Scientific Research

 This page contains links to open-access scientific journal  articles that may be freely downloaded without charge.

 The articles are as follows:

 Clark, I. A. & Vissel, B. (2016). Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents. Journal of Neuroinflammation. DOI: 10.1186/s12974-016-0708-2

Clark, Ian A., and Bryce Vissel. (2015) A neurologist’s guide to TNF biology, and to the principles behind the therapeutic removal of excess TNF in disease.,  Neural Plasticity, Hindawi Publishing Corporation. 

Hachinski V, Donnan GA, Gorelick PB, Hacke W, Cramer SC, Kaste M, et al. Stroke: working toward a prioritized world agenda. Stroke. 2010 Jun;41(6):1084-99. FREE FULL-TEXT. Quote: “It is time to step into other domains so that knowledge in other areas may be readily applied to the problem of stroke. In other words, we need to scan the scientific landscape to embrace new ideas and approaches.”

Hess, A., R. Axmann, J. Rech, S. Finzel, C. Heindl, S. Kreitz, M. Sergeeva, M. Saake, M. Garcia, G. Kollias, R.H. Straub, O. Sporns, A. Doerfler, K. Brune, and G. Schett, Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A, 2011. 108(9): p. 3731-6. Abstract: “There has been a consistent gap in understanding how TNF-alpha neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-alpha acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-alpha, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-alpha. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-alpha at these early time points. Moreover, arthritic mice overexpressing human TNF-alpha showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-alpha. These results suggest that neutralization of TNF-alpha affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.” FREE FULL-TEXT.

Hrobjartsson, A. and P.C. Gotzsche, Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med, 2001. 344(21): p. 1594-602.  FREE FULL-TEXT. Abstract includes: “We found little evidence in general that placebos had powerful clinical effects.”

Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs. 2014 Aug;28(8):679-97. FREE FULL-TEXT.

Ignatowski TA, Spengler RN, Tobinick E. Author’s Reply to Whitlock: Perispinal Etanercept for Post-Stroke Neurological and Cognitive Dysfunction: Scientific Rationale and Current Evidence. CNS Drugs, epub November 2014, doi: 10.1007/s40263-014-0212-0, published online 06 Nov 2014. FREE FULL-TEXT.

Ignatowski TA, Spengler RN, Dhandapani KM, Folkersma H, Butterworth RF, Tobinick E. Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence. CNS Drugs. 2014 Aug;28(8):679-97. FREE FULL-TEXT

Iwatsuki, K., T. Arai, H. Ota, S. Kato, T. Natsume, S. Kurimoto, M. Yamamoto, and H. Hirata, Targeting anti-inflammatory treatment can ameliorate injury-induced neuropathic pain. PLoS One, 2013. 8(2): p. e57721. FREE FULL-TEXT.

Johnson, V.E., J.E. Stewart, F.D. Begbie, J.Q. Trojanowski, D.H. Smith, and W. Stewart, Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain, 2013. 136(Pt 1): p. 28-42. FREE FULL-TEXT.Abstract includes: “These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans.”

Kaushal, V. and L.C. Schlichter, Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci, 2008. 28(9): p. 2221-30. FREE FULL-TEXT. Abstract concludes: “Together, these results support potential therapeutic strategies that target microglial group II mGluRs, TNFalpha overproduction, and NF-kappaB activation to reduce neuron death in the ischemic penumbra.”

Lei B, Dawson HN, Roulhac-Wilson B, Wang H, Laskowitz DT, James ML. Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage. J Neuroinflammation. 2013 Aug 20;10(1):103. FREE FULL-TEXT. Abstract includes: “Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH.”

Olmos G, Llado J. Tumor necrosis factor alpha: a link between neuroinflammation and excitotoxicity. Mediators Inflamm. 2014;2014:861231. FREE FULL-TEXT. Abstract includes: “Tumor necrosis factor alpha (TNF- alpha) is a pro-inflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-alpha; this de novo production of TNF-alpha is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. ….  As microglial activation and up-regulation of TNF-alpha expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-alpha signaling may represent a valuable target for intervention.”

McDonald, C.J., Is the placebo powerless? N Engl J Med, 2001. 345(17): p. 1276-7; author reply 1278-9. FREE FULL-TEXT. Authors’ reply includes: “The interesting commentaries did not demonstrate flaws in our systematic review, so our conclusion that there is little evidence that placebo interventions in general have powerful effects remains unchanged…..the burden of proof now rests with those who claim there are important effects of placebo interventions. Such claims should be based on reliable evidence, preferably data from rigorously conducted, systematic reviews of randomized trials”

Tobinick, E.L., (2016) Perispinal Delivery of CNS Drugs. CNS Drugs: 1 -12. doi:10.1007/s40263-016-0339-2. FREE FULL-TEXT

Tobinick E. (2010). Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Review of Neurotherapeutics  Jun;10(6):985-1002. FREE FULL-TEXT.

Trollor, J.N., E. Smith, B.T. Baune, N.A. Kochan, L. Campbell, K. Samaras, J. Crawford, Ward, A.C., The role of causal criteria in causal inferences: Bradford Hill’s “aspects of association”. Epidemiol Perspect Innov, 2009. 6: p. 2. FREE FULL-TEXT.

Wang K, Liu B, Ma J. Research progress in traumatic brain penumbra. Chin Med J (Engl). 2014 May;127(10):1964-8. FREE FULL-TEXT.