Questions and Answers
Session I: Clinical Trials and Beyond
QUESTIONS FOR DR. ANDREWS
From Dr. John Bowyer
What is known about CNTF expression when electrical stimulation is applied to
regenerating motor neurons?
ANSWER: Obviously an important issue—and one for which, to my knowledge, there
are few data at present. Although I have not searched the ciliary neurotrophic factor
(CNTF) literature exhaustively, there do not appear to be any studies similar to those
noted in the neuromodulation applications paper by Al-Majed et al. on BDNF and
electrical stimulation in peripheral nerve regeneration. Because CNTF appears to
stimulate axonal regeneration (W.V. McCallister, P. Tang, J. Smith, et al. 2001. J.
Hand Surg. [Am.] 26(3): 478–488), a replication of Al-Majed’s work assessing
CNTF in addition to BDNF under electrical stimulation could be productive—as also
could be considering the effects of injection of BDNF and CNTF on axonal regener-
ation (M. Watanabe & Y. Fukuda. 2002. Prog. Retin. Eye Res. 21(6): 529–553).
What is known about DBS and VNS in animal models with respect to long-term
biochemical changes and synaptic?
ANSWER: Not nearly enough. To secure FDA approval for clinical use, safety and
efficacy are the primary considerations. Histologic studies (in both animals and
humans) have not shown significant permanent injury to the brain (or vagus nerve in
the case of VNS) from chronic electrical stimulation. The rapid return to prestimu-
lation clinical status on turning the stimulator off (DBS or VNS) also argues for little,
if any, permanent or irreversible biochemical or physiologic changes. A recent
review on VNS has appeared since the Hilton Head ICNA meeting (T.R. Henry.
2002. Neurology 59(Suppl. 4): S3–S14).
What is known about repetitive TMS and increased risk of brain tumors?
ANSWER: To my knowledge, very little. Given the brevity of even repetitive TMS—
in comparison with, for example, MRI scanning—one might expect the risk for brain
tumor development to be low. It will certainly become an issue if TMS shows prom-
ise for “standard of care” treatment, such as for intractable epilepsy, where periodic
TMS treatments might be necessary.
From Dr. Merle Paule
How was the efficacy of VNS discovered?
ANSWER: Although the use of VNS to control seizures was first proposed and
demonstrated by Zabara (J. Zabara. 1985. Clin. Neurophysiol. 61: 162), perhaps the
first evidence, presented 65 years ago, was that vagus nerve stimulation can produce
Ann. N.Y. Acad. Sci. 993: 48–53 (2003). ©2003 New York Academy of Sciences.
, SESSION I: QUESTIONS AND ANSWERS 49
EEG desynchronization in cats (P. Bailey & F. Bremer. 1938. J. Neurophysiol. 1:
405–412).
So, VNS is used primarily in persons with intractable seizures (not contracted by
drugs)?
ANSWER: Yes, or for individuals who are adversely affected (usually sedation) by
anticonvulsant medications.
Is VNS better (more effective) for one seizure type than for others, for example,
petit versus grand mal?
ANSWER: That is one of the difficulties of selecting intractable epilepsy patients for
VNS—it works moderately well in most seizure types. It is difficult to predict who
will gain little or no benefit. The initial studies for FDA approval concentrated on
refractory complex partial epilepsy, but the benefit for patients with refractory gen-
eralized tonic–clonic epilepsy appears to be similar. There are some patients, such
as those previously candidates for corpus callosotomy (or who have had corpus cal-
losotomy), who appear to benefit especially well from VNS.
Given that VNS is continuous for treatment of epilepsy, what are the adverse
effects (for months/years)?
ANSWER: The primary complaints—tickle in the throat, cough, voice change—
diminish rapidly over the first few weeks to months of VNS stimulation. There do
not appear to be long-term adverse effects—just as there do not appear to be long-
term adverse effects from deep brain stimulation or spinal cord stimulation.
It is my understanding that TMS involves very large magnetic fields. Do you
think the very (by comparison) weak magnets sold to be worn (on wrist; Velcro to
the back of the spine, etc.) are potent or strong enough to actually have biological
effects?
ANSWER: I am not familiar with the “hard science” literature on such weak magnet
devices. Like many complementary or alternative (herbal) medications, there is
likely a combination of physiologic efficacy and psychologic belief in the therapy.
Certainly electromagnetic fields (even those emitted by small electrical appliances—
such as cell phones) are suspected of having significant biological effects—at close
range (cm), since the field strength drops off as a square of the distance from the
source.
From Dr. Aiden Doyle
What about failure of placebo-controlled trial in depression VNS study versus
placebo?
ANSWER: Yes—the verdict is not yet in on the efficacy of VNS for mood disorders.
Certainly much can be done with various methods of stimulation (i.e., rate, fre-
quency, etc.). Probably more promise is seen in deep brain stimulation for mood dis-
orders—which is compounded further by the various regions in the brain that
theoretically would be effective targets for stimulation.
Session I: Clinical Trials and Beyond
QUESTIONS FOR DR. ANDREWS
From Dr. John Bowyer
What is known about CNTF expression when electrical stimulation is applied to
regenerating motor neurons?
ANSWER: Obviously an important issue—and one for which, to my knowledge, there
are few data at present. Although I have not searched the ciliary neurotrophic factor
(CNTF) literature exhaustively, there do not appear to be any studies similar to those
noted in the neuromodulation applications paper by Al-Majed et al. on BDNF and
electrical stimulation in peripheral nerve regeneration. Because CNTF appears to
stimulate axonal regeneration (W.V. McCallister, P. Tang, J. Smith, et al. 2001. J.
Hand Surg. [Am.] 26(3): 478–488), a replication of Al-Majed’s work assessing
CNTF in addition to BDNF under electrical stimulation could be productive—as also
could be considering the effects of injection of BDNF and CNTF on axonal regener-
ation (M. Watanabe & Y. Fukuda. 2002. Prog. Retin. Eye Res. 21(6): 529–553).
What is known about DBS and VNS in animal models with respect to long-term
biochemical changes and synaptic?
ANSWER: Not nearly enough. To secure FDA approval for clinical use, safety and
efficacy are the primary considerations. Histologic studies (in both animals and
humans) have not shown significant permanent injury to the brain (or vagus nerve in
the case of VNS) from chronic electrical stimulation. The rapid return to prestimu-
lation clinical status on turning the stimulator off (DBS or VNS) also argues for little,
if any, permanent or irreversible biochemical or physiologic changes. A recent
review on VNS has appeared since the Hilton Head ICNA meeting (T.R. Henry.
2002. Neurology 59(Suppl. 4): S3–S14).
What is known about repetitive TMS and increased risk of brain tumors?
ANSWER: To my knowledge, very little. Given the brevity of even repetitive TMS—
in comparison with, for example, MRI scanning—one might expect the risk for brain
tumor development to be low. It will certainly become an issue if TMS shows prom-
ise for “standard of care” treatment, such as for intractable epilepsy, where periodic
TMS treatments might be necessary.
From Dr. Merle Paule
How was the efficacy of VNS discovered?
ANSWER: Although the use of VNS to control seizures was first proposed and
demonstrated by Zabara (J. Zabara. 1985. Clin. Neurophysiol. 61: 162), perhaps the
first evidence, presented 65 years ago, was that vagus nerve stimulation can produce
Ann. N.Y. Acad. Sci. 993: 48–53 (2003). ©2003 New York Academy of Sciences.
, SESSION I: QUESTIONS AND ANSWERS 49
EEG desynchronization in cats (P. Bailey & F. Bremer. 1938. J. Neurophysiol. 1:
405–412).
So, VNS is used primarily in persons with intractable seizures (not contracted by
drugs)?
ANSWER: Yes, or for individuals who are adversely affected (usually sedation) by
anticonvulsant medications.
Is VNS better (more effective) for one seizure type than for others, for example,
petit versus grand mal?
ANSWER: That is one of the difficulties of selecting intractable epilepsy patients for
VNS—it works moderately well in most seizure types. It is difficult to predict who
will gain little or no benefit. The initial studies for FDA approval concentrated on
refractory complex partial epilepsy, but the benefit for patients with refractory gen-
eralized tonic–clonic epilepsy appears to be similar. There are some patients, such
as those previously candidates for corpus callosotomy (or who have had corpus cal-
losotomy), who appear to benefit especially well from VNS.
Given that VNS is continuous for treatment of epilepsy, what are the adverse
effects (for months/years)?
ANSWER: The primary complaints—tickle in the throat, cough, voice change—
diminish rapidly over the first few weeks to months of VNS stimulation. There do
not appear to be long-term adverse effects—just as there do not appear to be long-
term adverse effects from deep brain stimulation or spinal cord stimulation.
It is my understanding that TMS involves very large magnetic fields. Do you
think the very (by comparison) weak magnets sold to be worn (on wrist; Velcro to
the back of the spine, etc.) are potent or strong enough to actually have biological
effects?
ANSWER: I am not familiar with the “hard science” literature on such weak magnet
devices. Like many complementary or alternative (herbal) medications, there is
likely a combination of physiologic efficacy and psychologic belief in the therapy.
Certainly electromagnetic fields (even those emitted by small electrical appliances—
such as cell phones) are suspected of having significant biological effects—at close
range (cm), since the field strength drops off as a square of the distance from the
source.
From Dr. Aiden Doyle
What about failure of placebo-controlled trial in depression VNS study versus
placebo?
ANSWER: Yes—the verdict is not yet in on the efficacy of VNS for mood disorders.
Certainly much can be done with various methods of stimulation (i.e., rate, fre-
quency, etc.). Probably more promise is seen in deep brain stimulation for mood dis-
orders—which is compounded further by the various regions in the brain that
theoretically would be effective targets for stimulation.
