METHODS Subjects

Twenty five patients (19 males, 6 females) who fulfilled the Diagnostic and Statistical Manual o f Mental Disorders - Fourth Edition (DSM IV) criteria for schizophrenia and thirty healthy controls (22 males, 8 females) were selected for this study. Their demographical characteristics are described in Chapter 7.

Clinical assessments

i) The National Adult Reading Test (NART)

This test (Nelson and Willison, 1991) provided an estimate o f premorbid IQ and was used to match patients and controls.

ii) Psychiatric symptoms

The subscales for positive and negative symptomatology o f the Positive and Negative Syndrome Scale (PANSS)(Kay et al, 1987) were used to provide a measure o f schizophrenic symptoms during the week prior to assessment. The PANNS is based on a standardised structured interview consisting o f 30 items which takes about 30-40 minutes to administer. There are 3 subscales - the positive, negative and general psychopathology scales. Only the positive and negative subscales were used in this study. The positive scale measures 7 symptoms: delusions, conceptual disorganisation, hallucinatory behaviour, excitement, grandiosity, suspiciousness and hostility. The negative scale also measures 7 symptoms: blunted affect, emotional withdrawal, poor rapport, social withdrawal, difficulty in abstract thinking, lack o f spontaneity or flow o f conversation and stereotyped thinking. Each symptom is rated 1-7 depending on the severity (l=absent; 2=minimal; 3=mild; 4=moderate; 5=moderately severe; 6=severe

and 7=extreme). The potential total score for either the positive or negative scale range from 7-49.

Hi) Neurological signs

The Annett questionnaire (Annett, 1970) was administered to assess handedness. This consisted o f 14 questions used to determine hand preference.

Soft neurological signs were assessed in all subjects using the ‘soft signs assessment’ section (Part 2) o f the Cambridge Neurological Inventory (Chen et al, 1995). This consisted o f three groups o f signs, namely ‘primitive reflexes’, repetitive sequential motor execution and integration o f sensory information. The primitive reflexes tested were snout, grasp and palmomental reflexes. Sequential motor execution was assessed for each hand using finger-nose, finger-thumb tapping, fmger-thumb opposition, mirror movements, diadochokinesis, fist-edge-palm and Osteretsky tests. Tests o f sensory integration included rhythm tapping, go/no-go test, left-right orientation and finger agnosia, stereognosis and graphesthesia for each hand. Apart from the snout and palmomental reflexes (0=absent; l=present), the scoring applied to the other tests ranged from 0-2 (0=no errors or normal; l=one error indicating minor abnormality and 2=two or more errors indicating major abnormality). A total score for the three group o f signs was calculated for each subject.

MRI

All subjects had a MRI scan which was performed on a GE Signa 1.5 Tesla scanner using a standard quadrature head coil and the total scanning time was approximately 60 minutes. The MT technique used in this study was based on a sequence developed

by Barker et al (1996) and has an advantage in that it minimises the effect o f motion which may affect the calculation o f MTR. The following sequences were used:

a. T2 weighted and proton density images were acquired initially using a dual echo sequence (TE [echo time] 15/90 ms, TR [repetition time] 3000ms, 28 contiguous 5mm axial slices, 256x256 pixel image matrix, 24x24cm^FOV [field o f view]). b. Imaging using a spin echo based magnetization transfer sequence (TE 30/80 ms,

TR 1720 ms, 28 contiguous 5 mm axial slices, 256x128 pixel image matrix, 24x24cm^ FOV) was acquired with and without a saturation pulse. The saturation pulse was a 16 ms, 23.2uT Hamming appodised 3 lobe sine pulse, applied IKHz from water resonance.

MT images were intrinsically coregistered with the proton density and T2 weighted images. M TR was calculated on a pixel by pixel basis as described in Chapter 5.

MRI and the clinical assessments were performed on the same day.

Data Analysis

A protocol was defined with guidance from a neuroradiologist for selecting regions of interest (ROIs) in the white matter based on the standard neuroanatomical divisions o f the frontal, temporal, parietal and occipital lobes (Appendix 1). ROIs in the corpus callosum and white matter o f the frontal, temporal, parietal and occipital regions o f both hemispheres were sampled with reference to this protocol. Regions in the corpus callosum, frontal, temporal and parietal lobes were selected for this study as they have previously been reported to be abnormal in schizophrenia whilst the ROI in the

occipital lobe was chosen to provide an internal control region. Specifically, the temporal ROI was placed in the middle temporal gyrus and the frontal ROI was placed in the middle frontal gyrus to ensure that ROIs were strictly in white matter. The ROIs were standardised at 35.2 mm^ and outlined on the T2 weighted images and not directly on the MT images to avoid any bias in placing them. Adjacent slices were checked to ensure that all ROIs were surrounded by white matter to minimise partial volume effects from grey matter and CSF. The interleaved MT images were co­ registered with T2 weighted images which helps in selecting the regions o f interest as T2 images provide good grey-white matter differentiation thereby reducing partial volume effects from grey matter or CSF. Selecting the regions on the T2 images also ensures that the rater is blind to the appearance o f the calculated M TR images. The ROIs were then automatically transferred onto the MT images and mean MTR measurements were obtained in these regions. Figure 8 illustrates ROIs in the temporal white matter.