide automatically, the necessary postural tone, to facilitate the more regulated, skilled actions of the distal musculature (via the lateral descending pathways mainly).

In Parkinson's disease, degeneration of 90% or more of the dopaminergic (DAergic) cells in the SN_c results in decreased activity in pathway (1) and increased activity in pathway (2), causing bradykinesia, poverty of movement, mask-like expressionless face, postural fixation, rigidity and tremor. The tremor differs from cerebellar tremor in being a tremor at rest. The rigidity occurs in both flexor and extensor muscles, but predominates in the flexors, giving a hunched over posture. It disappears in sleep. Treatment with l-dopa a DA precursor which crosses the blood brain barrier, promotes brain DAergic activity and alleviates the symptoms but does not reverse or slow the disease process. Side effects and "Tolerance" may develop. Side effects in the periphery (nausea; hypertension) may be minimized by simultaneous treatment with carbidopa which blocks dopa decarboxylase in the periphery, but does not cross the blood brain barrier. Deprenyl, a monamine oxidase B inhibitor, reduces degradation of catecholamines and appears to ameliorate the symptoms, and slow the progress of the disease. Lesion of the "tremorogenic" cells in the VA/VL thalamus or the GP improves the tremor and rigidity, but not the bradykinesia. Transplantation of embryonic DAergic cells into the brain is also being tried.

Following from the above, muscarinic cholinergic blockers (e.g. artane) which reduce ACh activity to match the reduced DA activity in Parkinson's patients may ameliorate the symptoms, while cholinergic agonists may worsen them.

In Huntington's Chorea, a hereditary disease in which GABAergic/enkephalinergic and cholinergic cells in the striatum (Pathway 2) degenerate (Glutamic Acid Decarboxylase and Choline Acetyl Transferase activity fall), symptoms include irritability, fidgeting and clumsiness, leading to dementia, choreic movements and inexorably to death. In later stages, GABA/Substance P cells related to Pathway 1 also degenerate, leading to failure to initiate normal movements. DA blockers help the symptoms, but no cure is known.

Lesion (e.g. by vascular occlusion) of the subthalamic nucleus, reduces output in pathway (3) and results in excessive, flailing movements of the appendages (hemiballismus). Lesion of the neostriatum/GP can lead to slow writhing movements of the distal appendages e.g fingers and toes (athetosis).

The picture is not always simple, since overtreatment with anti-schizophrenic dopaminergic blockers, can lead to symptoms such as tardive (treatment induced) dyskinesias (involuntary movements e.g. of face and tongue). These symptoms might be due to reactive upgrading of the sensitivity and numbers of DA receptors as a result of chronic blockade, or may be related to increasingly effective muscarinic agonistic side-effects of the drugs.

The causes for the degeneration of neurones seen in Parkinson's and in Huntington's diseases are not known. They may result from immunological malfunction, environmental toxins (Parkinson's) or genetically programmed cell death (Huntington's).

Note that the basal ganglia whilst being involved mainly in the control of motor activity, also have strong connections with the limbic and related areas of the brain. Basal ganglion lesions may therefore also induce cognitive as well as emotional disturbances.

Read BERNE & LEVY: Physiology, Chapter 17; Principles of Physiology, Pg.135-136.

GANONG, Review of Medical Physiology, Chapter 12, relevant pages.

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