Neurostimulation and Cognition

Abstract & Commentary

By Douglas Labar, MD, PhD, Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Labar reports no financial relationships relevant to this field of study.

Synopsis: Direct current transcranial stimulation of the human brain holds promise for helping to improve a variety of neurological functions, including learning and memory.

Source: Zimerman M, et al. Neuroenhancement of the aging brain: Restoring skill acquisition in old subjects. Ann Neurol 2013;73:10-15.

There is considerable interest in the prospects for enhancing neural function with stimulation devices. Zimerman et al now report transcranial direct current electrical stimulation (tDCS) improves acquisition of motor skills, particularly learning among older normal individuals.

The motor task studied was finger tapping on a four-button keyboard, acquired over 15 minutes of training, and then studied for skill retention 90 minutes and 24 hours later. The baseline rate of skill acquisition was better among 14 younger participants (mean age = 24 years) compared with 14 older participants (mean age = 68 years). When treatment with anodal tDCS over the hand knob of the motor cortex contralateral to the tested limb during training was compared with sham, the treatment produced significantly better motor skill retention at 90 minutes and 24 hours of follow-up (overall, for the combined age groups). However, when comparing 10 older with 10 younger participants, it was seen that tDCS increased the motor learning rate among the older subjects, but not in the younger subjects; tDCS had no effect in the younger individuals. It should be noted that the baseline performance in the older individuals was inferior, so they had more “room to improve” compared with the younger individuals. A performance ceiling effect also may have been operative for the younger subjects. The authors suggest that the tDCS mechanism of action was unmasking of excitatory connections within the cortex.

Over the years, numerous studies of cognitive function enhancement with varied stimulatory methods have been reported. For example, Marshall et al applied tDCS bifrontally during slow-wave sleep in 30 normal subjects.1 Recall for declarative memory items (paired associated words) presented the previous day was improved on the day after the tDCS in sleep. There was no effect if the tDCS was applied in the awake state, and no effect on procedural memory (mirror tracing) with either wake or asleep tDCS. Clark et al found in 96 subjects that 30 minutes of right inferior frontal and parietal tDCS during training accelerated identification of concealed objects in a discovery-learning paradigm.2 Word-recognition memory was shown to be improved when vagus nerve stimulation on-phases were delivered 30 seconds after paragraph reading in patients undergoing treatment for refractory epilepsy.3

These above described cognitive function enhancements in normal subjects may or may not be applicable to patients with cognitive impairments from disease. Such patients (by definition) have some degree of underlying abnormal neural substrate, which may or may not be as amenable to neurostimulatory interventions as is the neural substrate in normal individuals. Nonetheless, extrapolating from experimental findings in normal subjects to plan therapies for patients may be a fruitful endeavor. An interesting example is implanted electrical stimulation of the fornix for Alzheimer’s disease (AD). This began with the observation that a neurologically normal patient undergoing hypothalamic deep brain stimulation (DBS) to treat morbid obesity reported unexpected biographical memories during stimulation.4 In this patient, memory testing for word pair recollection specifically improved significantly during stimulation-on periods, without global improvement in neuropsychological functions. Electroencephalographic (EEG) source localization revealed stimulation-induced ipsilateral hippocampal and parahippocampal activation. The authors hypothesized that these effects were mediated by stimulation of the fornix, which is a fiber bundle connecting hypothalamic, mammillary body, and septal areas to the medial temporal lobe.

Subsequently, a pilot trial of hypothalamic/fornix DBS for AD was undertaken.5 After 6 months of DBS, four of six patients showed improvement on the AD Assessment Scale Cognitive Subscale (ADAS-Cog). After 12 months of DBS, compared with projected disease progression, two patients performed better than expected, one patient performed worse than expected, and three patients performed as expected. Medial temporal lobe activation on EEG, and reversal of impaired glucose utilization in temporal and parietal lobes on positron emission tomography, was seen in these patients, with stimulation. A multicenter clinical trial of fornix DBS for AD (four sites in the United States, one site in Canada) is underway (ClinicalTrials.gov identifier NCT01608061). There also may be therapeutic utility for noninvasive brain stimulation for AD,6 and tDCS for post-stroke.7

Commentary

These new neuromodulatory interventions seem to hold promise in a variety of cognitive function spheres. However, appropriate caution should be used before embracing these new techniques, and systematic assessment tools to detect both subtle adverse effects as well as subtle improvements are in order. Iuculano and Kadosh administered 20 minutes of tDCS (or sham stimulation) over dorsolateral prefrontal cortex (DLPFC) or posterior parietal cortex to 19 normal subjects during six daily 2-hour mathematics training sessions.8 Posterior parietal stimulation enhanced initial mathematical skill acquisition, but impaired later quick, automatic use of mathematical skills. In contrast, DLPFC stimulation did the opposite: It impaired the initial learning process, but enhanced later automaticity for use of the learned material. Transcranial magnetic stimulation of the DLPFC is in clinical use to treat depression, and has been reported to improve9 or disrupt10 cognitive functions. Further research is needed to clarify the benefits and risks of these exciting new therapies.

References

  1. Marshall L, et al. Transcranial direct stimulation during sleep improves declarative memory. J Neurosi 2004;24:9985-9992.
  2. Clark VP, et al. tDCS guided using fMRI significantly accelerates learning to identify concealed objects. Neuroimage 2012;59:117-128.
  3. Clark K, et al. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci 1999;2: 94-98.
  4. Hamani C, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008;63:119-123.
  5. Laxton AW, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010;68:521-534.
  6. Freitas C, et al. Noninvasive brain stimulation for Alzheimer’s disease: Systematic review and perspectives for the future. Exp Geron 2011;46:611-627.
  7. Holland R, Crinion J. Can tDCS enhance treatment of aphasia after stroke? Aphasiology 2012;26:1169-1191.
  8. Iuculano T, Cohen Kadosh R. The mental cost of cognitive enhancement. J Neurosci 2013;33:4482-4486.
  9. Guse B, et al. Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: A systematic review. J Neural Transm 2010;117:105-122.
  10. Osaka N, et al. Transcranial magnetic stimulation (TMS) applied to left dorsolateral prefrontal cortex disrupts verbal working memory performance in humans. Neurosci Lett 2007;418:232-235.