Project details


How to stimulate: Basal forebrain DBS parameters to restore the attentional performance of rats with cholinergic losses

dementia Deep brain stimulation (DBS) Parkinson disease

prof. dr. T. van Laar
drs. M. Nazmuddin
M. Sarter

Nature of the research:
Preclinical study using rat model of cholinergic deficiency by stereotactically injecting cholino-specific toxin at the basal forebrain, surgery for electrode implantation, histology assesment to quantify brain activation by electrical stimulation of the NBM, and behavioral testing with sustained attention task to test the effect of several DBS stimulation programs. The study is conducted in Sarter Lab, Biopsychology department in the University of Michigan USA.

Fields of study:
neurosurgery neurology psychiatry

Background / introduction
The degeneration of basal forebrain (BF) cholinergic neurons is an index of the severity of cognitive impairment in Alzheimer disease (AD) and Parkinson’s disease (PD).
Moreover, in PD patients, gait and balancing deficits, and an increased propensity for falls have been attributed to cholinergic losses. Thus, Deep Brain Stimulation (DBS) of the BF has been considered a potential therapeutic intervention to improve cognition and movement control in
these patients (Freund et al., 2009, Kuhn et al., 2015, Gratwicke et al., 2016). However, efficacy of BF DBS in clinical populations has yet to be conclusively demonstrated. Likewise, the demonstration of beneficial effects of BF DBS in rodent models has been hampered by uncertainties about useful animal models and behavioral tasks and, importantly, a lack of consensus concerning DBS parameters (duration, frequency, current, intermittent versus continuous, prior and/or during task, etc.).
Research question / problem definition
We will assess various DBS parameters in rats with a partial loss of the cortical cholinergic input system. In rats, such cholinergic losses have been frequently demonstrated to impair the detection of cues during the performance of a Sustained Attention Task (SAT) and to attenuate performance recovery
following a distractor challenge (dSAT). In PD patients with cholinergic losses, attentional
impairments were also attributed to cortical and thalamic cholinergic losses (Kim et al., 2017). The attribution of SAT impairments to cholinergic losses is consistent with evidence showing
that the detection of cues and associated attentional control parameters depend on cortical
cholinergic signaling (e.g., Howe et al., 2017). We predict that BF DBS will be particularly effective in restoring attentional performance in the dSAT condition. If confirmed, this finding will suggest that demonstration of efficacy in patients will require measures indicating their attentional capacities in response to taxing performance challenges.
Rats acquired the SAT will receive infusions of the cholino-specific neurotoxin 192-IgG-saporin into the BF, and will be implanted bilaterally with BF unipolar stimulation electrodes. Initial DBS parameters consisted of continuous high (130 Hz) versus low (20 Hz) frequency stimulation, intermittent (20-s ON at 80 Hz and 40-s OFF) stimulation, with pulse width and amplitude kept constant at 100 µs and 100 µA, respectively. The effects of these DBS parameters on the behavior of rats will be assessed in an open field space and then when administered during, or only prior to (for 1 hr), SAT and dSAT performance.
Freund H-J, Kuhn J, Lenartz D, Mai JK, Schnell T, Klosterkoetter J, et al. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009.

Gratwicke J, Zrinzo L, Kahan J, Peters A, Beigi M, Akram H, et al. Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia. JAMA Neurol. 2017.

Howe WM, Gritton HJ, Lusk NA, Roberts EA, Hetrick VL, Berke JD, et al. Acetylcholine Release in Prefrontal Cortex Promotes Gamma Oscillations and Theta-Gamma Coupling during Cue Detection. J Neurosci. 2017.

Kuhn J, Hardenacke K, Lenartz D, Gruendler T, Ullsperger M, Bartsch C, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia. Mol Psychiatry. 2015.
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