Effects of Acute Nicotine on Long-term Potentiation in the Dorsolateral Prefrontal Cortex of Patients With Schizophrenia and Healthy Controls

Background: Schizophrenia (SCZ) is frequently associated with marked working memory (WM) deficits whose pathophysiology is closely related to dorsolateral prefrontal cortex (DLPFC)-dependent dysfunction[1]. These deficits predict disease outcome and poor response to antipsychotic treatment[2]. Consequently, elucidating the physiology of DLPFC-dependent WM deficits in SCZ is key in better understanding this illness and its treatment.

Patients with SCZ display an unusually high prevalence of smoking and high rates of smoking cessation failures are commonly associated with WM deficits[3]. The central nicotinic acetylcholine receptor (nAChR) is the main target for nicotine. Several lines of evidence strongly suggest that the nAChR system is a promising target for treating cognitive deficits in SCZ. These include the following observations: (1) expression of nAChRs receptors is abnormal in several brain regions, including the PFC, in post mortem brains of patients with SCZ, (2) genes coding for nAChR subunits are candidate risk genes for SCZ and nicotine addiction, and (3) smoking abstinence produce deficits of WM, which correlate with blood levels of nicotine, are alleviated by smoking re-instatement and are blocked by nAChR antagonists in patients with SCZ, but not in healthy control smokers (e.g.,[4]). However, the underlying mechanism through which nicotine and nAChRs affect DLPFC-dependent memory in SCZ are still unknown. Nicotine-induced increases in neural plasticity may represent one such mechanism.

Neuroplasticity, which includes long-term potentiation (LTP), is a proposed physiological mechanism for memory formation. LTP is dependent on an optimal interaction between the glutamate (GLU), dopamine (DA) and γ-Aminobutyric acid (GABA) systems and perturbations in these systems likely explain why patients with SCZ demonstrate deficits in WM and neuroplasticity[5,6]. nAChR are present on GABA, GLU and DA neurons and nicotine could potentially improve cognition by modulating these systems. Studies have demonstrated that acute nicotine administration potentiates neural plasticity in the motor cortex of healthy human subjects. One of these studies used Paired Associative Stimulation (PAS), a powerful paradigm to index LTP in the motor cortex, to assess the effects of nicotine on LTP in non-smokers[7]. The results demonstrate that nicotine enhanced LTP-like mechanisms induced by PAS in the motor cortex[7]. To date, however, there has been no direct measure of LTP-like plasticity from the DLPFC in humans. To overcome this challenge, the investigators group has developed a novel PAS technique of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG)[8] to directly index LTP from the DLPFC.

Conventional methods of applying PAS involves the repetitive delivery of two paired stimulations: the first being an electrical peripheral nerve stimulation of the right median nerve of the hand and 25 ms later a second TMS pulse delivered to the contralateral motor cortex (hence PAS-25). Through repetitive pairing of these two stimulations, PAS-25 results in increased activation of output neurons that represents a direct measure LTP in humans[9]. The investigators lab has recently recorded PAS-LTP in the DLFPC using a novel technique of TMS-EEG[8]. Here, PAS is applied to the DLPFC by repetitive delivery of: (1) a peripheral nerve stimulation to the right side, followed 25 ms later by; (2) a TMS pulse delivered to the left DLPFC. PAS-induced potentiation of cortical evoked activity is then measured directly from the DLPFC and represents LTP in this region as interneurons activated from cortical stimulation and peripheral stimulation, in turn, activate DLPFC output neurons contemporaneously and increase their activity when repeated over 30 min. Thus, the activation of the somatosensory cortex by peripheral nerve stimulation will propagate to the DLPFC and arrive there simultaneously with the TMS pulse resulting in LTP. The validity of this technique relies on the observation that there are strong correlations between TMS induced evoked potentials in the motor and DLPFC (r=0.8-0.85, p<0.001)[8]. LTP is quantified as change in DLPFC cortical evoked activity from baseline (pre-PAS) to different time points following PAS-25 (post-PAS). Preliminary data from the investigators ongoing study using these novel methods, demonstrate that PAS-25 induces significant LTP in the DLPFC. For example, in healthy controls cortical evoked activity in the DLPFC was facilitated by 56% post-PAS (maximal point of facilitation) while in patients with SCZ the cortical evoked activity post-PAS was only increased by 16% (Cohen's d=0.80). This is to the investigators knowledge the first time LTP has ever been demonstrated in-vivo in the DLPFC of humans and the first time that LTP deficits in the DLPFC have been reported in patients with SCZ. The aim of this proposal is now to assess whether enhanced WM by nicotine is mediated by potentiation of LTP in the DLPFC.

Hypothesis: