Download An Overview of Trigeminal Nerve Stimulation: Basic Science

An Overview of Trigeminal Nerve Stimulation:
Basic Science, Clinical Results and Future Directions
Background
• Trigeminal Nerve Stimulation (TNS) is a promising neuromodulation technique that uses
gentle electrical impulses to stimulate the trigeminal nerve.
Embodiments
Clinical Results
Trigeminal Nerve Stimulation can be delivered via two different embodiments
Phase II Randomized Control Trial of eTNS™ for Drug Resistant Epilepsy
45%
• The Trigeminal nerve (CN V) is the largest cranial nerve, supplying sensation to the face and
motor to the muscles of mastication and the palate.
36.2%
35%
31.5%
Between Group
Comparison (GEE)
p = 0.08
30%
25%
17.8%
16.0%
20%
• TNS has several advantages over other neuromodulation techniques, including:
• Stimulation can be delivered via external or subcutaneous systems
• Stimulation can be delivered bilaterally and at a wide range of frequencies
• Low-risk therapy that is well-tolerated by patients
• Possibility to screen for responders with a non-invasive external system prior to
implantation of subcutaneous system
• Cost-effective, patient-directed treatment
• Phase I and II clinical trials of external TNS (eTNS™) for the treatment of drug resistant
epilepsy (DRE) and major depressive disorder (MDD) have been completed with favorable
results.
• A Phase II double-blind randomized control trial of eTNS™ for the treatment of drug
resistant epilepsy demonstrated that 40.5% of patients in the treatment group had a
≥50% reduction in seizure frequency after 18 weeks.
• A Phase I open-label pilot study of eTNS™ for MDD demonstrated a mean reduction in
depression severity of 51.5% after 8 weeks. Results of a Phase II double-blind RCT
are expected in Q1 2012.
40.5%
40%
• The Trigeminal nucleus is located in the brainstem with connecting fibers to the thalamus
and cortex; providing a high-bandwidth pathway to structures throughout the brain.
• Functional neuroimaging studies have demonstrated significant metabolic alterations in
brain regions associated with seizures and mood in subjects receiving eTNS™.
Within Group Comparison (GEE) p =
0.01
15%
15.6%
10%
Treatment
Active
Control
5%
0%
6 Weeks
12 Weeks
18 Weeks
Responders were defined as subjects having a ≥ 50% decrease in seizure frequency. At the
end of 18 weeks 40.5% of subjects in the treatment group responded versus only 15.6% of
subjects in the active control (p = 0.08).
External Trigeminal Nerve Stimulation
eTNS™
Subcutaneous Trigeminal Nerve Stimulation
sTNS™
Phase I Trial of eTNS™ for Major Depressive Disorder
p = 0.0001
Basic Science
p = 0.0002
p = 0.007
p = 0.0003
Functional Neuroimaging – O15 PET Data
• Five subjects with major depressive disorder (MDD) were enrolled to receive 8 weeks of
eTNS™ as adjunctive therapy and underwent O15 PET scanning during first use of eTNS™
• Significant metabolic changes were found in brain structures associated with seizures, mood, and
attention.
• Stronger caudate nucleus activation was associated with improved clinical response. Stronger superior
parietal deactivation was associated with less clinical response.
• Phase I studies of eTNS™ for ADHD and PTSD are ongoing with results expected in early 2012.
Activation
The Trigeminal Nerve – USB Port to the Brain™
Deactivation
PRE
POST
PRE
POST
PRE
POST
PRE
POST
A Phase I study of eTNS™ for depression enrolled 11 subjects for an 8 week period. At the
end of 8 weeks there were significant improvements in depression scores as measured by
HDRS-28, HDRS-17, QIDS, and BDI.
Future Directions
O15 PET scanning of subjects receiving eTNS™ for the first time revealed significant metabolic
changes in cortical structures associated with seizures, mood, and attention.
0
The Trigeminal Nerve (CN V) is the
largest cranial nerve, supplying
sensation to the face
The Trigeminal Nucleus in the brainstem has direct
projections to the ventral posterior nucleus of the
thalamus and the cortex.
Change in HDRS17 Score
Over 8 Weeks
-0.06
-0.04
-0.02
0
0.02
0.04
0.06
0.08
-5
R = 0.93
-10
p =0.023
-15
-20
-25
Patient with least clinical
response (-4)
demonstrated the most
activation in this area.
Patient with greatest
clinical response (-23)
demonstrated greatest
deactivation in this area.
Left Caudate Nucleus Deactivation
(TNS Stimulus On minus Stimulus Off)
Stronger caudate nucleus activation was
associated with improved clinical response
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-0.05
Change in HDRS17 Score
Over 8 Weeks
0
-0.04
-0.03
-0.02
-0.01
0
-5
Patient with
least clinical
response (-4)
demonstrated
the least
deactivation in
this area.
R = -0.85
p = 0.065
-10
-15
Patient with greatest clinical
response (-23) demonstrated
greatest deactivation in this
area.
-20
-25
Right Superior Parietal Deactivation
(TNS Stimulus On minus Stimulus Off)
Stronger superior parietal deactivation
was associated with less clinical response
• Trigeminal Nerve Stimulation is a novel neuromodulation treatment modality for
epilepsy and other neuropsychiatric disorders.
• Functional neuroimaging of subjects receiving eTNS™ shows significant changes in
cerebral metabolism that correlate with clinical response.
• Phase I and II studies of eTNS™ for MDD and DRE are encouraging, and show
dramatic reductions in seizure frequency and severity of depression. These results
warrant confirmation in larger clinical trials with more patients.
• A Phase II RCT of eTNS™ for depression in ongoing, with results expected in early
2012.
• Results of Phase I clinical trials of eTNS™ for PTSD and ADHD are expected in 2012.