MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS pada
Gangguan Bahasa
dan Kognitif
Dr. Amanda Tiksnadi, SpN, Subsp.NRE(K), PhD

Makassar, 15 Oktober 2022

 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS and the Brain

• Faraday’s principle of
electromagnetic induction
• TMS → the 2nd coil is the
brain
• TMS → a large current in the TMS
coil in a short periode of time
• TMS → induce a transient
interruption of normal brain
activity in a relatively restricted
area of the brain
Brain Electrostimulation
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS Delivery Method

• 3 basic types
✓Single-pulse TMS
❑One pulse is applied no faster than once every few sec

✓Paired-pulse TMS
❑2 pulses applied out of phase to Inh or Exc neurons within the same
hemisphere or Inh neurons in one hemisphere while Exc them in the
other hemisphere

✓Repetitive TMS (rTMS)

❑Multiple single-pulse stim at a specific freq, intensity, and time
duration, in one area
 Frequency (Hz) and MEP amplitude
iTBS
QPS_5
HF rTMS

cTBS
Repetitive Stimulation →
QPS_50
Alter Functional Effect
LF rTMS
Tiksnadi A, et al. Brain Stim (2020)
Effect of rTMS on Activation in a Healthy Subject

•Suppression cortical excitability

with low freq rTMS in Broca area
• Prolongation reaction time verb-
generation task
• CBF under coil decrease, but
increased in neighboring regions and
in contralateral homologous area
Therapeutic Modulation:
Interhemispheric Connections & Neural Plasticity

Fregni & Pascual-Leone (2007)

Ex1: little early activation of non-infarcted LH.
Ex2: large incr bilateral , > R-Bho & SMA
Ex3: normalization activation w/ re-shift of > LH
rTMS for Impaired Language Research
• Modulate interhemispheric interaction

• >> inhibit overactivation of RH

❖Animal studies
❖Case reports in humans
❖(fMRI)  RH blood flow after LH stroke
❖Cases: improvement chronic speech problem after acute RH TBI
 Post 1-week TMS
Pre-TMS Pre-TMS
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS and
Cognitive
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS and Cognitive Function

• Single and paired pulse TMS can assess cortical excitability
➢ Co-adjuvant diagnostic tool to assess neuroplastic changes
• Paired associative stimulation and cortical response to rTMS →
different aspects of cortical plasticity
• TMS + EEG or TMS + fMRI → information on local cortical
excitability and functional connectivity between motor cortex
and other cortical regions
• TMS studies on AD and MCI → abnormal:
➢ Cortical excitability, plasticity, or connectivity
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

TMS and Cognitive Function

• rTMS → induced long-lasting effects → modulating the cortical
excitability
• Sustained attention/concentration
• Executive function/working memory
• Verbal fluency/retrieval
• Problem solving/reasoning

→ Healthy subjects, neurodegenerative disease, psychiatric

disorders
 Excitation
(Neuronal depolarization)

iTBS
QPS_5
HF rTMS

cTBS
QPS_50
LF rTMS

Inhibition
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

Cognitive Impairment
• Cognitive impairment is substantial healthcare challenges in the 21st
century, and it determines the loss of independent functioning.
• Medications may improve cognition. Unfortunately, these drugs have only
limited and transient effects and do not modify the natural course of the
illness.
• Alzheimer’s disease (AD) is a neurodegenerative process characterized by
progressive neuronal loss, reduced levels of several crucial
neurotransmitters, and altered forms of synaptic plasticity.
• Mild cognitive impairment (MCI) is considered a transitional stage between
normal aging and a diagnosis of clinically probable AD.
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

Effects of TMS in Cognitive Impairment

• High-frequency rTMS showed a benefit in cognition amongst older

subjects with mild to moderate AD and had a good safety profile in the
current systematic review and meta-analysis.
• rTMS was shown to have great potential as an alternative intervention for
cognition.
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

Effects of TMS in Cognitive Impairment

• High-frequency rTMS showed a benefit in cognition amongst older

subjects with mild to moderate AD and had a good safety profile in the
current systematic review and meta-analysis.
• rTMS was shown to have great potential as an alternative intervention for
cognition.
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

Effects of TMS in Cognitive Impairment

• Active iTBS improves global cognitive performance significantly in

patients with Parkinson's disease who have mild cognitive impairment
and the positive effect is maintained for up to one month after the
stimulation .
Average Z-scores throughout all four
neuropsychological assessments corrected
for the disease duration. Average composite
Z-scores in (A) overall cognition, (B)
attention, (C) executive function, (D)
language, (E) memory and (F) visuospatial
function during each assessment. Lines
represent the sham (grey) and the active
iTBS (black) group. Significant differences are
illustrated by asterisks: *Bonferroni-
corrected p < 0.0
 Effects of TMS in Cognitive Impairment

• Patients with AD may have

better responses to
rTMS and tDCS than MCI.
• Combining CT with NIBS,
particularly tailored CT and
stimulation site of left DLPFC,
may be beneficial for specific
cognitive subdomain.
• Sustained cognitive protective effects were observed at 1-month follow-up.
 Effects of TMS in Cognitive Impairment
• The stimulation parameters that appear
more helpful in cognitive improvement in MCI
o high frequency (5– 20Hz) rTMS
o applied over the left or bilateral hemisphere
(especially DLPFC or PFC)
for ≥ 20 treatment sessions with a
stimulation intensity from 80 to 110% resting MT.
• The most common stimulation target
• DLPFC.
• The anterior temporal lobe and
• PFC
• High-frequency rTMS significantly enhanced global cognitive function and
memory.

5. Jiang L, Cui H, Zhang C, Cao X, Gu N, Zhu Y, Wang J, Yang Z and Li C (2021) Repetitive Transcranial Magnetic Stimulation for Improving Cognitive Function in Patients With Mild Cognitive Impairment: A Systematic Review. Front. Aging Neurosci. 12:593000. doi: 10.3389/fnagi.2020.593000
6. Kim TD, et al. Cognitive Enhancement in Neurological and Psychiatric Disorders Using Transcranial Magnetic Stimulation (TMS): A Review of Modalities, Potential Mechanisms and Future Implications. Exp Neurobiol. 2019 Feb;28(1):1-16. https://doi.org/10.5607/en.2019.28.1.1
6. Kim TD, et al. Cognitive Enhancement in Neurological and Psychiatric Disorders Using Transcranial Magnetic Stimulation (TMS): A Review of Modalities, Potential Mechanisms and Future Implications. Exp Neurobiol. 2019 Feb;28(1):1-16. https://doi.org/10.5607/en.2019.28.1.1
Neurological pathway
underlying the effects of
TMS
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

Factors affecting the effect of TMS

• Demographic characteristics such as age and education level, the type and severity of illness,
and the amount of brain atrophy.

• Area of stimulation: The DLPFC is the most common target of rTMS and has been well proven
in many studies. Other areas such as the right inferior frontal gyrus, right superior temporal
gyrus, Broca’s area, Wernicke’s area and the parietal cortex, anterior temporal lobe, were
chosen as candidate sites for rTMS, and all showed initial promising results.
 Visuo-motor learning task
Hikosaka O, Rand MK, Miyachi S, Miyashita K (1995)
Learning of sequential movements in the monkey: process of learning and
retention of memory. J Neurophysiol 74:1652-1661.

Hikosaka O, Sakai K, Miyauchi S, Takino R, Sasaki Y, Pütz B (1996)

Activation of human presupplementary motor area in learning of
sequential procedures: a functional MRI study. J Neurophysiol 76:617-621.

Sakai K, Hikosaka O, Miyauchi S, Takino R, Sasaki Y, Pütz B (1998)

Transition of brain activation from frontal to parietal areas in visuo-motor
sequence learning. J Neurosci 18:1827-1840.
Visuo-motor sequence
learning

Courtesy of Dr Shimo,
Juntendo UNIV
 Figure 2. Scheme of the 2×10 task

Error Error Error Error

OK OK OK OK Trial Success

Home Key Set 1 Set 2 Set 3 Set 10

Hyperset

2 1 1
1
Correct 2 1
Response OK 2 OK OK OK 2

Hikosaka O, Sakai K, Miyauchi S, Takino R, Sasaki Y, Pütz B (1996) Activation of human presupplementary
motor area in learning of sequential procedures: a functional MRI study. J Neurophysiol 76:617-621.
Activation of Human Presupplementary Motor Area in Learning of Sequential Procedures: A
Functional MFCI Study. JNP 76: 617- 621, 1996

Difference between preSMA and SMA

preSMA
learning related
early stage active

SMA
performance related
late stage more active
Figure 3 Plasticity induction in the pre-supplementary motor area (pre-
A. Experiment 1 SMA) and SMA-proper differentially affects visuomotor sequence
learning. Shimizu et al, Brain Stimul 13:22-238, 2020

2×10 New sequence learning

QPS-5, QPS-50 or Sham Task
over the pre-SMA or SMA post

30min > 8min

Over-trained sequence learning
B. Experiment 2 same sequence

2×10 2×10 2×10 2×10

Task Task Task QPS-5, QPS-50 or Sham Task
pre1 pre2 pre3 over the pre-SMA or SMA post

C. Experiment 3
4-choice
QPS-5 or sham reaction time
over the pre-SMA task
4-choice reaction time task
post
30min
> 8min
 Plasticity induction in the pre-supplementary motor area (pre-SMA) and
A. QPS protocol SMA-proper differentially affects visuomotor sequence learning.
Shimizu et al, Brain Stimul 13:22-238, 2020
ISI = 5ms or 50ms

5s
360 D. EFmax for pre-
trains SMA/SMA stimulation
B. pre-SMA stimulation C. SMA stimulation
VCA
pre-SMA (EFmax)
SMA
(EFmax)

6cm Cz 3cm Cz AC-PC

motor point of r.TA

motor point of r.TA
Plasticity induction in the pre-
supplementary motor area (pre-SMA)
and SMA-proper differentially affects
visuomotor sequence learning.
Shimizu et al, Brain Stimul 13:22-238,
2020
 MAKASSAR NEURORESTORASI UPDATE (M AKNA)

The Study of Autistic Savants

• Savant-like skills exposed in normal people
by suppressing the left-fronto-temporal lobe
(Synder et al., 2003)
• 15 min 1Hz rTMS over the left fronto-temporal;
11 healthy participants
• Task: complete drawing & proofreading tasks
▪ Before real & sham rTMS
▪ During real & sham rTMS
▪ Immediately after real & sham rTMS
▪ 45 min after real & sham rTMS
Drawing Task 1

After 10 min of stimulation, NR and

AJ radically changed their schema
for dogs from their initial 2
drawings before stimulation.
During and after stimulation, the
style dramatically changed, with
the drawings becoming more
complex.

The horses became more life-like,

even flamboyant, compared to the
drawing he completed before
stimulation.
Drawing Task 2
During and after real stimulation,
RY changed his convention for
drawing faces
- in placebo stimulation, a
distinct schema is present in the
drawings

During and after real stimulation,

this style changed, and RY became
preoccupied by the details of eyes
- this drawings were executed
in one minute by RU after viewing
the corresponding image of figure
4 for 30 seconds
 Table 1 MAKASSAR NEURORESTORASI UPDATE (M AKNA)
Summary of Published studies using TMS as a diagnostic tool.
TMS
Distribution of Age of Parameters
Number Adverse
Autism vs. AS Participan (Number of
Study of ASD Effects Events/Side
(Diagnostic ts Sessions
Subjects Effects
Criteria) (years) Frequency,
Location)
Theoret et al., 10 Not Indicated 23–58 One session of No group difference in RMT or response to Not
2005 (DSM-IV-R) spTMS ppTMS. Impaired corticospinal facilitation in Indicated
and ppTMS response to finger movements viewed from
over M1 the egocentric point of view in ASD group.
Minio-Paluello et 16 16 AS (DSM- M = 28.0 One session of No modulation of corticospinal excitability in Not
al., 2009 IV) (SD = 7.2) spTMS over response to the observation of painful stimuli Indicated
M1 affecting another individual in AS group.
Oberman et al., 5 5 AS (DSM-IV- 26–54 Two sessions Heterogeneous response to ppTMS. Greater None
2010 TR) of spTMS, and longer-lasting
ppTMS, and response to TBS in AS group.
TBS over M1
Enticott et al., 25 11 HFA, 14 AS M = 16.67 One session of Reduced intracortical inhibition in the HFA Not
2010 (DSM-IV) (SD = spTMS group as compared to the AS or control group Indicated
4.33) and ppTMS
over M1
 TMS
Distribution of Age of Parameters
Number Adverse
Autism vs. AS Participan (Number of
Study of ASD Effects Events/Side
(Diagnostic ts Sessions
Subjects Effects
Criteria) (years) Frequency,
Location)
Enticott, et al., 34 Not Indicated M = 26.32 One session of No group difference in degree of corticospinal Not
2012a (DSM- (SD = spTMS over excitability in response to observation of Indicated
IV) 10.70) M1 single static hand stimuli. Impaired
corticospinal facilitation in response to single
hand transitive hand actions in ASD group.
Enticott et al., 36 Not Indicated M = 26 One session of No group difference in RMT. Heterogeneous Not
2013a (DSM- (SD spTMS and response to ppTMS in ASD group. Indicated
IV) = 10.48) ppTMS over
M1
Jung et al., 2013 15 7 HFA, 6 AS, 2 M = 17.8 One session of No group difference in response to ppTMS. None
PDD- (SD = 3.5) ppTMS Impaired PAS facilitation in ASD group.
NOS (ICD 10 and PAS
and
DSM-IV)
Enticott et al., 32 Not Indicated M = 24.75 One session of No group difference in degree of corticospinal Not
2013b (DSM- (SD = spTMS excitability in response to single static hand Indicated
IV) 8.11) over M1 stimuli or two person interactive hand actions
 Table 2
Summary of Published studies using TMS as a therapeutic tool.

Study Number Distribution of Age of TMS Parameters Open Label Effects Adverse-Events/Side Effects
of ASD Autism vs. AS Participants (Number of Sessions or Sham
Subjects (Diagnostic (years) Frequency, Location) Controlled?
Criteria)
Sokhadze et 8 8 Autism 12–27 150 pulses (fifteen 10 s trains Open Label Compared to the "waitlist control group" Not Indicated
al., 2009 (DSM-IV-TR, with a 20–30 s interval the stimulation group showed a
ADI-R) between the trains) at 0.5 Hz normalization
and 90% RMT over left DLPFC in event-related potentials (ERPs) and
twice per week for 3 weeks. induced gamma frequency EEG)activity and
a reduction in repetitive-ritualistic behavior
as reported by their caregivers.
Sokhadze et 13 Not Indicated 9–27 150 pulses (fifteen 10 s trains Open Label Compared to the participant’s pretest None
al., 2010 (DSM-IV-TR, with a 20–30 s interval scores, the posttest scores showed the
ADI-R) between the trains) at 0.5 Hz stimulation group showed a normalization
and 90% RMT over left DLPFC in event-related potentials (ERPs) reduction
twice per week for 3 weeks. in repetitive- ritualistic behavior as
reported by their caregivers. No differences
were seen in the "waitlist" group.
Baruth et al., 16 Not Indicated 9–26 150 pulses (fifteen 10 s trains Open Label Compared to the participant’s pretest Five participants reported an
2010 (DSM-IV-TR, with a 20–30 s interval scores, the posttest scores showed itching sensation around the
ADI-R) between the trains) at 1 Hz improvement in discriminatory evoked nose during stimulation and
and 90% RMT over left DLPFC gamma responses and improvements in one participant reported a
once per week for 6 weeks irritability and repetitive behavior as transient headache in the
then the same procedure over reported by their caregivers. No differences hours following stimulation.
the right DLPFC once per week were seen in the "waitlist" group.
for 6 weeks.
Study Number Distribution of Age of TMS Parameters Open Label Effects Adverse-Events/Side
of ASD Autism vs. AS Participant (Number of Sessions or Sham Effects
Subjects (Diagnostic s Frequency, Location) Controlled?
Criteria) (years)
Enticott et 1 1 AS (Not 20 1500 (thirty 10-second trains with a Double Blind Compared to before stimulation, Not Indicated
al., 2011 Indicated) 20 second interval between the Sham both the participant and her
trains) at 5 Hz and 54% of stimulator Controlled family members noted
output over medial prefrontal cortex improvements in social relating
each consecutive weekday for an 11- and interpersonal
day period for a total of 9 sessions. understanding.
Fecteau et 10 10 AS (DSM- M = 36.6 1800 pulses at 1 Hz and 70% Double Blind Compared to the sham condition, There were two reports
al., 2011 IV, ADOS, (SD stimulator output over left and Sham stimulation of left pars triangularis of a stiff neck and one
ADI-R) = 16.0) right pars triangularis and pars Controlled improved naming skills while report of subtle
opercularis and sham (a single stimulation of the adjacent left pars disorientation following
session at each location separated by opercularis impaired naming skills. sham stimulation. There
at least 5 days). were two reports of a
stiff neck, six reports of
sleepiness, two reports of
being more emotional,
one report of
dizziness, three reports
of trouble concentrating,
one report of discomfort
at the stimulation site
and one report of a
headache following
active stimulation.
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