The study involved 33 subjects aged 65 years and over. Subjects were
community dwelling in the North East of England. Sixteen patients were recruited from referrals to Newcastle and Gateshead Old Age Psychiatry Services and met diagnostic criteria for Major Depression according to DSM-IV, as assessed during a standardised interview by an experienced psychiatrist (Dr Jonathan Richardson). Seventeen similarly aged controls were recruited by advertisement; none of the control subjects had past or
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present history of depression. All subjects were cognitively intact, had no history or clinical evidence of dementia, and all scored > 24 on the Mini-Mental State
Examination (MMSE) (Roth et al., 1986). Patients were assessed using a standardised interview and received a structured physical examination. Current depression severity was rated using the Montgomery-Asberg Depression Rating Scale (MADRS)
(Montgomery and Asberg, 1979). Exclusion criteria were; co-morbid or previous history of drug or alcohol misuse, previous head injury, history of epilepsy, myocardial infarction in the preceding 3 months, a carotid bruit on physical examination, or any contraindication to MRI. The study received ethics committee approval and all subjects gave verbal and written consent.
5.4.2 Imaging
Subjects were scanned in a 3 Tesla Philips Intera Achieva MRI System at the Newcastle Magnetic Resonance Centre, Newcastle University. An 8 channel head coil was used to collect anatomical 3D T1-weighted, fluid attenuated inversion recovery (FLAIR) and resting-state functional MRI (fMRI) scans. The scanning protocol
involved asking subjects to lie still in the scanner, to keep their eyes closed, to think of nothing in particular, but not to fall asleep.
The timing and parameters used to collect anatomical scans were as follows;
Anatomical 3D T1-weighted: Magnetisation-prepared rapid acquisition with gradient echo (MPRAGE), sagittal acquisition, slice thickness = 1.2 mm, voxel size = 1.15 x 1.15 mm, repetition time (TR) = 9.6 ms, echo time (TE) 4.6 ms, flip angle = 8o, sensitivity encoding (SENSE) factor = 2.
FLAIR: Number of slices = 60, slice thickness = 2.5 mm, voxel size = 1.02 x 1.02, TR = 11000 ms; TE = 125 ms, inversion time (TI) = 2800 ms; SENSE factor = 1.5.
Resting-state fMRI scans were collected using a gradient-echo echo-planar imaging (GE-EPI) sequence. The timing and parameters used were similar to those that have been used in previous studies to detect resting-state networks (De Luca et al., 2006); 25 axial slices, 128 volumes, anterior-posterior
acquisition, in-plane resolution = 2 x 2 mm, slice thickness = 6 mm, TR = 3000 ms, TE = 40 ms, field of view = 260 x 150 x 260 mm, and acquisition time = 6.65 minutes.
77 5.4.3 Selection of the Seed Region
The head of caudate nucleus was used as the seed region in this study. The caudate is a basal ganglia structure. The basal ganglia are a collection of subcortical nuclei involved in controlling motor, cognitive and emotional functions. The caudate nucleus, putamen and nucleus accumbens, collectively termed the striatum, are the input nuclei for signal circuits that originate in the cerebral cortex. These input nuclei project to the intrinsic nuclei (external segment of the globus pallidus, subthalamic nucleus, substantia nigra pars compacta, ventral tegmental area) and output nuclei (internal segment of the globus pallidus, ventral pallidum, substantia nigra pars reticulate). The caudate nucleus is C-shaped and is a continuous structure although three separate names are given to its portions; head, body and tail. The caudate nucleus is connected to the putamen by cell bridges and the nucleus accumbens is located ventromedially. Figure 5.1 illustrates the organisation of the basal ganglia (Martin, 1996).
Figure 5.1: Overview of the Input-Output Organisation of the Basal Ganglia Figure extracted from (Martin, 1996)
Early studies investigating the role of the basal ganglia nuclei suggested they integrate influences from cortical association and sensorimotor areas to common thalamic target zones and contribute to the initiation and control of movement (Allen and Tsukahara, 1974; Kemp and Powell, 1971; Evarts and Thach, 1969). Though subsequently, it has been shown that there are at least 5 basal ganglia thalamocortical
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circuits; motor, oculomotor, prefrontal (2 circuits) and limbic (Alexander and Crutcher, 1990; Alexander et al., 1986):
i. Motor circuit:
Focussed on the precentral motor fields
Controls skeletal musculature ii. Oculomotor circuit:
Focussed on the frontal and supplementary eye fields
Controls extraocular muscles iii. Prefrontal circuits (2 circuits):
Focussed on the dorsal lateral prefrontal cortex and lateral orbitofrontal cortices
Control cognition and spatial memory iv. Limbic circuit:
Focussed on the anterior cingulate and medial orbitofrontal cortices
Controls motivational regulation of behaviour and emotions
Each individual circuit is organised in parallel and the basic design is similar; output is received from the cerebral cortex and projections are then sent to the input and output nuclei, the thalamus, and a portion of the frontal lobe (as outlined in figure 5.1).
As was discussed in detail in Chapter 3, a number of studies have investigated the caudate nuclei in depression. Decreased caudate volumes have been reported in LLD (mean age 71 years) (Butters et al., 2009), in older depressed subjects (mean age 58 years) (Beyer et al., 2004) and in younger depressed subjects (mean age 48 years) (Krishnan et al., 1992). Caudate volumes have also been shown to be smaller in LLD compared to early-onset depression (Greenwald et al., 1997) and anterior white matter lesion volumes have been negatively associated with total and right caudate nuclei volumes in LLD (mean age 70 years) (Hannestad et al., 2006). Conversely, other studies have reported no significant differences in caudate volumes between depressed patients and controls, though these subjects had early-onset depression (mean age 41 years) (Lacerda et al., 2003). The methods used to delineate the caudate nucleus vary between studies, with some studies measuring the head of caudate nucleus only (Butters et al., 2009), whereas others have measured the whole caudate volume (Lacerda et al., 2003), which could explain the differences found between studies.
79 5.4.4 Placing of the Seed Region
The Functional MRI of the Brain (FMRIB) Software Library (FSL)
(www.fmrib.ox.ac.uk/fsl) tools were used for analysis (FMRIB Analysis Group, 2007) (version 4.1). Brain extraction, using the FSL Brain Extraction Tool (BET) (version 2.1) (Smith, 2002), which segments brain from non-brain, was previously carried out by Dr. David Cousins. Using the FSLView tool (version 3.1), the head of caudate nuclei seed regions were placed directly on the first volume of the resting-state fMRI scans. The seeds, of 2 by 2 voxels, were place on one slice only in both the left and right
hemispheres, with the images in the axial view and radiological orientation noted (i.e. right side of the computer is the left hemisphere of the brain) (see Figure 5.2). The seeds were places by a sole investigator (the author) blinded to the identity and diagnosis of each scan and guided by a standard brain atlas (DeArmond et al., 1989). In a second display window, the FSL tools were used to display an echo planar image in standard space with the head of caudate nucleus overlayed for further reference. The seeds were placed on the most inferior slice where the head of caudate nucleus and the putamen are separated by the internal capsule, similar to guidelines used in previous studies (Beyer et al., 2004; Aylward et al., 2003). In some subjects, placing the seed was more difficult than in others due to greater ventricular atrophy. However, on reviewing all seeds after placement, in all cases the seed was observed to be accurately placed and within the caudate nucleus boundaries. To check for motion in the images the movie mode function was used which enables all volumes of the brain to be viewed. No study subjects exhibited a significant amount of head motion.
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Figure 5.2: Overlay of the Head of Caudate Nucleus in the Axial View on the Functional Image