On Overcoming Barriers to Application of Neuroinflammation Research Edward L. Tobinick, Tracey A. Ignatowski and Robert N. Spengler

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Chapter 7
On Overcoming Barriers to Application of
Neuroinflammation Research
Edward L. Tobinick, Tracey A. Ignatowski and
Robert N. Spengler
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/intechopen.68940
Abstract
Throughout history, new ideas in medicine or science have met initial resistance by
entrenched medical or scientic communities. Barriers to medical innovation fall into
six main categories as listed here in order of historical chronology: (1) Theological, (2)
Academic, (3) Scientic, (4) Financial, (5) Governmental, and (6) Commercial. Researchers
in the eld of neuroinammation often encounter such obstacles that may include denial-
ism. Despite these barriers, recognition of the therapeutic potential of targeting neuroin-
ammation for treatment of stroke, traumatic brain injury, Alzheimer’s disease, spinal
pain, and a variety of additional brain disorders has accelerated in the past 10 years.
Consequently, a paradigm shift in scientic thinking regarding neuroinammation as a
therapeutic target is now underway.
Keywords: denialism, perispinal, etanercept, stroke, traumatic brain injury, Alzheimer’s,
sciatica, neuroinammation, spasticity, cognitive dysfunction, TNF
1. Introduction
I remember at an early period of my own life showing to a man of high reputation as a teacher some
maers which I happened to have observed. And I was very much struck and grieved to nd that, while
all the facts lay equally clear before him, those only which squared with his previous theories seemed to
aect his organs of vision. (Lister [1]).
There is growing scientic evidence of the central involvement of neuroinammation in
the pathogenesis of a diverse group of neurological disorders [2–31]. This is particularly
important since basic research fuels applied science’s innovations. Despite this evidence,
© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

translation of neuroinammation research ndings by basic scientists into therapeutic meth-
ods that are widely employed has been hindered by the traditional barriers that are put into
place by entrenched medical and scientic communities [32–40]. Of these barriers, denialism,
the refusal to accept or even examine veriable facts that conict with one’s philosophy, is
particularly onerous and may undermine public health [40, 41]. Recognition of the existence
of these barriers and careful consideration of their nature promise to facilitate the treatment
of neuroinammatory disorders [22, 38, 42, 43].
2. Barriers to translation of medical innovation
A new scientic truth does not triumph by convincing its opponents and making them see the light,
but rather because its opponents eventually die, and a new generation grows up that is familiar with
it. (Planck [33]).
Barriers to medical innovation fall into six main categories, in approximate order of chro-
nology: (1) Theological, (2) Academic, (3) Scientic, (4) Financial, (5) Governmental, and (6)
Commercial. Any one of these barriers by itself can present an insurmountable blockade to
the translational practice of a new medical discovery. Within each of these categories, denial-
ism often operates to obstruct the progress of a new scientic discovery.
Historically, theological barriers to the acceptance of new scientic concepts have been formi-
dable [34]. Prominent historical examples include the resistance of the Church to the scien-
tic ideas of Galileo and Darwin [32, 34, 35, 40]. While theological barriers have diminished,
they remain to the present day, including theological barriers to stem‐cell and contraception
research and practice.
Academic barriers can also impede or prevent scientic progress [32, 34, 35, 38, 39]. Ever since
scientists and physicians organized into special societies, these societies have wielded their
political and economic power to inuence the acceptance [or nonacceptance] of new scientic
concepts relevant to their interests [32, 34, 35, 38–40].
Scientic barriers are complex and multifaceted [32, 34–37, 39]. Scientic communities orga-
nize around certain shared assumptions, termed “paradigms,” that form the foundations of
their scientic beliefs [35]. New scientic discoveries, at odds with existing scientic dogma,
have historically been aacked and willfully ignored, often by the reigning scientic “authori-
ties” of the time [32, 34–40].
Financial barriers have always created diculties for scientists because hypothesis gener-
ation, scientic discovery, data conrmation, and publication of a new scientic concept
necessitates the gathering of sucient nancial resources to support what is characteristi-
cally a lengthy and expensive endeavor [39, 44]. Particularly expensive is drug develop-
ment, which typically requires hundreds of millions of dollars of investment to achieve a
new FDA indication, with some recent Alzheimer clinical trials costing more than a billion
dollars [44, 45].
Mechanisms of Neuroinflammation146

Governmental barriers have become increasingly complex over time, particularly so in recent
decades. These barriers are justied by ethical, humanitarian, and public interest consider-
ations as illustrated, for example, by the Tuskegee experiment. Nevertheless, as exemplied
by the considerations that led to the passage of the recent twenty‐rst century Cures Act,
governmental regulations have the potential to slow the pace of medical progress and may
be subject to misuse.
Viewed in totality, the diculty in achieving translation of any radically new or dierent
medical innovation, particularly one that breaks new scientic ground, is readily appreciated
[32, 34, 35, 38–40, 46]. Awareness of these barriers may help facilitate the process of success-
fully surmounting them [32, 34, 35, 38–40, 46–48].
3. Galileo: denialism during the dawning of the scientic method
What do you say to the leading philosophers of the university faculty here who, with the lazy obstinacy
of a glued adder, despite invitations a thousand times repeated, refuse even to glance either at the
planets or the moon, or even at the telescope itself? Truly the eyes of these men are closed to the light of
truth. (Galileo [40]).
Galileo is considered by many to be the father of the scientic method. Despite his many
pioneering scientic discoveries, it is well known that his scientic work was actively resisted
by the Church. The denialism regarding Galileo’s observational astronomical discoveries,
including his discovery of the four largest moons of Jupiter, was, however, not limited to the
theological barrier promulgated by Cardinal Bellarmine and the Roman Catholic Church, the
dominant religion of Galileo’s Italy. Rather it notably included an academic barrier: denial-
ism by the university academics of the time, who joined the Church in refusing to even look
through the telescope that Galileo had invented [32].
Galileo’s leer communicates the single reason he was imprisoned and his ideas obstructed:
denialism, due to willful ignorance or “willful blindness” by the academics and theologians
of his time to the natural scientic truths regarding astronomical bodies that he had discov-
ered [32]. It is tragic that willful blindness to life‐saving medical discoveries, epitomized by
the example of Semmelweis, may persist for decades before such denialism is overcome and
still operates today [1, 22, 32, 36–39, 43, 47, 49].
4. Denialism in the nineteenth century: Semmelweis
The innate resistance of science to revolutionary change means that when truly major change is called
for, the scientic community often and wrongly opposes it at rst.
Dogmatism in science and medicine: how dominant theories monopolize research and stie the search
for truth.(Bauer [39]).
On Overcoming Barriers to Application of Neuroinflammation Research
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147

New medical discoveries need to overcome all of the enumerated barriers to achieve wide-
spread acceptance and translation [32, 34, 38, 39]. A well‐known historical example is illus-
trative of the existence of many such barriers. In mid‐nineteenth century Vienna, Ignaz
Semmelweis, through astute observation and careful study, deduced and then provided
compelling scientic evidence that handwashing by obstetricians prior to assisting in child-
birth dramatically reduced maternal mortality [36, 37]. His ground‐breaking discovery, how-
ever, failed to achieve acceptance during his lifetime, due to academic denialism [36, 37].
The entrenched obstetrical community of his time simply refused to recognize his life‐saving
ndings for decades [36, 37].
[Semmelweis] made the intriguing observation that obstetrical mortality within the conveniences of a
hospital seing, and in the hands of sophisticated physicians, was far greater than that in the hands of
simple midwives….He postulated that doctors coming from the autopsy room to the maternity ward
brought with them the cause of childbed fever. His crude antiseptic measures, years before Lister, were
sucient to bring the mortality rate down from 25% to around 1%.
Semmelweis’s thinking was greeted with skepticism, and, at times, derision. His colleagues resented the
constraints he had placed on them and the implications that they were the agents of death [49].
It is not dicult to see how Semmelweis’s ndings threatened their specialty [36, 37, 49].
Semmelweis faced denialism by the leading obstetrical specialists of his time, a barrier he
was unable to overcome [32, 34–39]. Additionally, Semmelweis’s discovery that handwashing
prevented life‐threatening maternal infection conicted with the scientic dogma followed by
the obstetricians and general medical community of his time [32, 34–39].
A dierent and opposite historical example demonstrates the value of medical specialty
support for the dissemination of medical innovation. In 1884 Sigmund Freud and his col-
league Carl Koller were studying the medicinal eects of cocaine in Vienna [50, 51]. Koller
discovered that topical eyedrops containing cocaine could be fashioned into an aqueous
solution that produced eective local anesthesia of the cornea [50, 51]. On September 11,
1884, he performed the rst ophthalmologic surgery using cocaine as a local anesthetic
on a patient [50]. Koller’s preliminary report was presented by his friend, opthalmologist
Joseph Breauer, at the conference of the German Opthalmologic Society in Heidelberg on
September 15, 1884 [50]. Koller’s discovery was rapidly embraced by the world‐wide opthal-
mology community [50]. Within months cocaine was being used to achieve painless eye
surgery around the world [50].
5. Commercial barriers to application of scientic discoveries
When the work was presented, my results were disputed and disbelieved, not on the basis of science but
because they simply could not be true. (Marshall [47]).
Neither Semmelweis nor Koller faced commercial barriers to application of their medical dis-
coveries. In the twenty‐rst century, commercial barriers may be those most signicant in
preventing translation of a new scientic discovery [39]. This is particularly true with respect
to translation of new discoveries regarding drugs and biologics [39, 44]. Marshall faced years
Mechanisms of Neuroinflammation148

of skepticism and resistance from gastroenterologists prior to his 2005 Nobel Prize for the
discovery of Helicobacter pylori as a cause of peptic ulcers, recognition that led to the com-
mercialization of his discoveries by Procter and Gamble [47]. Regulatory approval of new
indications for existing drugs or biologics requires voluminous specialized regulatory lings
and, traditionally, the completion of multiple, large, randomized, controlled clinical trials
[44]. These requirements routinely necessitate not only the expenditure of hundreds of mil-
lions of dollars but also the explicit cooperation of the drug’s manufacturer [44, 45]. Without
such cooperation, regulatory approval is not possible.
There is a widespread misconception that drug manufacturers readily provide nancial sup-
port for the implementation of randomized clinical trials (RCTs) of their drugs for any new
indication supported by the peer‐reviewed medical literature [52]. In fact, many novel uses of
drugs are discovered by clinicians, rather than by drug manufacturers [44, 52]. In reality, com-
panies consider the competitive landscape, market size, cost and diculty of manufacturing,
anticipated regulatory hurdles, patent structure (indications, patent life, etc.) covering their
drug and its competitors and their projected earnings in their calculus [44]. Additional di-
culties involved in successful RCT design include selection of indication, suitable patient pop-
ulation and inclusion criteria, exclusion criteria, drug dosing (amount and dosing interval),
drug formulation (vehicle, pH, viscosity), and delivery method (particularly critical for cen-
tral nervous system indications) [44, 51]. Independent drug discovery start‐ups and academic
research centers are, in many ways, more suited to performing such research, but have dif-
culty independently nancing such costly undertakings. Alternative funding sources, such
as government research grants, are extraordinarily competitive, particularly for researchers
unaliated with leading research universities.
6. Medical dogma as a barrier to neuroinammation research
The Semmelweis case shows in striking fashion that too much respect for the dominant paradigm can
damage the interests of patients. (Gillies [36]).
Today, more than 150 years after Semmelweis and 30 years after Marshall’s discovery, medi-
cal dogma still operates to interfere with medical progress [32, 34, 35, 38, 39, 47, 53]. The
example of most relevance to neuroinammation research is the dogma surrounding the use
of antiamyloid therapeutics for Alzheimer’s disease [53, 54]. The continuing clinical trial fail-
ure of these drugs suggests that the underlying hypothesis is, in some way, faulty [45, 53,
54]. It is well known that investments in developing and testing antiamyloid drugs [all of
which have failed] have dominated Alzheimer research funding for more than two decades,
eectively funneling billions of dollars of research money away from competing drugs, such
as therapeutics directly targeting neuroinammation [45, 53, 54]. The recent announcement
from the new UK Dementia Research Institute acknowledges these accumulated failures and
indicates a resulting shift in research direction [53]. As Bart De Strooper, the new head of the
institute, recently said, “The evidence suggests that inammation is another key factor in kill-
ing brain cells and we should be targeting that” [53].
On Overcoming Barriers to Application of Neuroinflammation Research
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149

7. Perispinal injection as a novel method for delivery of CNS drugs
So how should scientists respond to denialism? The rst step is to recognize when it is present. Denial-
ism changes the rules of the game. Conventional approaches to scientic progress such as hypothesis
generation and testing, and argument and counterargument which seek to elicit the underlying truth
no longer apply. 
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8. Overcoming denialism in the twenty‐rst century: perispinal
etanercept
Confronted with any illness of whatever type or severity, a doctor has two ethical imperatives. The
rst is to ensure that a specic patient receives the best available current medical care. The second is to
develop new treatments so that the patient and others with the same problem can be treated completely,
easily, and economically. The second ethical imperative will, if it leads to a successful outcome, have an
enormous eect on the health and well‐being of humankind. (]).
            
      
  -
 
         
             
   , , , , – 
   
 , , , , ,   
Complementing randomized clinical trials, the ability to collect data from actual
clinical practice presents a great opportunity to gain new insights about the ecacy and safety of new
drugs
              

Mechanisms of Neuroinflammation150

the major role of clinicians in the discovery of new indications for existing drugs [7, 16, 51, 52,
62, 63, 67, 68].
Rapid neurological improvement is characteristic for each of the four o‐label indications,
often noticeable within minutes of the rst dose [7, 8, 16, 51, 62, 64, 67, 68, 70, 71]. The spec-
trum of improvement as well as its rapidity are novel and may be aributed to the unique
physiological eects of etanercept as well as the novel perispinal method of delivery enabled
by the cerebrospinal venous system [8, 10, 16, 51, 55, 65, 68]. For example, in a series of 612
consecutive patients with chronic poststroke neurological dysfunction treated with perispinal
etanercept, statistically signicant improvements in motor impairment, spasticity, sensory
impairment, cognition, psychological/behavioral function, aphasia, and pain, with evidence
of a strong treatment eect even in the subgroup of patients treated more than 10 years after
stroke, have been documented [16].
Signicant neurological improvement of the degree documented after perispinal etanercept
had not been previously noted with any therapeutic modality, but recently, the possibility of
motor recovery years after stroke has been conrmed using modied bone marrow‐derived
Figure 1. The cerebrospinal venous system, detail of Plate 5 from Breschet [61], Courtesy of the Sidney Tobinick
Collection. ©2017 Edward Tobinick, used with permission.
On Overcoming Barriers to Application of Neuroinflammation Research
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151

mesenchymal stem cells [72]. This stem cell trial involved 18 patients with stable, chronic
stroke treated with surgical transplantation of specialized allogeneic stem cells by needle
injection into the peri‐infarct brain after burr‐hole craniostomy [72]. The clinical results in this
trial were not aributed to the conversion of these specialized cells into neuronal cells [72–74].
Rather, as one scientist not involved with the trial suggested in his leer to the lead author,
….injecting SB623 cells into the chronic poststroke brain can be predicted to generate, over time, an
increasingly anti‐tumor necrosis factor state in this compartment. This would be consistent with clinical
observations (hp://www.strokebreakthrough.com/videos‐by‐category/) that introducing a widely used
specic antitumor necrosis factor agent, etanercept, into this same compartment through Batson’s plex-
us, followed by a short period of head‐down positioning, has led to safe and rapid onset of poststroke im-
provements similar to those reported to evolve slowly after intracranial introduction of SB623 cells [73].
The lead author of the stem cell study responded,
Immunomodulation related to protein and molecular factors secreted by the SB623 cells could be one of
the mechanisms underlying the observed neurological recovery in our patients and could suggest that
there is ongoing chronic inammation >6 months after stroke that is suppressing intact neural circuits
and rendering them nonfunctional. This concept has some support in the recent preclinical and clinical
literature. In addition, it is conceivable that the transplanted SB623‐secreted factors are enhancing na-
tive neurogenesis or synaptogenesis, potentially through blocking excess tumor necrosis factor eects
after stroke, although this is unproven [74].
Furthermore, the favorable eects of etanercept on spinal neuropathic pain, rst documented
clinically after perispinal injection [7, 10, 62, 65, 75], have been conrmed in four subsequent
randomized, double‐blind, placebo‐controlled clinical trials [76–79]. These studies and others
have led “to the emergence of TNF inhibitors as available strategies for clinical treatment of
pain associated with intervertebral disc herniation” [60] and foreshadowed the reduction in
central pain reported after stroke and traumatic brain injury (TBI) in patients treated with
perispinal etanercept [16, 67, 68].
Additional scientic support for the perispinal etanercept stroke and TBI results has come
from basic science studies of etanercept in stroke and TBI models, all of which demonstrated
favorable results [80–86]. Recent independent scientic publications have also been support-
ive of these results [15, 18, 20–26, 28–31, 42, 59, 60, 79, 87–105].
Our current thinking regarding the rapid and sustained neurological improvement docu-
mented after perispinal etanercept for neuroinammatory indications involves the following
mechanisms, each of which involves amelioration of neuroinammatory pathophysiology by
etanercept (Table 1).
8.1. Immediate neutralization of excess TNF
Rapid neutralization of TNF by binding to excess circulating TNF is a known physiological
eect of etanercept and the main scientic rationale behind its use for its approved indications
[10]. Excess TNF has been implicated in the pathogenesis of Alzheimer’s disease, stroke, TBI
and neuropathic pain [10, 18, 21, 60, 65, 66, 68].
Mechanisms of Neuroinflammation152

8.2. Modulation of neurotransmission at the individual synapse
TNF’s role as a gliotransmier that modulates synaptic transmission and synaptic strength sup-
ports this as a physiological mechanism underlying the clinical eects of perispinal etanercept
[8, 10, 15, 16, 65, 66, 68, 71, 106]. When applied exogenously to superfused brain tissue, TNF
inhibits the stimulation (stimulations 1 and 2, S1 and S2, at 2 Hz, 120 shocks) evoked release
of norepinephrine from noradrenergic axon terminals in the isolated median eminence [107].
Similarly, when TNF is applied to slices of the hippocampus, it inhibits stimulated (S1 at 1 HZ
and S2 at 4 Hz) norepinephrine release in a concentration‐ and frequency‐dependent manner
[108–110]. In both studies, the addition of TNF was 15–16 minutes prior to stimulation, indicat-
ing that TNF does not require a long exposure time to develop modulatory eects. Interestingly,
TNF inhibition of stimulated norepinephrine release under physiological conditions is altered
in pathophysiological conditions. For example, the inhibition of stimulated norepinephrine
release by TNF is supersensitized, or increased, during conditions whereby TNF expression
is enhanced in the brain (chronic pain) [111, 112]. Thus, it is proposed that descending mono-
aminergic pain pathways providing endogenous analgesia are no longer engaged [23]. The
rapid alleviation of chronic pain experienced by patients receiving perispinal etanercept may
be explained by disinhibition of norepinephrine release and descending pain modulation.
8.3. Modulation of neuronal network function by mediation of synaptic scaling
The central role of TNF in modulating synaptic scaling and synaptic strength and thereby
modulating neuronal network function may help explain the rapid and widespread neu-
rological eects of perispinal etanercept, including its rapid improvement of cognition in
Alzheimer’s disease, poststroke cognitive dysfunction, and cognitive dysfunction after trau-
matic brain injury [8, 15, 16, 62, 67, 68, 71, 106].
8.4. Reduction of microglial activation
Etanercept has been shown to reduce microglial activation in multiple experimental models
[81, 113, 114]; reviews: [10, 19]. Activated microglia release excess TNF, contributing to the
Physiological eect
1. Immediate neutralization of excess TNF
2. Modulation of neurotransmission at the individual synapse
3. Modulation of neuronal network function (synaptic scaling)
4. Reduction of microglial activation
5. Reduction in neuropathic pain
6. Activation of neurogenesis
Table 1. Mechanisms of amelioration of neuroinammatory pathophysiology by etanercept.
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153

neurotoxicity and perturbations in synaptic mechanisms seen in neuroinammatory disor-
ders [10, 19, 26, 63, 68, 81, 93, 114, 115]. Reduction of microglial activation may be a mecha-
nism whereby perispinal etanercept reduces central homeostatic dysregulation of TNF levels
induced by microglial activation after stroke or traumatic brain injury.
8.5. Reduction in neuropathic pain
Brain TNF is overexpressed during the development of neuropathic pain [4, 111, 116, 117].
Treatment using TNF inhibitors has been shown to reduce neuropathic pain in both basic sci-
ence models and in the clinical seing [5, 10, 16, 19, 25, 60, 62, 68, 76–79, 99, 114]. Preclinical
studies have shown that blockade of TNF synthesis in the brain is antinociceptive [99]. Also,
clinical case studies report that targeting TNF centrally is analgesic [62, 71, 79]. This may be
due to blockade of TNF that restores neurotransmission homeostasis along pain pathways.
8.6. Activation of neurogenesis
Although there is some conicting data, a variety of experimental models suggest that
TNF or other pro‐inammatory cytokines, if present in excess, may inhibit neurogenesis
[118–122]. TNF and interleukin‐1 are involved in the decrease of neurogenesis evidenced
in pain and depression models [123–125]. Mice receiving sciatic nerve chronic constriction
injury to induce neuropathic pain developed depressive‐like behavior for 4 weeks follow-
ing ligature placement that was associated with increased hippocampal TNF and impaired
dentate gyrus neurogenesis dependent on TNF receptor‐1 signaling [126]. There is data
suggesting that inammatory blockade may restore adult neurogenesis [122]. This, theo-
retically, might be a potential mechanism that could contribute to the increasing neurologi-
cal improvement observed after perispinal etanercept treatment over the course of months
in some patients [16, 63, 68, 120–122].
Perispinal etanercept has successfully traversed a variety of scientic, academic, and gov-
ernmental barriers to achieve scientic acceptance and recognition [9, 11, 13, 15, 18, 20–26,
28–31, 42, 57, 59, 60, 79, 81, 82, 88–91, 93–98, 100–105, 114, 115, 123, 125, 127–133]. This was
accomplished despite considerable misinformation published online by competing medical
specialists, who refused the opportunity to observe, rst‐hand, the rapid neurological eects
of perispinal etanercept, despite repeated invitations to do so [43, 48]. Such denialism is in
the tradition of that faced by Galileo, Semmelweis, Lister and Marshall, but it has no place in
science or medicine [1, 22, 32, 33, 35–39, 41–43, 47].
As Glaziou and colleagues have stated [134]:
Condent inferences about the eects of treatment are justied in several situations in which treatment
eects are unlikely to be confused with the eects of biases. These include, in particular, … interven-
tions … where there is a rapid response on a stable background [134].
The rapid neurological improvement repeatedly observed in thousands of patients with
chronic, intractable neurological dysfunction after treatment with perispinal etanercept,
Mechanisms of Neuroinflammation154

combined with strong, independent, basic science support, constitutes compelling evidence
that mandates the recognition of these clinical eects and the initiation of the necessary
actions, including the funding of randomized clinical trials, by the relevant medical special-
ties and governmental agencies, for the benet of the public.
9. Overcoming barriers to the application of neuroinammation research
I by no means expect to convince experienced naturalists whose minds are shocked with a multitude of
facts all viewed, during a long course of years, from a point of view directly opposite to mine….But I
look with condence to the future, to young and rising naturalists, who will be able to look at both sides
of the question with impartiality.
Charles Darwin [135], The Origin of Species, 1845.
The key to overcoming barriers to application of neuroinammation research is education. It
is essential that medical students and neuroscientists receive training in basic immunology,
the role of cytokines in physiology and pathophysiology and the essential concepts under-
lying neuroinammation. Because neuroinammation is not concrete and visible under the
microscope in the same way that pathology such as amyloid plaques are, improved meth-
ods, access and utilization of new and emerging methods for imaging neuroinammation are
also essential. Today, fortunately, the initial promise of neuroinammation research is bearing
fruit, and a paradigm shift in scientic thinking in this regard is well underway. Recognition
of the necessity of neuroinammation research for the successful development of new treat-
ments for neurological disease must be a key goal of society. The allocation of sucient
research and educational funding to this end is essential.
Conict disclosures
Edward Tobinick has multiple issued and pending US and foreign patents, assigned to
TACT IP, LLC, that claim perispinal methods of use of etanercept and other drugs for treat-
ment of neurological disorders, including but not limited to US patents 6419944, 6537549,
6982089, 7214658, 7629311, 8119127, 8236306, 8349323, 8900583; and Australian patents 758523
and 2011323616 B2. Dr. Tobinick is the CEO of TACT IP, LLC and founder of the Institute
of Neurological Recovery, a medical practice that utilizes perispinal etanercept and trains
physicians in its use as a therapeutic modality. Tracey Ignatowski and Robert Spengler have
been unpaid expert witnesses for the INR. Tracey Ignatowski and Robert Spengler’s profes-
sional activities include their work as co‐directors of neuroscience at NanoAxis, LLC, a com-
pany formed to foster the commercial development of products and applications in the eld
of nanomedicine that include novel methods of inhibiting TNF. The article represents the
authors’ own work in which NanoAxis, LLC was not involved.
On Overcoming Barriers to Application of Neuroinflammation Research
http://dx.doi.org/10.5772/intechopen.68940
155

Author details
Edward L. Tobinick1*, Tracey A. Ignatowski2 and Robert N. Spengler3
*Address all correspondence to: nrimed@gmail.com
1 Institute of Neurological Recovery, Boca Raton, FL, USA
2 Pathology and Anatomical Sciences, University at Bualo‐SUNY, Bualo, NY, USA
3 Nanoaxis LLC, Bualo, NY, USA
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