Past events

Hypnosis was the first Western form of psychotherapy, yet it remains underutilized in part because of insufficient understanding of its neural basis. Hypnosis involves highly focused attention, coupled with dissociation of aspects of awareness, relatively automatic response to social cues, and an enhanced ability to modulate perception. New evidence regarding this sensory processing ability will be presented, including studies employing event-related potentials, PET and fMRI. Our recent resting state fMRI data demonstrate functional connectivity between the executive control and salience networks among high but not low hypnotizable individuals. This hypnotic ability to modulate perception has clear clinical application, especially in pain and anxiety control. Randomized clinical trials that we have conducted demonstrate the efficacy of hypnosis in reducing pain, anxiety, somatic complications, and procedure duration during radiological interventions.

There is consistency in how health people move their eyes, arms, and legs. What is good about this way of moving, and why has our brain settled on this pattern? Here, I focus on the control of eye movements and suggest that the purpose of any movement is to acquire a more rewarding state. I suggest that the way the brain discounts reward in time strongly affects why we move the way that we do. This framework has the potential to explain why disorders that affect processing of reward in the brain, like Parkinson's disease, depression, and Schizophrenia, result in changes in control of movements.

Major failures in AD patients with several low molecular weight (LMW) compounds and certain immunotherapies indicate that the etiology of the disease is still elusive. Therefore future therapies should address all AD hallmarks, regardless of prime etiological culprits. In this lecture several low molecular weight (LMW) compounds and their respective target(s) are critically discussed as potential treatments for AD including, inter alia: cholinergic modulators [cholinesterase inhibitors (AChE-Is), alpha7-nicotinic agonists, M1 muscarinic agonists], alpha-secretase activators, BACE1 inhibitors, gamma-secretase inhibitors or modulators, inhibitors of beta-amyloids (Abeta) aggregation or Abeta-induced neurotoxicity, inhibitors of tau proteins hyperphosphorylation and/or tau proteins aggregation, GSK-3beta inhibitors and sigma-1 receptor (Sig1R) agonists. Comparison among these compounds is made when possible also with M1 muscarinic agonists and a new compound, AF710B. In this context the M1 muscarinic receptor (M1 mAChR) appears to be a pivotal target for treatment of AD, Parkinson's disease (PD) and Lewy body dementia (LBD). Notably the M1 muscarinic agonists AF102B, AF267B, AF292 are effective cognitive enhancers and disease modifiers with a wide safety margin. Thus - i) AF102B decreased CSF Abeta in AD patients (Nitsch et al, Ann Neurol 2000); ii) AF267B rescued cognitive deficits and decreased Abeta42 and tau pathologies in 3xTg-AD mice (Caccamo et al, Neuron, 2006); and iii) AF102B and AF267B decreased brain alpha-synuclein aggregates in transgenic mice overexpressing human alpha-synuclein (Fisher et al., ADPD 2011). However in spite of their potential in disease modification (DM) and cognitive enhancement, M1 agonists (either orthosteric or allosteric) still do not address a prime disease hallmark, e.g. mitochondrial dysfunctions, which can be ameliorated via the molecular chaperone Sig1R. In this context we have designed a novel molecule, AF710B (MW, 357.5) which shows a novel mechanism of action (MoA) of enhancing neuroprotection and cognition via Sig1R activation and M1 muscarinic allosteric modulation, but not resembling Sig1R, M1 muscarinic (allosteric or orthosteric) and dual Sig1R/M1 agonists, respectively. The effects of AF710B at low concentrations in vitro against neurodegeneration, oxidative stress, Abeta, Tau-phosphorylation and GSK-3beta activation translate into down-regulation of the apoptotic protein Bax and mitochondrial dysfunction, up-regulation of anti-apoptotic Bcl2. AF710B has an exceptional pharmacology being an excellent cognitive enhancer in rats (at 1-30 and 10-100mcg/kg, po in trihexyphenidyl- and in MK801-induced passive avoidance impairments, respectively). AF710B is devoid of side effects, having an unprecedented safety margin > 50,000 (po). Furthermore, AF710B mitigated cognitive impairments, reduced Abeta40, Abeta42 levels and tau pathology and inflammation in 3xTg-AD mice AF710B (at 10 mcg/kg, ip/daily for 2 months; Morris water maze). The unique effects of AF710B can be explained by a super-sensitization of M1 mAChR through a hypothetical heteromerization with Sig1R. Conclusions: Only some of the reviewed compounds can bridge treatment of both cognitive impairments with DM. In this context, AF710B is the 1st reported low MW CNS-penetrable mono-therapy that meets comprehensively this challenge. The unmatched potency of AF710B on cognition and on amyloid and tau pathologies, combined with its beneficial effects on inflammation and mitochondrial dysfunctions, indicates extensive therapeutic advantages for AF710B in AD and other protein-aggregation related diseases vs. a plethora of experimental and licensed treatments. Keywords: M1 muscarinic receptor, M1 agonist, disease modifiers, beta-amyloids, sigma-1 agonist, tau proteins, alpha-synuclein

Throughout the history of neuroscience, from the Chinese to the Egyptians and Romans, it was a key problem to find the seat of human experience. Once it was discovered that the brain is the sole proprietor of the human mind, a second flurry of scientific discourse focused on defining the localization of cognitive functions in the vast mantle of the brain. In my talk, after a brief historical overview, I will discuss the notion of localization of function in the brain in light of recent data from intracranial electrophysiological recordings during real life settings and electrical stimulation of the brain in conscious human subjects.