Preliminary outlines for more proposals

Noam Y. Harel

(originally posted 8/21/2008, updated 3/31/2013)

Hebbian rehabilitation approaches for spinal cord injury

  • Most spinal cord injuries (SCI), even if they cause complete paralysis and sensory loss below the lesion, tend to spare a variable amount of nerve fibers passing through the lesion (Kakulas, 1987).
  • Brainstem circuits comprise the majority of spared fibers (Nathan, 1996). However, people with SCI may have difficulty consciously controlling these subcortical circuits.
  • The locomotor central pattern generator (CPG), located within the thoraco-lumbar junction of the spinal cord, mediates reflexive walking with only minimal conscious control. The CPG is located below the level of injury in roughly 85% of human SCI patients.
  • Currently, gait training rehabilitation for SCI patients often focuses on stimulating the CPG through weight-supported treadmill training. Rehabilitation exercises are not as focused on re-establishing supraspinal voluntary control of the CPG (van den Brand et al., 2012).
  • Neural learning is strengthened by simultaneous multisensory input/activation - "Fire Together, Wire Together" (Hebb's Principle).
  • Could motor learning (eg SCI rehab) benefit from a similar simultaneous sensorimotor approach? Especially if the approach is aimed higher, above rather than below spinal lesions?

  • To strengthen cortical connections to the brainstem circuits that more likely retain spared fibers across spinal injuries.
  • This could be achieved using combinations of physical exercises that stimulate brainstem pathways (eg balance exercises-->vestibulospinal, reticulospinal circuits) and cortical pathways (eg skilled hand exercises-->corticospinal tract).
  • This should result in formation of detour pathways that re-establish volitional control over subcortical and spinal circuits.
  • Strengthened detour pathways should result in improved motor function and electrical transmission across and below spinal injuries.
  • We have tested this approach in mice with incomplete injuries (Harel et al., 2010; Harel et al., in preparation).
  • We are now testing this approach in humans with incomplete thoracic SCI (see NCT01740128).
  • In mice, we see improved behavioral outcomes with multimodal 'Hebbian' training. We do not see a corresponding increase in anatomical growth of the corticospinal or raphespinal tracts.
  • In humans, we are following both functional outcomes and electrophysiological outcomes (using transcranial magnetic stimulation and electromyography).
  • We hope to test a similar strategy of combining brainstem-activating balance exercises with cortical-activating direct current stimulation (DCS).

Lumping rare diseases sharing similar etiologies into broader clinical trials

(Inspired by conversations at the Clinical Trials Methods Course sponsored by NINDS and Univ. of Rochester; special thanks to Dr. John Marler)
(Reinforced by publications that have appeared since originally posting this entry: Dobkin 2009; Hodes et al., 2013)

  • Many neurological diseases are extremely rare.
  • Some of these diseases fall into broader groups such as muscular dystrophies, lysosomal storage disorders, or neurodegenerative diseases.
  • Each of these broad groups of neurological diseases share several putative pathologic mechanisms - for example, protein aggregation in various neurodegenerative diseases; apoptosis in almost all of these diseases.
  • In many cases, similar drugs are tested in clinical trials for various different diseases in the same broader group - for instance, Coenzyme Q10 in ALS, Parkinson's, and Huntington's disease.

  • To increase recruitment, cut administrative costs, and expand generalizability, conduct larger trials recruiting patients with various diseases within broader groups, with fewer exclusion criteria.
  • Would need to normalize outcome measures on disease-specific scales - the new NIH Toolbox provides the perfect set of tests to do this.
  • Use pre-specified subgroup analyses to determine if a drug shows efficacy for one or more of a group of diseases.