None listed
Conditions
Brief summary
There is an urgent need for the development of novel approaches to the treatment of Alzheimer’s disease (AD). AD is characterised by progressive decline in cognitive functioning in most areas, including in memory, attention, visuospatial ability, language and executive function. Although there are medications that can slow the progression of symptoms somewhat, there are currently no effective treatments for these hallmark symptoms of AD. Recent research has indicated that the progressive cognitive decline seen in AD may be a result of decreased functional connectivity throughout what is known as the default mode network (DMN), a brain network whose anatomy closely mirrors the pattern of cortical atrophy seen in AD patients (i.e. prefrontal, posterior parietal, and medial temporal). An approach that is able to specifically target this network in order to enhance connectivity, and thus functioning, could result in a highly effective therapy for the cognitive impairments in AD. Non-invasive brain stimulation (NIBS) techniques have considerable promise in this regard. NIBS has been shown to modulate activation throughout large scale cortical networks, such as the one implicated in cognitive impairment in AD, to enhance cognition in a number of disorders and to produce long lasting behavioural effects. In particular, Theta Burst Stimulation (TBS) is a highly effective form of NIBS and allows for multi-site stimulation within a single treatment session. The use of TBS for the treatment of cognitive impairment in AD is an area of significant potential, and one that has yet to be adequately explored. We propose to conduct a double-blind placebo-controlled randomised pilot study comparing a treatment course of active TBS to sham TBS (i.e. 21 daily treatment sessions over six weeks). In each treatment sessions TBS will be sequentially provided to four brain regions, the left and right dorsolateral prefrontal cortex (lDLPFC, rDLPFC) and the left and right posterior parietal cortex (lPPC, rPPC).
Interventions
Transcranial Magnetic Stimulation involves the repeated application of a strong but highly localised magnetic field to a small cortical area, and when given at high frequency (i.e. greater than one pulse per second) can increase lasting changes in local cortical activity.
Theta Burst Stimulation (TBS) is a form of TMS where pulses are applied in patterned bursts (3 at a time) but at high frequency (usually 50 Hz).These short bursts are repeated at an inter-burst interval of 200ms (5 Hz). Interm
Transcranial Magnetic Stimulation involves the repeated application of a strong but highly localised magnetic field to a small cortical area, and when given at high frequency (i.e. greater than one pulse per second) can increase lasting changes in local cortical activity. Theta Burst Stimulation (TBS) is a form of TMS where pulses are applied in patterned bursts (3 at a time) but at high frequency (usually 50 Hz).These short bursts are repeated at an inter-burst interval of 200ms (5 Hz). Intermittent TBS (iTBS) involves applying TBS in two second trains every 10 seconds and has been shown to result in significantly greater, and longer lasting, increases in cortical excitability than standard high frequency TMS. A typical rTMS protocol is likely to take between 40 and 45 minutes per day whereas iTBS stimulation is complete within 3 minutes. Therefore, TBS would allow for targeting of multiple brain regions in the one treatment sessions, as well as potentially producing greater and longer lasting effects compared with standard TMS. Patients will undergo a total of 21 sessions over six weeks (daily sessions Mon-Fri for week one to week three, followed by 3 treatments in week four, 2 treatments in week five and 1 treatment in week six) of either active or sham iTBS to the left dorsolateral pre frontal cortex (lDLPFC), right dorsolateral pre frontal cortex (rDLPFC), left posterior parietal cortext (lPPC) and right posterior parietal cortex (rPPC). All sites will be stimulated using 3 bursts of high frequency TBS (pulse 50-Hz) lasting a total of 2 seconds, repeated every 10 seconds for a total of 180 seconds per site. Therefore stimulation for all four sites will take 12 minutes per treatment session. iTBS will be applied at 100% of the participants resting motor threshold (RMT). Sham stimulation will be provided with a sham coil. All stimulation will be conducted by a fully qualified and TMS certified research nurse. Participants will be seated in a comfortable chair with their neck supported whilst the TMS coil is held in position against the scalp. They will be monitored at all times. A record of treatment time and date will be logged on a participant's treatment sheet.
Sponsors
Professor Paul Fitzgerald
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
50 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
100 individuals with AD will participate in the study. Participants will be included if they: (1) are competent to consent based on their ability to provide a spontaneous narrative description of the key elements of the study, as assessed by a clinical staff member independent of the research project; (2) have a diagnosis of AD based on general medical, neurological, and neuropsychological examinations according to the National Institute of Neurological and Communication Disorders–Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA) criteria for probable Alzheimer’s disease and the DSM-IV clinical criteria for dementia of the Alzheimer’s type; (3)meet criteria for mild-to-moderate AD as indicated by a score of 12 or above on the Mini-Mental State Evaluation (MMSE); and (4) are either not on psychotropic medication or their dose of medication has been unchanged for a minimum of 4 weeks prior to entry into the study. Medication dose will not be able to be altered during participation: if this is clinically required the patient will be withdrawn from the study.
Exclusion criteria
Patients will be excluded if they (1) have metal in the cranium, a pacemaker, cochlear implant, medication pump or other electronic device ;(2) have a DSM-IV history of substance abuse or dependence in the last 6 months; (3) have a concomitant major and unstable medical, psychiatric or neurological illness; (4) have a history of seizures (5) are pregnant or breast feeding; (6) have had brain stimulation in the past three months or (7) are professional drivers.
Outcome results
None listed