This is a very interesting report showing that treatment with the antiepileptic levetiracetam improves both the task-specific hyperactivity in the DG/CA3 hippocampal circuit seen by fMRI in patients with amnestic MCI and also the cognitive task that reflects the function of this circuit. It is exciting to follow how better functional imaging can provide ever more detailed insights into the brains of living people with MCI, and now even connect therapy to improvement in a selected brain circuit. At the same time, this particular treatment provided no overall improvement on standard neuropsychological testing, including other memory tests. Mucke, Palop, and others have underscored the importance of better understanding of the neural circuitry dysfunction, in particular aberrant hyperactivity, in Alzheimer's disease.

In Parkinson's disease, research into circuitry dysfunction has led to therapies (such as lesioning of hyperactive subthalamic nucleus). It wasn't as clear why the authors wrote that some have viewed hippocampal hyperactivity in aMCI as beneficial. Dysfunctional...  Read more

This is a very interesting report showing that treatment with the antiepileptic levetiracetam improves both the task-specific hyperactivity in the DG/CA3 hippocampal circuit seen by fMRI in patients with amnestic MCI and also the cognitive task that reflects the function of this circuit. It is exciting to follow how better functional imaging can provide ever more detailed insights into the brains of living people with MCI, and now even connect therapy to improvement in a selected brain circuit. At the same time, this particular treatment provided no overall improvement on standard neuropsychological testing, including other memory tests. Mucke, Palop, and others have underscored the importance of better understanding of the neural circuitry dysfunction, in particular aberrant hyperactivity, in Alzheimer's disease.

In Parkinson's disease, research into circuitry dysfunction has led to therapies (such as lesioning of hyperactive subthalamic nucleus). It wasn't as clear why the authors wrote that some have viewed hippocampal hyperactivity in aMCI as beneficial. Dysfunctional brain circuits typically lead to imbalances, including hyper- and hypoactive circuits. The authors previously noted hypoactivity in the ERC-to-DG/CA3 circuit in aMCI (Yassa et al., 2010). One might not expect that this hypoactive ERC circuit would also benefit from low-dose levetiracetam. The relative contributions of elevated versus reduced (and also resting versus task-related) activity to the disease process remain unclear. Current evidence supports that both hyperactive (Mohajeri et al., 2002) as well as hypoactive (Tampellini et al., 2010) circuitry can negatively impact the disease process.

View all comments by Gunnar K. Gouras

Cortical and hippocampal hyperactivity of neuronal networks are early events in AD pathogenesis and are associated with early amyloid deposition in non-demented humans with and without mild cognitive impairment (MCI) (Sperling et al., 2009; Putcha et al., 2011). However, it was unclear whether such hyperactivity was a beneficial compensatory response or just a detrimental overactivation of neuronal networks. Michela Gallagher’s data clearly suggest that attenuation of hippocampal hyperactivity by levetiracetam improves memory performance in amnestic MCI patients, indicating a primary and detrimental effect of network hyperactivity in MCI patients. This is a quite remarkable and important finding that may lead to novel therapies in a short period of time.

References:
Putcha D, Brickhouse M, O'Keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R (2011) Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults. J Neurosci 31:17680-17688. Abstract

Sperling RA, Laviolette PS, O'Keefe K, O'Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178-188. Abstract

View all comments by Jorge J Palop