The brain comprises billions of neurons, which apparently form functional and anatomical structures at various levels of organisation. The inter- and intra-interaction of these structures, as well as their detailed functional capacity is still a controversial subject and much is speculative. The basal ganglia (BG) is a group of highly interconnected anatomical structures positioned approximately in the middle of the brain, and is critically involved in muscle and cognitive control. The BG nuclei appear in two sets, in the left and right cerebral hemispheres. Most BG-directed research effort is motivated by its direct link to a wide range of disorders, including PD, Huntington‘s disease and schizophrenia. In addition, there is the possibility of extracting (invasive) data, known as Local Field Potentials (LFP), which quantify neuronal activity in regions within the brain.
The BG consist of the striatum, the globus pallidus (GP) (subdivided into the internal segment GPi and the external segment GPe), the subthalamic nucleus (STN) and the
substantia nigra (which is further subdivided into the pars compacta (SNc) and pars reticulata (SNr)). The BG receive input into the striatum from the cortex and another brain
region called thalamus, and project their output into the thalamus and the brainstem through the SNr and GPi. The interconnections between each pair of these BG nuclei are either
inhibitory or excitatory and are facilitated by the neurotransmitter dopamine, a substance
produced by the dopaminergic cells. Fig. 2.2 shows the schematic functional architecture diagram and the interconnections of the BG according to Gurney et al. (2001a).
Fig. 2.2: Schematic diagram of the basal ganglia (BG) architecture, showing the input into the BG from the cortex and the thalamus, the BG processing, the BG output, and the interconnections between the BG nuclei. The abbreviations of the BG nuclei are explained in the text.
2.1.3 Parkinson’s disease: mechanisms, symptoms, diagnosis, and management
The aetiology (underlying cause) of PD is largely unknown (Lang and Lozano, 1998), but the symptoms are caused by substantial dopaminergic neuron reduction, leading to dysfunction of the BG which mediates motor and some cognitive abilities (Singh et al., 2007). The dopaminergic cells assist in neurotransmission (transmission of information between neurons); consequently their decline leads to malfunction of the CNS which can no longer co- ordinate muscle movements appropriately and delicately. The clinically noticeable symptoms appear when the disease has progressed considerably and about 60-80% of the dopaminergic
BG input BG output Striatum Cortex, thalamus BG processing GPi/SNr STN GPe Inhibitory Excitatory Tha lamus, bra inst em
cells have already died (Bernheimer et al., 1973); by that time it is too late to intercept the degradation. The evolution of the disease involves progressive dopaminergic loss which results in gradually more severe symptoms such as tremor and loss of muscle control.
The main symptoms are tremor, rigidity and movement disorders. Vocal impairment is also common (Hanson et al., 1984; Ho et al., 1998) and is met in approximately 70-90% PWP (Logemann, 1978; Hartelius and Svensson, 1994; Ho et al., 1998). Moreover, it may be one of the earliest indicators (Duffy, 2005) and 29% of patients consider it one of their greatest hindrances associated with the disease (Hartelius and Svensson, 1994). Typically, the symptoms initially appear unilaterally (on either the left or right side, indicating that dopaminergic loss is more pronounced in the BG of one of the brain hemispheres) but in time proceed bilaterally.
There is no consensus for diagnosing a patient with PD, which is the cause of many misdiagnoses (Lang and Lozano, 1998; Rajput et al., 2007). According to de Rijk et al. (1997) a patient should be diagnosed with PD if they fulfill at least two of the following three criteria: bradykinesia (slow movement), rigidity, and tremor. Additionally, if the individual is known to suffer from chronic essential tremor (kinetic tremor mostly in the arms, neck and jaw which is apparent during voluntary movement), then a PD diagnosis should be made if all three criteria are present (Rajput et al., 1993). The term idiopathic PD (Rajput et al., 1984), which means that the underlying cause of the observed symptoms is unknown, has been introduced to differentiate PD from other neurological disorders eliciting Parkinsonian characteristics5. These are known as Parkinsonism, and may be due to, for example, drugs or neurotoxins (Rajput et al., 1984; Bower, 1999; Baldereschi et al., 2000). Although accurate
pathophysiological classification (diagnosis of PD or some form of Parkinsonism) of subjects
5 Some studies separate idiopathic PD from the remaining Parkinsonism variants referring to it as IPD. In the
is extremely difficult, it has clinical importance and facilitates better treatment (Rajput et al., 2007).
Thanks to the use of pharmacopathological manipulation (drug treatment of PD), the mean life expectancy of PWP disease has increased significantly over the previous decades. Currently, it is estimated that a patient diagnosed with PD at the age of 62 is expected to live for about 20 more years (Rajput et al., 2007). Pharmaceutical (combinations of levodopa and other agents) and surgical interventions such as Deep Brain Stimulation (DBS) (Benabid et al., 2009) are documented to improve motor functionality and reduce tremor, delaying disease progression and offering reasonably good quality of life (Singh et al., 2007). Of relevance to this study, however, the impact of treatment on speech is inconclusive (Larson et al., 1994; Ho et al., 2008).
Management of PD involves the administration of physical examinations applying tests assessing the subject‘s ability to perform a range of tasks, and these tests are designed to enable the quantification and monitoring of disease progression. The UPDRS is the standard reference scale (Ramaker et al., 2002), approved by the Movement Disorders Society (MDS), and has lately been revised as the MDS-UPDRS scale (Goetz et al., 2008). This revision addresses some deficiencies of the current version, which were previously discussed in Goetz et al. (2003). UPDRS tests along with the indications the medical rater will use to score the subject‘s symptoms appear in Appendix II. The UPDRS metric consists of 44 sections6
, where each section addresses different symptoms in different parts of the body and spans the range 0-4, with 0 denoting no symptoms and 4 severe impairment or problem. Summing up these 44 sections gives rise to the total-UPDRS score, which spans the range 0-176, with 0 representing perfectly healthy individual and 176 total disability.
6 Note that the UPDRS scale discussed in this thesis is for untreated patients because that is the kind of data used
The UPDRS metric can be divided in three major parts, which we will henceforth refer to as components: (1) Mentation, Behavior and Mood (MBM); (2) Activities of daily living (ADL); (3) Motor. The motor component (we will refer to it as motor-UPDRS) is comprised of sections 18-44 and ranges from 0-108, with 0 denoting symptom free and 108 severe motor impairment, and encompasses tasks such as speech, facial expression, tremor and rigidity. This component contributes most of the points in the UPDRS scale and many studies focus exclusively on that, because motor symptoms are often the most problematic and the most prominent aspect of PD. In this study we deal with both ‗motor-UPDRS‘ and ‗total-UPDRS‘. Alternative metrics monitoring PD progression may also be used, such as the Hoehn-Yahr (H&Y) stage (Hoehn and Yahr, 1967), and recent studies have shown that it is possible to map UPDRS onto H&Y (Tsanas et al., 2012c).
As discussed above, dopaminergic depletion within the BG is the hallmark of PD, and clinicians often rely on brain scans in order to noninvasively reveal the subject‘s brain pathophysiology (structural and functional operational condition) so that they can augment their PD diagnosis. For a recent review of the current imaging methods refer to Brooks (2007). Nevertheless, although imaging biomarkers are measuring the relevant physiological process, they do not measure dopamine density, and therefore cannot be used as a monitoring tool (Ravina et al., 2005).