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Anatomical connections of the basal ganglia - How these are affected in Parkinson's disease

The subcortical nuclei known as the basal ganglia receive many connections from both outside and within their structures.  It is these connections that underlie the role they play within the control of movement; failures of which lead to disorders of movement such as Parkinson’s disease.

What are the Basal ganglia?

The basal ganglia are a collection of nuclei located in the telencephalon aspect of the forebrain, beneath the lateral ventricles (see figure 1 for gross anatomical view)
Figure 1. The locations of the basal ganglia and connected structures (adapted from Hall & Olias, 1998).

There are 4 main parts to the basal ganglia:

There are, however, other parts of the basal ganglia, but their inclusion within the collection of ‘basal ganglia’ does depend on the purpose of the description, but include:

For simplicity this account focuses on the main, accepted parts of the basal ganglia, which underlie the main purposes of the brain area.

External connections of the basal ganglia

Input structures

The striatum is the input stage of the basal ganglia and receives excitatory connections from cortical areas as well as thalamic nuclei (Morris, Nevet, & Bergman, 2003).  Inputs are received from the frontal, parietal and temporal cortex (Carlson, 2001).  However inputs are also received to the subthalamic nucleus (McHaffie, Stanford, Stein, Coizet, & Redgrave, 2005).  Direct afferents are received from the cortex, limbic structure and the thalamus with indirect inputs coming from midbrain structures such as the dorsal raphe nucleus (McHaffie et al., 2005).

Output structures

The main output structures of the basal ganglia are the globus pallidus internal (GPi) and the substantia nigra pars reticulata (SNPr). (McHaffie et al., 2005)  There are direct inhibitory connections to the thalamus, medulla and midbrain, but also indirect inhibitory (Morris et al., 2003) connections via the thalamus to the cortical and limbic regions from which efferents had been received (McHaffie et al., 2005).
The globus pallidus sends information to the motor cortex via the ventral anterior and ventrolateral nuclei of the thalamus (Carlson, 2001).
Therefore the connections of the basal ganglia ensure that somatosensory information is passed from the cortex through the basal ganglia to the motor cortex (Carlson, 2001), to ensure that an appropriate motor response is initiated.  In addition the information carried within the basal ganglia is arranged somatotopically so that neurones in the putamen receiving somatosensory cortical information are connected to the motor cortex neurones corresponding to the same part of the body.

Pathways in the basal ganglia

The basal ganglia have traditionally been viewed only as motor nuclei, due to the motor symptoms that occur when they are damaged and the lack of gross cytoarchitectural differentiation (Alexander, DeLong, & Strick, 1986).  However, more recently, it has been accepted that the basal ganglia also connect to areas of the premotor and prefrontal cortex that are involved in limbic and cognitive functions (Middleton & Strick, 2000).  The basal ganglia can now be viewed as being components of multiple, parallel, segregated circuits (Alexander et al., 1986).  Evidence, from studies using viruses that are transmitted interneuronally, has shown that the basal ganglia often project back to the areas from which they received efferent connections (Middleton & Strick, 2000). 
Whilst the connections of the basal ganglia are generally considered to be feed forward, there exist many recurrent connections and lateral connectivity (Morris et al., 2003).  These extra connections, together with the fringe constituents of the basal ganglia, such as the pedunculopontine nucleus, are the focus of much recent research (Obeso et al., 2000; McHaffie et al., 2005; Morris et al., 2003).  However, as there is still debate about the importance of each of these structures, the traditional motor loop is the focus of this account. 

The Motor loop

The motor loop, as the name suggests, is the collection of connections that are involved in the normal control of voluntary movement.  There are 2 main routes through the motor loop, known as the direct and indirect routes respectively.  These can be seen in the simple motor loop illustrated in figure 3 below.
Figure 3. The direct and indirect pathways of the motor loop (adapted from Hall, Olias, & Robinson, 2000)

The direct pathway involves fewer stages, running directly from the input striatum to the output GPi / SNPR.  By contrast the indirect pathway involves the extra stages of the GPe and subthalamic nucleus between the input and output stages.
There are a number of different neurotransmitters involved in the motor loop, of which a key one, in terms of Parkinson’s disease, is dopamine.  This uses at least 2 types of receptor (highlighted as D1 and D2 within figure 4) which modulate different effects of the transmitter.
Figure 4 The normal motor loop (adapted from We Move 2003)

The final inhibitory outputs of the GPi and SNPR are crucial in modulating the excitatory connection from the thalamus to the cortex and muscles. 
The complexity of the outputs of the striatum is illustrated in figure 5 below, which gives some idea of the number of neurotransmitters and receptors involved.
Figure 5 The extensive interconnections of the motor loop (adapted from Richardson, Kase, & Jenner, 1997)

The main axis of the basal ganglia is the cortex, striatum and GPi / SNPR (Morris et al., 2003).  This pathway is divided into layers, characterised by a reducing number of neurons in each successive layer.  Thus there are at least twice as many projections from the cortex to the striatum as there are projections from the striatum to the globus pallidus (Morris et al., 2003).  This becomes important when the deficits underlying Parkinson’s disease are considered

The basal ganglia in Parkinson’s disease

Parkinson’s disease is a chronic neurodegenerative disease, primarily affecting those over 65.  It is characterised by the following cardinal symptoms:

The underlying deficit of Parkinson’s disease is a drastically reduced amount of dopaminergic neurones found within the substantia nigra.  Whilst all neurones gradually die off throughout life, Parkinson’s disease symptoms become apparent when more than 80% of the substantia nigra neurones present at birth have gone (Ben-Shlomo, 1996).
The effect of Parkinson’s disease on the motor loop
Figure 6 below shows how the reduction in dopamine affects the motor loop.  It can be seen that the output of the basal ganglia is markedly reduced, due to the disinhibition of the globus pallidus external (GPe) and the knock on effect leading to excessive inhibition of the thalamus.
Figure 6 The motor loop in Parkinson's Disease, showing the changes in transmitter levels and effects (adapted from We Move 2003)

Output neurones within the indirect pathway are controlled via the inputs of different neurotransmitters.  An example output neurone within the indirect pathway receives excitatory input from acetylcholine and glutamate, along with inhibitory input from dopaminergic and GABAergic neurones.  Where there is a reduction in dopaminergic input this input will become unbalanced, with the excitatory input higher than the inhibitory input.  This leads to abnormal control of the output neurone, which will then have a much higher output than normal (Richardson et al., 1997).  See figure 7 for illustration:
Figure 7. A diagram indicating how the control of an output neurone within the indirect pathway is affected by the incoming neurotransmitter actions.  (adapted from Richardson et al., 1997).

As the majority of output neurones of the basal ganglia are inhibitory ones from the SNPr and GPi the overall effect of reducing dopamine within the basal ganglia is an increased inhibitory output onto the thalamus, leading to a reduction in movement.
It may be that the extensive collateral connections within the basal ganglia underlie the relative lack of symptoms of Parkinson’s disease before more than 80% of substantia nigra neurones are lost (Ben-Shlomo, 1996).  However, this has yet to be proven.

Conclusion

The anatomical connections of the basal ganglia were traditionally viewed to be simply related to their role in the control of voluntary movement.  The motor loop is a well accepted series of interactions which link the cortex and thalamus, and modulate the influence that the somatosensory cortex has on movement.  Damage to the motor loop, via the dopaminergic neurones of the substantia nigra, leads to the movement disorder of Parkinson’s disease.  Removal of the dopaminergic feedback inhibition of the striatum leads to overall inhibition of voluntary movement.
More recently the role of the basal ganglia in other functional loops, such as the limbic loop involving cognition and emotion, has been explored.  However, as yet, there are no firm conclusions that have been drawn.

References