Download Neurofeedback Treatment of Epilepsy

Neurofeedback Treatment of Epilepsy
by
Jonathan E. Walker, MD, Neurotherapy Center of Dallas
Clinical Professor of Neurology, Southwestern Medical School
(Corresponding Author)
and
Gerald Kozlowski, Ph.D., Neurotherapy Center of Dallas,
Professor of Physiology, Southwestern Medical School
Mailing Address (for both authors): Neurotherapy Center of Dallas
12870 Hillcrest Rd., Suite 201
Dallas, TX 75230
Phone: 972-991-1153
Fax: 972-991-1346
Email: [email protected]
Web site: neurotherapydallas.com
Neither author has a relationship with a commercial company that has a direct financial interest in the
subject matter or materials discussed in this article or with a company having a competing product.
1
SUMMARY
By using neurofeedback, it is possible to train the brain to de-emphasize those
rhythms which lead to generation and propagation of seizure, and to emphasize those
rhythms that make seizures less likely to occur. With recent improvements in quantitative
EEG measurement and improved neurofeedback protocols, it is often possible now to
eliminate seizures or reduce the amount of medication required to control them.
The use of neurofeedback to treat human epilepsy dates back to the early 1970’s.1
Subsequent studies (without QEEG guidance) showed that seizure frequency could be
reduced in the majority of patients who were trained to decrease slow frequencies in the
3-8 Hz range and reward frequencies in the 9-18 Hz range. However, complete abolition
of seizures was rare.
With the development of sophisticated QEEG date bases it has become possible to
more precisely characterize power and coherence abnormalities associated with drugresistant epilepsy. If there is focal excessive power in a frequency band, it may be
downtrained. If there is a focal deficiency in power, it may be uptrained. Similarly,
significantly decreased coherence between brain areas may be uptrained, and
significantly increased coherences may be downtrained. This approach has been found to
decrease or abolish seizures in all patients thus trained. Many even become drug-free.
In this chapter, we discuss the history of neurofeedback for epilepsy, followed by
discussions of the relevant neurophysiology of epilepsy. A model of how neurofeedback
might raise the seizure threshold in then presented. We then summarize our results
between 2002-2003, using our approach. Finally, we discuss potentially profitable future
directions for making this training even more effective.
2
Neurofeedback is noninvasive, safe, and relatively inexpensive in comparison to surgical
therapy of drug-resistant epilepsy. Commonly, drugs may be reduced or eliminated, and
side effects consistently reduced. Improvements in comorbidities, such as ADD, learning
disabilities, depression, anxiety, and memory loss also occur. It should be an integral part
of the treatment of these patients.
We have also been able to use neurofeedback in patients who have intolerable
side effects from drugs to protect them from seizures. We have also been able to stop
antiepileptic therapy of epileptic women who wish to become pregnant, as it poses no
risk to the fetus.
3
Neurofeedback for Epilepsy
I. A Brief History
The value of neurofeedback for human epilepsy was first established by Stevman
and his colleagues in 1974.1 12-16 Hz activity (“SMR”) at 20-25 μV was rewarded over
central and frontal areas in 4 medically refractory patients, 3 sessions/week for 6-18
months. All 4 patients exhibited a reduction in seizure frequency during “SMR” training
over 0.5-1.5 years. A rebound in seizure frequency occurred after cessation of training in
3 patients. Finley et al2 found that reduction of “SMR” was associated with reduced
seizure frequency and normalization of the EEG in a severely epileptic patient. In an
important paper, Lubar and colleagues3 carried out a double-blind study of neurofeedback
for uncontrolled epilepsy. They found that reward to inhibit 3-8 Hz activity, along with
reward to increase 11-19 or 12-15 Hz activity was associated with a decrease in seizure
frequency. If increase in 3-8 Hz activity was rewarded there was an increase in seizure
activity. Wyler et al4 rewarded desynchronizing action (increase in fast activity, decrease
in slow activity) which was effective in reducing seizure frequency in several medically
intractable patients. Ayers5 reported successful treatment of absence epilepsy by training
patients to inhibit 4-7 Hz activity and reward 15-18 Hz activity, using bipolar training at
T3/C3 and T4/C4. Ten patients became and remained seizure-free for 10 years. In
another study, non-contingent training had no effect on seizures, but seizure reduction
was observed with 9-14 Hz or 14-26 Hz training (Kuhlman6). Later, Lantz and Sterman7
showed that contingent training was superior to non-contingent training in 24 patients,
and the effect persisted at least 6 months. Reward of 6-9 Hz activity increased seizure
activity, while reward of 12-15 Hz activity decreased seizure activity (using the same
4
patients, with an A-B-A design).8 Sterman reported that he trained at CZ because that was
where the 12-15 Hz activity was best seen. Sterman reviewed all of the literature up to
2000, and found that every single study of neurofeedback for epilepsy reported positive
results.1 In his meta-analysis, 82% of patients demonstrated > 30% reduction in seizures,
with an average greater than 50% reduction. Approximately 5% remained seizure-free for
up to 1 year. There has been no systematic study to determine which precise frequencies
should be trained to maximize the reduction in seizures. Several other studies, not
reviewed by Sterman in 2000, also support the effectiveness of neurofeedback in
reducing seizure frequency in poorly controlled epilepsy.9-12
In recent years, in our clinic, we have tried a different approach to try to
normalize the EEG of epileptics by using QEEG to guide our neurofeedback training.
The general approach is to determine the most significant abnormalities and train those
areas to normal. Power training alone resulted in significant seizure reductions, but rarely
resulted in cessation of seizures. Based on our successful use of coherence training in
closed head injury, 13 we began using protocols to normalize coherence in medically
refractory epileptics. The combination of power and coherence training to normalize the
EEG has proven dramatically effective in several cases.14 Recent advances in QEEG,
notably reliable databases which include single-hz bins15,16 and broadly based coherence
determinations, have made more precise determinations of what to treat possible.
Several studies have looked at QEEG abnormalities in epileptic patients.17,18,19
Traditional broad-band spectral analyses generally find focal increases in relative power
of theta, with decreased values in the alpha and delta bands when compared with
normative data. Diaz et al 20 found a positive correlation between the magnitude of the
5
quantitative abnormalities and the amount of paroxysmal activity. There was a slowing of
mean frequency of alpha in the epileptic group. They found that focal epilepsy may be
associated with wide-spread changes in the frequency spectra. We have also seen widespread abnormalities in coherence and phase, often remote from the spike focus. We
could find no published studies of coherence abnormalities in epileptic patients.
Another important issue relates to the transition from interictal to ictal EEG.21 We
think an important goal of EEG biofeedback is to prevent that transition, if the
transitional discharge leading to seizures can be inhibited by the training. This proved to
be the key to controlling episodic status epilepticus in one of our patients, whose seizures
invariably began with rhythmic theta activity in one or the other temporal lobe.14 Long
term monitoring may be required to determine those rhythms responsible for the
transition from interictal to ictal activity.
III.
Possible Mechanisms of Reducing Seizures in Epilepsy
A. Neurophysiology of Epilepsy
The human brain must be both stable and flexible to operate efficiently.22 By
changing the amounts of excitation and stimulation in simulated neural networks, one can
induce synchronous bursting behavior of large neural networks (the hallmark of
epilepsy).23 In an animal model of epilepsy (low-magnesium), Nyikos et al24 have shown
that recurrent seizure-like events in brain slices are initially characterized by high
amplitude electrical triplets (“paroxysmal spikes”4) with a single rhythm that starts at 200
Hz and continuously declines to below 1 Hz at termination of the seizure-like event.
High frequency bursts have also been described in a high-potassium in vitro model.25
These rapid oscillations (100-300 Hz) have also been observed in vitro.26 They are not
6
usually detected in conventional EEG recordings, because of muscle artifact and
remoteness from surface electrodes. Medvedeu27 has pointed out that intense gamma
activity (40-60 Hz) often precedes epileptic discharges in patients and in some animal
models. He analyzed power, coherence, and phase in the Kainic acid model in the rat
hippocampus and neocortex. At onset of discharges, highly coherent, intense gamma
rhythms were followed by a slow rhythm of epileptiform spikes and sharp waves. During
the spike activity and immediately afterwards, the gamma power and coherence were
significantly decreased. He hypothesizes that epileptiform spike activity may result from
extreme activation of the “anti-binding” mechanism controlling temporal binding at high
frequencies, i.e., the “epileptiform4” discharge develops as a protective mechanism
suppressing fast activity. Fisher et al28 found an increase in 40 Hz activity just before
epileptiform discharges in patients with complex partial seizures. Medvedev suggests
that post-ictal depression of the EEG may represent a selective decrease in coherence at
high frequencies, rather than a non-specific suppression of all frequencies. It may be that
fast activity is desynchronized and suppressed by spike activity. Previously, Engel29 had
suggested that interictal spikes may inhibit seizure activity in Kindling models of
epilepsy. Nuwer17 noted a decrease in beta frequencies over well-defined epileptic spike
foci.
Another way to view the pathophysiology of epilepsy is to consider seizures as an
example of a disturbance in excitatory and inhibitory input to the seizure focus.30,31 The
simplest models are consistent with the generation of seizures when there is a disruption
of the normal balance of inhibitory/excitatory input, such that there is an excess of
excitatory input (e.g., glutamergic) connections or a deficiency in inhibitory connections
7
(e.g., GABA ergic). Drugs that increase glutamergic activity typically produce seizures,
while drugs that enhance GABA-ergic activity typically are anti-epileptic. It is not clear
that human epilepsy is produced in this way, however. Slices of brain taken from seizure
foci in children undergoing surgical treatment for epilepsy, appeared to be qualitatively
normal in terms of synaptic transmission and local neurological circuits.32 Often, ictal
recordings show that seizure onset is remote from the spike focus.33 Stevens has
suggested that the interictal spikes must have survival value to have persisted through
evolutionary history.34 Spikes (vertex waves) are normal when confined to certain axial
nuclei of the brain during sleep (K-complexes) or during photic or sexual excitation and
may be compensatory after deafferentation or hypoxia. In epilepsy surgery, it is usually
assumed that the structural and biochemical pathology is confined to the area in and
around the spike “focus”, based on the fact that seizures often stop when the focus is
removed. However, there is evidence from animal models and humans that, in many
cases, the behavioral abnormalities responsible for the epileptic activity are remote from
the focus. When a freezing lesion is made in the right posterior cortex of the rat, the
spike focus is likely to be in the anterior cortex on the same of the other side. Slowing is
seen over the site of the biochemical lesion. Application of tetanus toxin to one
hemisphere is associated with seizure development in the contralateral hemisphere.35
Lieb et al 36 looked at propagation of ictal discharge in patients with complex partial
seizures of mesial temporal origin, using depth electrodes in mesial temporal, lateral
temporal and frontal lobes. During seizure onset there was a marked increase in
intrahemispheric coherence, indicating that areas remote from the focus participate in the
initiation of focal seizures. Steriade et al 37 have reviewed a body of evidence which
8
supports the importance of thalamocortical synchronization in the genesis of epileptic
rhythms. Bartolomei et al 38 implanted temporal lobe depth electrode in patients with
drug resistant epilepsy and describe four different seizure types. One type begins in the
medial cortex with phasic discharges spreading to neocortex and high coherence between
medial temporal cortex and neocortex. A second group had seizures starting in medial
cortex and spreading to lateral cortex with a fast low-voltage discharge (FLVD) which
spread rapidly to neocortex and high coherence between medial and lateral structures. A
third group exhibits FLVD starting in lateral neocortex and spreading rapidly to
hippocampus and amygdala, with high coherence between these structures. These studies
suggest that a technique, such as neurofeedback, which can normalize coherence, could
likely reduce propagation of seizures from the site of onset. Interhemispheric
connections probably play a less important role then intrahemispheric connections, even
when the seizures spread to the opposite hemisphere.39 Chavez et al 40 have recently
described decreased synchrony at 10-25 Hz in the seizure onset zone 30 minutes prior to
seizures. It may be that transient synchrony changes are being prevented by
neurofeedback training of coherence (see below).
III.
Thoughts on how neurofeedback might lower seizure threshold in epileptic patients.
There have been few efforts at developing a model of how neurofeedback works.
Lubar has proposed an excellent model for how neurofeedback enhances attentional
capabilities.41 This is easily adapted for explaining how neurofeedback might work for
epilepsy. (Fig. 1) A more detailed model, which could be adapted to include
neurotransmitter influences, may be found in the Hughes and John paper.42 For our
purposes, it is sufficient to say that out goal is to produce optimal coherence and phase
9
synchronization, to raise seizure threshold and reduce the likelihood of having a seizure.
Lubar has pointed out that this training produces very long-lasting and perhaps
permanent, learning. Thus, one literally learns not to have seizures.
Obviously, one would not want to diffusely decrease gamma or delta/theta activity,
but rather train the epileptic foci or connections relevant to the seizure, since delta, theta
and gamma are important for normal sleep and learning.
IV.
Results of QEEG – guided power and coherence training at our center.
Our approach is to “train away” abnormalities of power and coherence in an
attempt to thereby decrease and hopefully abolish seizure likelihood. We generally treat
the most statistically abnormal power or coherence abnormality first, then the next most
severe abnormality, then the next most severe, with 5-10 sessions of each protocol.
Details of our methodology may be found in our paper on closed head injury. Table II
indicates details for each patient, including the spike focus (if one was found), training
protocols, and degree of success. These results appear to be superior to previously
published results in neurofeedback for partial complex seizures, in that all patients
became seizure free and many were able to stop their anticonvulsant treatment. A
detailed abstract on one patient was presented as an abstract at the ISNR conference in
2003. 14
10
Table I. Epilepsy Patients
Class I – Seizure-free off medications x 3 mos.
Class II – Seizure-free on medications x 3 mos.
Class III – Occasional seizure (< 1/mo.) x 3 mos.
Class IV – > 1 sz/mo. (failure) (none seen)
Patient
#1 – M
Age
62
#2 – F
43
#3 – F
19
#4 – M
31
#5 – F
#6 – F
5
Pre-NF
Type seizure
Sz freq
PCS, 2° gen
3/wk
(F8)
Simple
partial
(P3)
PCS (brief)
5/day
(average)
PCS (no
3x/week
focus)
PCS, status
epilepticus
(no focus)
6/day
4x/month
PCS
(No focus)
1/day
PCS –
Multifocal
spikes
1/week
On
meds
Dilantin,
300 mg/d
Neurontin,
3600 mg/d
Dilantin,
300 mg/d
Lamictal,
50 mg bid
Tapetol,
400mg bid
Protocols
1) Downtrain 1-8 Hz F4
2) Uptrain 27-30 Hz F4
3) Downtrain coh α
T3/F3
#
sessions
5
5
10
Class II
Class I
Uptrain coh Θ F3/O1
Downtrain coh Θ FP1/F3
Downtrain coh β C4/P4
Downtrain coh α FP1/F3
Uptrain coh β O1/O2
5
5
5
5
10
Uptrain coh α O1/O2
Uptrain coh Θ T5/T6
Downtrain coh Θ/↑ SMR
C4
Downtrain coh Θ/↑ 15-18
Hz Cz
Downtrain coh Θ/ ↑ 1518 Hz C3
Downtrain coh SMR
C4/P2
Tegretol,
Uptrain coh Θ O1/O2
400 mg
Uptrain coh Θ F7/F8
bid
Downtrain coh Θ/ ↑ 15Neurotin, 18 Hz C3
300 mg tid Downtrain coh 22-30 Hz
C3
Downtrain coh 4-7 Hz
FZ
9
10
5
10
10
10
Lamictal
25mg tid
Result
Downtrain 4-8/↑15-18 F8
Downtrain 4-8/↑15-18 P4
Uptrain coh ∆ P3/O1
Downtrain coh Θ FP1/T3
Class II
Class II
5
5
5
10
2
Class
III
No
seizures
but
“drop
attack”
1 x/
week
10
6
9
3
T=28
11
Class II
Patient
#7 – F
#8 – M
#9 – M
Age Type seizure
6
PCS –
Right
occipital
spike focus
19 PCS with 2°
generalization
sharp waves –
O1
FP1
Biparietal
35
#10 – M
9
Pre-NF
Sz freq
5/day
5/month
PCS with 2°
gen No spike foci
1/week
PCS with 2°
gen
No spike foci
1/week
On
meds
5/day
Primidone
125mg
Lamictal
350mg/d
Topamax
200mg/d
Tegretol,
300mg tid
Protocols
Downtrain 27/↑ 15-18 Hz
O1
Downtrain 27/↑ 15-18 Hz
O2
Downtrain 1-7 Hz O2
Uptrain coh ∆ F3/C4
Uptrain coh Θ F7/CZ
Uptrain coh α FP1/F3
Downtrain coh β C4/T6
Downtrain 2-7 Hz/↑ 1518 Hz T5
Downtrain 1-6 Hz/↑ 1518 Hz FP1
Uptrain coh ∆ F7/FP2
Uptrain coh β F3/T5
Downtrain 1-4 Hz FP1
Uptrain coh ∆ C3/C7
Uptrain coh α F8/O2
Downtrain coh Θ F8/O2
Uptrain coh α F3/FZ
Downtrain coh Θ FP1
Downtrain coh Θ T6
Uptrain α coh F3/O1
Uptrain α coh F4/O2
Uptrain α coh T3/T5
Uptrain β coh T3/T5
Uptrain SMR CZ
Depakote, Downtrain Θ coh F1/F3
500mg bid Downtrain Θ coh F2/F4
Downtrain α coh F1/F3
Downtrain Θ power F8
#
sessions
10
7
T=17
Result
Class I
7
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
T=82
10
10
7
10
4
T=41
8
5
5
5
10
T=25
PCS = partial complex seizures
2° gen = secondary generalization
12
Class II
Class II
Class II
IV.
Possible Future Directions
Recent work suggests that feedback of slow D.C. potentials could be quite
effective in reducing seizure frequency. Future magnetoencephalography machines will
be able to record simultaneously from both hemispheres to better localize deep
epileptogenic zones and determine where training is most likely to be effective.43
LORETA neurofeedback may be used to train some deep foci.44 EEG-linked fMRI has
been used to image single interictal discharges and could be used to image sites of seizure
onset. Then LORETA training might be used to train at the focus rather than at the
surface. Modern spectral analysis techniques allow high resolution in the highter beta
range (> 18 Hz).45 There have been few studies of higher beta in epilepsy or
neurofeedback, and it appears that higher beta may be very important in both fields.46 The
availability of implantable subdural electrode arrays has made systematic studies of
electrocorticographic coherence possible.47 These could enable more precise coherence
training, which might spare the need for brain resection.
Non-linear dynamic approaches to studying epilepsy have recently come to the
fore (e.g., chaos theory).48 Newer feedback systems that use non-linear approaches have
been developed.49 These may prove very valuable in remediating seizures.
Finally, down training of gamma activity over the spike focus may be an effective
way of inhibiting seizure activity. This is possible with some of the newer biofeedback
systems.50 We have tried this recently in 3 drug-resistant patients, with early success in
reducing seizures. We do not know if the effects will be long-lasting.
13
FIGURE 1
Thalamic
Activity
Low frequency
burst mode
Single action potential mode
(specific thalamocortical)
Projection to neocortical
Layer 1
EEG
DELTA
THETA
Projections to neocortical
Layer 4
ALPHA
BETA
GAMMA
Hyper-coupled States
Hyper-coupled States
Optimal Coupling
Seizure
Likelihood
Greater than Normal
Normal
Greater Than Normal
(“Safe zone” ≈ 10 -18 Hz)
Behavioral
States
Hypnosis
Normal
Increase attention
Light Sleep
consciousness
Learning
Visualization
Propagation of seizures
Onset of
seizures
(focal)
14
CASE REPORT:
A 31-year-old man had recurrent partial complex and secondarily generalized
seizures and frequent episodes of status epilepticus. Treatment with nine different
anticonvulsants singly, and in combination, did not control his seizures or prevent
status episodes. He was not a surgical candidate because of depth electrode
monitoring revealed independent foci of onset in the left and right temporal lobes. A
vagal nerve stimulator was implanted and did not reduce his seizures or prevent status
episodes.
METHOD
A QEET (John database) revealed an increase in absolute theta at F7 and T4 and
increased relative theta at FP1, FP2, F7 and F8. Decreased coherence of theta was
found at T3/T5, O1/O2 and C3/C4. Decreased beta coherence was found at O1/O2.
Training was done three times per week. First, theta coherence was down trained at
T3/T5 (10 sessions), then O1/O2 theta coherence was down trained (5 sessions).
Next, beta coherence was down trained at O1/O2. Then theta coherence was down
trained at C3/C4. Finally, theta was down trained and SMR (12-15 Hz) was up
trained at T3.
RESULTS
Since completion of the first protocol, there have been no further episodes of status
epilepticus. Generalized seizures decreased to one per week after the first protocol
and none have occurred since the second protocol was done. Partial complex seizures
decreased to 10 per week after the first protocol, to 5 per week after the second and 1
per week after the third. When an increase in seizure frequency was noted with the
15
fourth protocol, it was discontinued and the fifth protocol was done. Training was
completed December 1, 1998. The patient has had no more seizures. He was able to
return to work full time and to begin driving again. Phenytoin was discontinued in
October of 1998. His speech is no longer slurred and his memory is improved. He
chose to continue his other medication, not wanting to risk a seizure while driving.
CONCLUSION
This case illustrates the powerful potential of QEEG-guided neurofeedback in the
management of severe epilepsy. The training is noninvasive and was effective in a
relatively short time. The cost is quite low compared to epilepsy surgery or vagal
nerve stimulation. It may prove to be particularly important for drug resistant
epilepsy. The combination of coherence training with traditional power training may
work better than either approach alone.
16
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12
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