Cortical Lesions in Patients With Multiple Sclerosis
Cortical Lesions in Patients With Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disease, leading to inflammation and degeneration of
 neurons in the entire central nervous system (CNS). Not only does MS attack CNS white matter,
 the wiring of the brain, but it also affects so called grey matter, involved in communication
 between brain cells. Some studies have shown that grey matter damage and lesions to the
 outermost layer of the brain, the cortex, might serve as a better diagnostic and prognostic
 tool for MS patients. The issue is that cortical lesions only to a limited extent can be
 visualized by conventional magnetic resonance imaging (MRI) at 3 tesla. The new generation of
 ultra-high field MR scanners with a field strength of 7 tesla, has a higher sensitivity
 towards detecting these cortical lesions. We therefore wish to use the improved sensitivity
 of ultra-high field MRI to improve detection of cortical lesions, and to elucidate the
 detrimental effects of single lesions to the cortex, thereby improving both diagnosis and
 prognosis of the disease.

 By implementing newly developed ultra-high-resolution MR-sequences the amount and extent of
 cortical lesions to the area of the brain responsible of the sensory and motor function of
 the hand (sensorimotor hand area - SM1-HAND) will be investigated in patients with relapsing
 remitting and secondary progressive MS. We will also assess how these lesions affect manual
 dexterity and sensory function and how cortical lesions affect communication within brain
 areas. It is hypothesized that the amount and size of cortical lesions is highly involved in
 brain communication and manual function, a major problem in MS, and that this project will
 shed new light on how the disease damages this important brain area.
BACKGROUND. In recent years, several lines of research have shown that multiple sclerosis
 (MS) affects cortical grey matter and that the degree of cortical grey matter involvement is
 associated with cognitive and physical disability, but the specific impact of a cortical
 lesion on regional function remains to be clarified.

 High-field Magnetic Resonance Imaging (MRI) at 3T has been used to detect cortical lesions in
 MS, but histological examinations have shown that only 'the tip of the iceberg' is detected.
 Ultra-high field 7T MRI has a higher diagnostic sensitivity than 3T MRI. Although not every
 cortical lesion is detected even at 7T, a recent post-mortem verification study concluded
 that ultra-high field MRI "more than doubles detection of cortical MS lesions, compared to 3T
 MRI". Implementing 7T MRI in detection of cortical lesions and elucidating the behavioural
 and neurophysiological impact of cortical lesions is therefore a good candidate in aiding to
 resolve the clinico-radiological paradox reported in MS.

 AIMS and HYPOTHESES. This study is designed to clarify the occurence of cortical lesions
 within the primary sensory-motor hand area (SM1-HAND) and their impact on manual motor and
 sensory function, as well as regional cortical connectivity. The SM1-HAND is well suited to
 address this question, because functional integration in SM1-HAND can be studied in detail
 with transcranial magnetic stimulation (TMS) and high-resolution fMRI.

 Exploiting the increased sensitivity of 7T MRI to detect cortical lesions, the number, size
 and regional distribution of cortical lesions in SM1-HAND will be assessed and lesion load in
 SM1-HAND will be related to MRI-based, electrophysiological, and behavioral correlates of
 hand function.

 Specifically the following parameters will be assessed:

 1. The extent that the primary sensorimotor cortex is affected by cortical lesions in
 patients with relapsing remitting and secondary progressive multiple sclerosis (MS).

 2. The impact of a single cortical MS lesion in the sensorimotor cortex on upper extremity
 sensorimotor function.

 3. The impact of a single cortical MS lesion in the sensorimotor cortex on regional
 intra-cortical connectivity.

 Hypotheses:

 1) The extent of cortical damage to the primary sensorimotor cortex is unknown, but based on
 clinical symptoms of motor function it is expected that up to 40% of patients show focal
 cortical lesions in this area and that this will include all subtypes of cortical lesions.

 2a) It is hypothesized that unimanual motor function correlates negatively with the total
 cortical lesion load within the contralateral sensorimotor cortex, independent of age,
 gender, handedness, white matter lesion volume, axonal integrity of the cortico-spinal tract,
 central motor conduction time and cortical thickness of the sensorimotor cortex. 2b) It is
 hypothesized that the amount and size of cortical lesions within the primary sensorimotor
 cortex correlates positively with motor fatigue. 2c) It is hypothesized that unimanual
 sensory acuity correlates negatively with the total cortical lesion load within the
 contralateral sensorimotor cortex.

 3a) It is expected cortical lesions to cause a shift in the digit representation, measured as
 the task related BOLD signal of the contralateral somatosensory cortex, away from the lesion.
 3b) It is hypothesized that cortical lesions within the primary sensorimotor cortex affects
 the regional intra-cortical excitatory/inhibitory balance.

 4) It is further expected that the functional impact of regional cortical lesions are
 independent of age, gender, handedness, white matter lesion volume, axonal integrity of the
 cortico-spinal tract, central motor conduction time and cortical thickness of the
 sensorimotor cortex and scales with lesion type, number and volume.

 3. RESEARCH PLAN.

 Part 1. Whole-brain 7T MRI study to identify cortical lesions.

 Participants: The project is planned to involve 80 mildly to moderately affected patients
 (Expanded Disability Status Scale of <5.5) with relapsing-remitting MS (RR-MS, n=40) or
 secondary progressive MS (SP-MS, n=40) who had no clinical relapse within the last three
 months and 20 healthy age-matched controls (age range: 18-70 years).

 Ultra-high field MRI. All participants will be studied with whole-brain ultra-high field MRI
 at 7T, using a research-only 7T Achieva MR system (Philips, Best, The Netherlands) located at
 Hvidovre Hospital. Whole-brain MR scanning will be performed with a dual transmit, 32-channel
 receive head coil (Nova Medical Products), including 3-dimensional (3-D),
 magnetization-prepared rapid acquisition of gradient echoes (MPRAGE) imaging at 0.65-mm
 isotropic resolution and 3-D, magnetization-prepared, fluid attenuated inversion recovery
 (MPFLAIR) imaging at 0.7-mm isotropic resolution (5). Whole-brain semi-quantitative
 (MP2RAGE), as well as a quantitative T2* sequence will also be conducted.

 Additional examinations. Outside the MR scanner, physical impairment (EDSS), fatigue (Fatigue
 Scale for Motor and Cognitive Functions, FSMC), cognition (Symbol Digit Modalities Test, SMDT
 & Paced Auditory Serial Addition Test, PASAT), depression (Beck Depression Inventory, BDI II)
 as well as sensorimotor hand function (9HPT, Jebsen Taylor Hand Function Test (JTT), Finger
 tapping, Grating Orientation Discrimination Test (GODT)) will be assessed.

 Part 2. Selected 7T MRI of the SM1-HAND.

 Participants: A sub-group of individuals who participated in part 1 will be asked to
 participate in part 2: It is expected that at least 20 patients will show at least one
 cortical lesion in the right or left SM1-HAND on 7T MRI. The lesion-positive patients (n>20),
 an age- and EDSS- matched lesion-negative MS group (n>20), and an age-matched healthy control
 group (n=20) will be studied. Recruitment will be done continuously to minimize the delay
 between part 1 & 2.

 Participants will be scanned again with the 7T Achieva MR system using a reduced coronal
 field-of-view, covering the right and left SM1-HAND and the corticospinal tract. Structural
 imaging will include a 0.7 mm isotropic FLAIR sequence, and an ultra-high resolution MP2RAGE
 (0.5 mm isotropic) sequence as well as whole brain diffusion weighted imaging (DWI).
 Proton-Magnetic Resonance Spectroscopy (MRS) will be performed to measure regional
 N-acetyl-aspartate (NAA), GABA and glutamate concentration in right and left SM1-HAND. Lastly
 high-spatial resolution functional Blood Oxygen Level Dependent (BOLD) (fMRI) will be used to
 map the somatotopy of sensory and motor representations in SM1-HAND. Activation maps will be
 superimposed to individual lesion maps.

 TMS. The corticospinal conduction will be quantified with transcranial magnetic stimulation
 (TMS). A novel neuronavigated TMS mapping method developed by this group, which is sensitive
 to changes in cortico-motor representations of intrinsic hand muscles will also be
 implemented. Finally, aspects of intracortical inhibition in both SM1-HAND with established
 single-pulse and double-pulse TMS paradigms will be carried out. Conduction in the afferent
 somatosensory pathway will be assessed by recording somatosensory evoked potentials (SSEP).
Inclusion Criteria:

 Patients

 -  Expanded Disability Status Scale of < 7.5

 -  Diagnosed with either relapsing-remitting or secondary progressive multiple sclerosis

 -  No clinical relapse within last three months

 -  Have the ability to comply with all requirements of the study protocol, as determined
 by the investigator

 Healthy controls

 -  Able bodied

 -  Have the ability to comply with all requirements of the study protocol, as determined
 by the investigator

 Exclusion Criteria:

 Patients

 -  Pregnancy

 -  Pacemaker or other implanted electronic devices

 -  Claustrophobia

 -  Psychiatric disorder

 -  Administration of acute cortisol

 -  Changes in pharmacological treatment within the last 3 months

 -  Close relatives suffering from epilepsy (only relevant for TMS)

 -  Migraine (only relevant for TMS)

 -  Any contraindication to TMS or MRI

 -  Persons who do not wish to be informed about abnormal findings as part of the
 investigations

 Healthy controls

 -  Pregnancy

 -  Under medication at the time of the experiment (with the exception of contraceptive
 drugs)

 -  History of neurologic disease

 -  Pacemaker or other implanted electronic devices

 -  Close relatives suffering from epilepsy (only relevant for TMS)

 -  Migraine (only relevant for TMS)

 -  History of cerebral hemorrhage or brain damage

 -  Claustrophobia

 -  Psychiatric disorder

 -  Any contraindication to TMS or MRI