The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer’s disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Adaptively Timed Learning

This chapter explains how humans and other animals learn to adaptively time their behaviors to match external environmental constraints. It hereby explains how nerve cells learn to bridge big time intervals of hundreds of milliseconds or even several seconds, and thereby associate events that are separated in time. This is accomplished by a spectrum of cells that each respond in overlapping time intervals and whose population response can bridge intervals much larger than any individual cell can. Such spectral timing occurs in circuits that include the lateral entorhinal cortex and hippocampal cortex. Trace conditioning, in which CS and US are separated in time, requires the hippocampus, whereas delay conditioning, in which they overlap, does not. The Weber law observed in trace conditioning naturally emerges from spectral timing dynamics, as later confirmed by data about hippocampal time cells. Hippocampal adaptive timing enables a cognitive-emotional resonance to be sustained long enough to become conscious of its feeling and its causal event, and to support BDNF-modulated memory consolidation. Spectral timing supports balanced exploratory and consummatory behaviors whereby restless exploration for immediate gratification is replaced by adaptively timed consummation. During expected disconfirmations of reward, orienting responses are inhibited until an adaptively timed response is released. Hippocampally-mediated incentive motivation supports timed responding via the cerebellum. mGluR regulates adaptive timing in hippocampus, cerebellum, and basal ganglia. Breakdowns of mGluR and dopamine modulation cause symptoms of autism and Fragile X syndrome. Inter-personal circular reactions enable social cognitive capabilities, including joint attention and imitation learning, to develop.

The Medial Septum as a Potential Target for Treating Brain Disorders Associated with Oscillopathies

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer’s disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Design of Soft-Switching Hybrid DC-DC Converter with 2-Phase Switched Capacitor and 0.8nH Inductor for Standard CMOS Process

A soft-switching hybrid DC-DC converter with a 2-phase switched capacitor is proposed for the implementation of a fully-integrated voltage regulator in a 65 nm standard CMOS process. The soft-switching operation is implemented to minimize power loss due to the parasitic capacitance of the flying capacitor. The 2-phase switched capacitor topology keeps the same resonance value for every soft-switching operation, resulting in minimizing the voltage imbalance of the flying capacitor. The proposed adaptive timing generator digitally calibrates the turn-on delay of switches to achieve a complete soft-switching operation. The simulation results show that the proposed soft-switching hybrid DC-DC converter with a 2-phase 2:1 switched capacitor improves the efficiency by 5.1% and achieves 79.5% peak efficiency at a maximum load current of 250 mA.