Although the body of research literature on adult neurogenesis is enormous, we cite these works with comments to explain the innovation of our protocol we propose for clinical trial. But before we cite the research that led us to focus our investigation on the brain's capacity to heal itself, it is important to know that we chose Parkinson's Disease (PD), instead of traumatic brain injury (TBI) to begin with, because this intractable disease is coming under scrutiny as a single disease in itself. Many experts are re-thinking the concept identified by Dr. James Parkinson less than 200 years ago in the light of the new discoveries during the 1990s "decade of the brain" that are being assimilated in the first decade of the 21st Century. Please see "Highlights" for only two examples from many researchers who are shifting their perspective on PD, its causes and treatment.

RESEARCH:
1. Outcome of Ceregene's Phase-2 Trial CERE-120, Todd Sherer, interview of Raymond Bartus, PhD, 1/29/2009, Michael J. Fox Foundation: This frank discussion of the "profound placebo effect" (PPE) and its intrusion into the gold-standard double-blind clinical trial opens the door to re-considering the PPE as an "endogenous brain-repair mechanism" due to the organ function of the brain itself -- that of consciousness -- as a self-organizing, dynamic process known for centuries as 'healing' and being re-discovered as "cognitive therapy" in rehabilitation medicine. Further, this effect was noted in the literature of sociology following productivity tests conducted by MIT at the Hawthorne, MA plant of Western Electric Company, in 1924.
See in connection with what Dr. Bartus calls "The Profound Placebo Effect" the following: "Placebo mechanisms and reward circuitry: clues from Parkinson's disease" dela Fuente-Fernández R, Schulzer M, Stoessl AJ. Biol Psychiatry. 2004 Jul 15;56(2):67-71.

2. "Nanomedicine Targets Cancer: Viewing each human body as a system of interacting molecular networks and targeting disruptions in the system with nanoscale technologies can transform how disease is understoood," Heath, James R., Davis, Mark E. and Hood, Leroy, Scientific American, vol. 300, no. 2, February 2009, pp. 44—51. [specific ref. to PD and "MS, AD and prion disease models"]
This article offers the Western therapeutic approach of Systems Medicine, which we find converging with that of Eastern Medicine, specifically Acupuncture.

3. "DNA hypermethylation of the alpha-synuclein promoter in patients with alcoholism." Bonsch D, Lenz B, Kornhuber J, and Bleich S (2005). Neuroreport 16, 167--70. A 2004--2009 CRISP search on PD and alcoholism, yielded 25 grants funded.
Here is the most relevant information on the shared mechanism for the alternate motor pathway (prefrontal cortex -- nucleus accumbens -- ventral tegmentum -- cerebellar vermis) to investigate for PD. This and the above reference (2) illustrate current epigenetic approach to protein networks.

4. Practice Parameter: Neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology, NEUROLOGY 2006;66:976-982 O. Suchowersky, MD, G. Gronseth, MD, J. Perlmutter, MD, S. Reich, MD, T. Zesiewicz, MD and W. J. Weiner, MD www.neurology.org SEARCH: 66/7/976 Although this article finds no evidence for Complementary Alternative Medicine (CAM), we take care to observe Quality Standards model for our protocol based on systems-medicine (protein chains) to improve axonal transport [2, above]

5. "Moving beyond the Decade of the Brain," Peter G. Bain, MD, Anthony Lang, MD, Connie Marras, MD, PhD, Neurology, Vol. 72, Issue 6, 579 February 10, 2009.

6. "Biofeedback for Movement Disorders (Dystonia and PD): Theory and Preliminary Results," Thompson, Michael MD, Thompson, Lynda PhD, Journal of Neurotherapy, Vol. 6(4) 2002, pp. 51--70.
BWI comment: Neurofeedback is a method by which the brain's capacity to mimic or entrain frequencies is used to enhance focus, acquire skill rapidly, and achieve optimal rest and regeneration after cognitive exertion for re-newed activity. This study, which teaches breathing in synchrony with muscle spindle frequencies, achieves brain coordination, through neurofeedback, at a level hitherto achieved only in high-performance or skilled activities in sports and music.

7. "Lighting Up the Brain: a clever combination of optics and genetics is allowing neuroscientists to map--and even control--brain circuits with unprecedented precision," Gero Miesenbock, Scientific American, October 2008, 299:4, pp. 52--59.

8. "Pharmacology and Physiology of Retinal Ganglion Cells," Ishida, Andrew T., 5R01EY008120-18 atishida@ucdavis.edu Abstract: Vertebrate retinas use "fast" (rapidly acting) neurotransmitters to signal moment-to-moment changes in properties of incident light, and "slow" (modulatory) neurotransmitters to regulate signal flow and processing. The long-term goal of this grant is to understand how slow neurotransmitters modulate action potentials that retinas use to encode their input to the brain.
BWI's comment: Given that severe diplopsia is one of the PD degenerative changes of the brain, our investigation of axonal transport, advocated by Dr. Bartius subsequent to the Cere-120 Phase-2 results, begins here.

9. "Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses" David J. Scott, BS; Christian S. Stohler, DDS, PhD; Christine M. Egnatuk, BS; Heng Wang, PhD; Robert A. Koeppe, PhD; Jon-Kar Zubieta, MD, PhD Arch Gen Psychiatry. 2008;65(2):220-231. Important PD Bibliography and CONCLUSIONS for disease therapeutics:
"We have herein demonstrated that placebo [pleasure] and nocebo [pain] effects engage specific neurotransmitter systems as a consequence of cognitive-emotional assessments of their efficacy. Dopaminergic and opioid systems modulate a number of processes, including the regulation of reward and affective states, cardiovascular, immunological, and neuroendocrine functions, as well as the effects of substances of abuse and the development of drug dependence. This line of inquiry offers the possibility that nonpharmacological interventions exploiting these systems may affect the capacity of the organism to adapt to allostatic challenges, modifying risk for various illnesses or their progression."

10. a.) "Active Music Therapy in Parkinson’s Disease: An Integrative Method for Motor and Emotional Rehabilitation," Claudio Pacchetti, MD, Francesca Mancini, MD, Roberto Aglieri, Cira Fundarò, MD, Emilia Martignoni, MD and Giuseppe Nappi, MD. PD and Movement Disorders Centre, U of Pavia, 27100 Italy, Email: pacchett@mondino.it
METHODS: This prospective, randomized, controlled, single-blinded study lasted 3 months. It consisted of weekly sessions of MT and physical therapy (PT). Thirty-two patients with PD, all stable responders to levodopa and in Hoehn and Yahr stage 2 or 3, were randomly assigned to two groups of 16 patients each. ... MT sessions consisted of choral singing, voice exercise, rhythmic and free body movements, and active music involving collective invention. PT sessions included a series of passive stretching exercises, specific motor tasks, and strategies to improve balance and gait.
RESULTS: MT had a significant overall effect on bradykinesia as measured by the Unified Parkinson’s Disease Rating Scale (p < .034).

11. "Neurorestoration in Parkinson's Disease," Parkinson Report, Official Journal of the National Parkinson Foundation, Vol. XVII, Issue 2, Spring 2006, "Creativity and Parkinson Disease" issue, Etienne C. Hirsch, MD, pp. 9—12.

12. "MBAT A novel psychosocial cancer intervention," NCCAM grant no. 5R01CA111832-04, (2005--2010) and NCCAM Grant no. NCT00034970 (2002--2005) Daniel Monti, Mind-Body Med Thomas Jefferson University, Philadelphia.

13. a) Resistance Training With Creatine Monohydrate Improves Upper-Body Strength in Patients With Parkinson Disease: A Randomized Trial, C. J. Hass, M. A. Collins, and J. L. Juncos [Emory U], Neurorehabil Neural Repair, March 1, 2007; 21(2): 107 - 115.
13. b) "Chinese Exercise Modalities in PD" Jorge L. Juncos, MD, NCCAM 2002, Grant R01-AT000612

14. "Mitochondria in Parkinson disease," Muqit et al.Arch Neurol 2006;63:649-654

15. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease, The NINDS NET-PD Investigators Neurology 2007;68:20-28.

16. "The Role of h-pyloris in PD," 2003 grant by Michael J. Fox Foundation for Parkinson Research and "The Role of Inflammation in PD" Fernando Pitossi PhD, U Buenos Aires, 2003 MJFF grant ". . . peripheral inflammation could exacerbate on-going microglial activation. . . . evidence that systemic infections exacerbate . . . brain inflammation in PD and shift microglial function towards neurodegeneration." Research refers to PD: "MS, AD and prion disease models" as does [2]

Rehabilitation Medicine practice:
The return of soldiers with TBI has accelerated the opening of new practices in hospitals throughout the U.S., as well as the investigation of brain plasticity in research.

• Walter Reed Army Medical Center, Washington, D. C. [Dr. Col. Rocco Armonda, Sr. Neurosurgeon]
• Bethesda Naval Hospital
• New York University Langone Medical Center, Dr. Mary Hibbard, Prof. of Rehabilitation Medicine
• Rusk Institute, New York, Dr. Steve Flanagan, Chair of Rehabilitation Medicine
• Emory University School of Medicine, Department of Neurology and
• Wesley Woods Center, Atlanta, GA (Stroke Rehabilitation)