Cognitive Remediation Combined with Transcranial Magnetic Stimulation in Alzheimers Disease

Lukas Schilberg1, Anna-Katharine Brem1, Catarina Freitas1, Natasha Atkinson1, Erica Seligson1, Edward Gold1, Ilya Vidrin1, Alvaro Pascual-Leone1 1BerensonAllen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, USA

Introduction
Alzheimers disease (AD) is the most common cause of dementia. Histopathologically AD is characterized by amyloid plaques, fibrillary tangles, and cortical atrophy. Growing evidence suggests that aberrant plasticity as an early pathophysiologic process. Existing AD treatments show limited benefit and have side effects. We are evaluating a novel, non-pharmacological intervention merging transcranial magnetic stimulation (TMS) with computer based cognitive remediation (CR) in mild-moderate AD. TMS can be used to modulate brain plasticity and it may enhance the effects of cognitive intervention methods when administered in combination. Neuropsychological assessment (ADAS-Cog)

Results
Within 1 month after the end of the active treatment period, patients improved on average by 6.48 points ( 3.68). AD patients in the sham group decreased on average by 0.66 ( 2.91) points (Fig.4). The difference between the two groups after the NICE-treatment is 7.14 points and is statistically significant (Mann-Whitney-U, p=0.004). The individual data shows that all subjects in the treatment group improve within the first month after the treatment. Within-group comparisons show a significant change for the treatment group (Willcoxon signed rank, p=0.043). Neurophysiological measures show an increase in brain excitability and plasticity for the active treatment group (Fig.5). However, the changes do not reach significance.

Brain plasticity assessment

Methods
Patients
N= 12, 6 Control, 6 Treatment Age Male/female MMSE Medicated

Main Inclusion Criteria : Main Exclusion Criteria:

Treatment
70.33 2.07 2/4 21 2.97 6/6

Control
69.83 10.82 4/2 21.67 3.01 6/6

Fig. 4 Clinical Treatment response The NICE system (NeuroADTM, Neuronix Ltd., Israel) interleaves cognitive training and rTMS (Fig. 1). Cognitive training is matched to to the six regions targeted (right and left dorsolateral prefrontal cortex, right and left inferior parietal cortex, Broca, Wernicke) (Fig.2). treatment
Treatment course consisted in a 6 week course of 5 daily sessions per week. Sham treatment: combination of sham cognitive training and sham rTMS for a period of 6 weeks. Before and after the 6-week training, brain plasticity was assessed by applying single pulses (120% RMT) before and after intermittent theta burst stimulation (iTBS; 80% AMT) over the left hemisphere (Fig. 3). Brain plasticity of M1 was assessed with TMS-EMG measures of the first dorsal interosseus muscle (FDI).

Mild to Moderate AD patients Brain related illness/injury Age 55-85 years Epilepsy MMSE 18-24 Unstable medical condition

ADAS-Cog Change Post Treatment

ADAS-Cog Change Post Treatment (Individuals)

6 4 2

*
1

0.66

0 -2

-2

-4

Real (n=6) Sham (n=6)

-6 -8 -10 -12

Real Treatment Sham Treatment

-4

-6

-14

Real Treatment

1Month

Fig. 1 Study Protocol

Screening Baseline
Plasticity - pre

6 weeks
Sham Treatment Plasticity - post

Follow-Up
1Month

Fig. 5 Excitability and plasticity measures from M1 (TMS-EMG)

-8

-6.48

3500

MEP Amplitude
80.00 70.00 60.00 50.00

% Change of MEP Amplitude (post-pre)

3000

2500 Amplitude % Change

2000

Combined training: 6 weeks, 5 sessions per week, 1 hour per session Assessment Points: ADAS-Cog
Patient Touchscreen NeuroAD Magnetic coil
Right and Left DLPFC Right and Left IPL

1500

Real pre (n=5) Real post (n=5) Sham pre (n=4) Sham post (n=4)

post-pre real

40.00 30.00 20.00 10.00 0.00

post-pre sham

Fig. 2 NeuroAD System

Arm support Technician stand Computer
IFG (Broca)

rTMS stimulation: 20 x 2 sec (10 Hz) per region at 120% RMT. 3 of 6 different brain regions are stimulated per day.

1000

500

0 -10 0 10 20 30 Time (min) 40

5 Time (min)

10

Treatment chair

Electronic computerized unit

STG (Wernicke)

Conclusion 1. Combined CR and rTMS with the NeuroAD seems to be a promising intervention to improve cognitive function in patients with AD. 2. Cognitive improvement is greater than that typically seen with medication. 3. Excitability and plasticity measures obtained from M1 increased after the NeuroAD intervention.
This study was sponsored and supported by Neuronix Ltd. (www.neuronixmedical.com), Nexstim, Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institute of Health Award #UL1 RR 025758), and the Berenson-Allen Foundation. Contact: lschilbe@bidmc.harvard.edu

LTP-like Plasticity

Fig. 3 Plasticity Visits

Plasticity