Clinically indicated electrical stimulation strategies to treat patients with medically refractory epilepsy.

Focal epilepsies represent approximately half of all diagnoses, and more than one-third of these patients are refractory to pharmacologic treatment. Although resection can result in seizure freedom, many patients do not meet surgical criteria, as seizures may be multifocal in origin or have a focus in an eloquent region of the brain. For these individuals, several U.S. Food and Drug Administration (FDA)-approved electrical stimulation paradigms serve as alternative options, including vagus nerve stimulation, responsive neurostimulation, and stimulation of the anterior nucleus of the thalamus. All of these are safe, flexible, and lead to progressive seizure control over time when used as an adjunctive therapy to antiepileptic drugs. Focal epilepsies frequently involve significant comorbidities such as cognitive decline. Similar to antiepilepsy medications and surgical resection, current stimulation targets and parameters have yet to address cognitive impairments directly, with patients reporting persistent comorbidities associated with focal epilepsy despite a significant reduction in the number of their seizures. Although low-frequency theta oscillations of the septohippocampal network are critical for modulating cellular activity and, in turn, cognitive processing, the coordination of neural excitability is also imperative for preventing seizures. In this review, we summarize current FDA-approved electrical stimulation paradigms and propose that theta oscillations of the medial septal nucleus represent a novel neuromodulation target for concurrent seizure reduction and cognitive improvement in epilepsy. Ultimately, further advancements in clinical neurostimulation strategies will allow for the efficient treatment of both seizures and comorbidities, thereby improving overall quality of life for patients with epilepsy

Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury.

Traumatic brain injury (TBI) can result in persistent cognitive, behavioral and emotional deficits. However, the vast majority of patients are not chronically hospitalized; rather they have to manage their disabilities once they are discharged to home. Promoting recovery to pre-injury level is important from a patient care as well as a societal perspective. Electrical neuromodulation is one approach that has shown promise in alleviating symptoms associated with neurological disorders such as in Parkinson's disease (PD) and epilepsy. Consistent with this perspective, both animal and clinical studies have revealed that TBI alters physiological oscillatory rhythms. More recently several studies demonstrated that low frequency stimulation improves cognitive outcome in models of TBI. Specifically, stimulation of the septohippocampal circuit in the theta frequency entrained oscillations and improved spatial learning following TBI. In order to evaluate the potential of electrical deep brain stimulation for clinical translation we review the basic neurophysiology of oscillations, their role in cognition and how they are changed post-TBI. Furthermore, we highlight several factors for future pre-clinical and clinical studies to consider, with the hope that it will promote a hypothesis driven approach to subsequent experimental designs and ultimately successful translation to improve outcome in patients with TBI

Modeling the hippocampus : finely controlled memory storage using spiking neurons

The hippocampus, an area in the temporal lobe of the mammalian brain, participates in the storage of personal memories and life events. As such traumatic memories and the consequent symptoms of post-traumatic stress are thought to be stored or at least processedin the hippocampus. While a fundamental understanding of a traumatic memory is still elusive, studying the physiology and functional properties of the hippocampus are anessential first step. Towards that goal, I developed a detailed computational model of the hippocampus. The model included the important effects of the neuromodulator Acetylcholine that switches the hippocampal network between the memory encoding state and the memory retrieval state. In the first study, I examined the mechanisms for controlling runaway excitation in the model. The results indicated different mechanisms for controlling runaway excitation in the memory encoding state as opposed to the memory retrieval state of the circuit. These findings produced the first functionally-based categorization of seizures in animals and humans, and may inspire specific treatments for these types of seizures. The second study examined the underpinnings of the rhythmic activity of the hippocampus. These oscillations in the theta range (4-12 Hz) are theorize to play a major role in the memory functions and in processing sequences of events and actions in both place and time. We found the generation of theta rhythmic activity to be best described as a product of multiple interacting generators. Importantly, we found differences in theta generation depending on the functional state of the hippocampus. Finally, the third study detailed the rules of the complex interactions between these multiple theta generators in the circuit. Our results shed more light on the role of specific components in the hippocampal circuit to maintain its function in both health and disease states

Encoding and recall of memory for reward location in the mouse hippocampus

The memory of where to find food can be crucial for an animal’s survival. Encoding and recall of these spatial memories involves the hippocampus, but whether and how hippocampal activity integrates memories of spatial relationships and locations is poorly understood. This thesis investigates how hippocampal activity facilitates the encoding of reward memories and how this encoding shapes hippocampal activity during memory recall in mice learning reward locations. Encoding of memory happens in stages that depend on the hippocampal state. The thesis interrogated how two different hippocampal states, one during movement and the other during reward consumption, are affected by acetylcholine – a neuromodulator released predominantly during movement and exploration. The findings highlight how acetylcholine modulates hippocampal state and how, when experimentally altered, it can impede memory encoding. Hippocampal activity facilitates navigation towards the learned reward locations. Individual neurons fire at specific locations of the environment, and, collectively, they cover the environment forming its cognitive map. To answer how the hippocampal activity could encode a memory of reward location, the thesis investigated how these spatial representations and the population activity change after learning. I found that the reward memory shapes the activity in the dorsal CA1 of the hippocampus by modulating its overall population activity and in the intermediate CA1 by modulating the activity of a reward-specific cell population. Together, these results suggest how hippocampal activity could facilitate encoding and recall of memory for reward locations

Acetylcholine neuromodulation in normal and abnormal learning and memory: vigilance control in waking, sleep, autism, amnesia, and Alzheimer's disease

This article provides a unified mechanistic neural explanation of how learning, recognition, and cognition break down during Alzheimer's disease, medial temporal amnesia, and autism. It also clarifies whey there are often sleep disturbances during these disorders. A key mechanism is how acetylcholine modules vigilance control in cortical layer

Central relaxin-3 receptor (RXFP3) activation increases ERK phosphorylation in septal cholinergic neurons and impairs spatial working memory.

The medial septum/diagonal band (MS/DB) is a relay region connecting the hypothalamus and brainstem with the hippocampus, and both the MS/DB and dorsal/ventral hippocampus receive strong topographic GABA/peptidergic projections from the nucleus incertus of the pontine tegmentum. The neuropeptide relaxin-3, released by these neurons, is the cognate ligand for a Gi/o-protein-coupled receptor, RXFP3, which is highly expressed within the MS/DB, and both cholinergic and GABAergic neurons in this region of rat brain receive relaxin-3 positive terminals/boutons. Comprehensive in vitro studies have demonstrated that a range of cell signaling pathways can be altered by RXFP3 stimulation, including inhibition of forskolin-activated cAMP levels and activation of ERK phosphorylation. In this study we investigated whether intracerebroventricular (icv) injection of RXFP3-A2, a selective relaxin-3 receptor agonist, altered ERK phosphorylation levels in the MS/DB of adult male rats. In addition, we assessed the neurochemical phenotype of phosphorylated (p) ERK-positive neurons in MS/DB after RXFP3-A2 administration by dual-label immunostaining for pERK and key neuronal markers. RXFP3-A2 injection significantly increased pERK levels in MS/DB, compared to vehicle at 20 and 90 min post-injection. In addition, icv injection of RXFP3-A2 increased the number of cells expressing pERK in the MS/DB after 90 min, with increases detected in cholinergic, but not GABAergic neurons. Moreover, we found that septal cholinergic neurons express RXFP3 and that icv infusions of RXFP3-A2 impaired alternation in a spatial working memory behavioral paradigm. The presence of the receptor and the specific RXFP3-related activation of the MAPK/ERK pathway in MS/DB cholinergic neurons identifies them as a key target of ascending relaxin-3 projections with implications for the acute and chronic inhibition of cholinergic neuron activity/function by relaxin-3/RXFP3 signaling.This research was supported by a predoctoral fellowship (FPI-UJI: PREDOC/2014/35) to HAG; a traineeship fellowship (UJI P1·1A2014-06) to AGA; the FP7-PEOPLE-IRSES PIRSES-GA-2012-318997 NEUREN project to ALG and FEO-B; NHMRC (Australia) project grants (1027522, 1026939) and a Brain and Behavior Research Foundation (USA) NARSAD Independent Investigator Award to ALG; Generalitat Valenciana (AICO/2015/042) project grant and Universitat Jaume I (P1·1A2014-06) project grant to AMS

Rightward-biased hemodynamic response of the parahippocampal system during virtual navigation

Phase reset of parahippocampal electrophysiological oscillations in the theta frequency range is said to contribute to item encoding and retrieval during spatial navigation. Although well-studied in non-human animals, this mechanism is poorly understood in humans. Previously we found that feedback stimuli presented in a virtual maze environment elicited a burst of theta power over right-posterior areas of the human scalp, and that the power and phase angle of these oscillations were greater following right turns compared to left turns in the maze. Here we investigated the source of this effect with functional magnetic resonance imaging. Consistent with our predictions, we found that 1) feedback encountered in the maze task activated right parahippocampal cortex (PHC), 2) right PHC was more activated by rewards following right turns compared to left turns in the maze, and 3) the rightward-biased activation was more pronounced in individuals who displayed good spatial abilities. These findings support our previous electrophysiological findings and highlight, in humans, a role for PHC theta oscillations in encoding salient information for the purpose of spatial navigation

The effects of cholinergic and dopaminergic neurons on hippocampal learning and memory processes

Dysfunction of cholinergic and dopaminergic systems has been implicated in memory function de cits that are core pathology and associated features of several neurological disorders. However, in order to develop more effective treatments, it is crucial to better understand how different aspects of learning and memory are modulated by these neuromodulatory systems. Using optogenetic stimulation or silencing, this thesis aims to investigate the effects of cholinergic and dopaminergic modulation on various hippocamal learning and memory processes. To understand how these neuromodulatory systems modulate hippocampal network activity, I first examined their effects on hippocampal local field potentials in urethane-anaesthetised mice. I demonstrated that optogenetic cholinergic activation suppressed slow oscillations, shifting brain activity to a state dominated by theta and gamma oscillations. In contrast, dopaminergic activation suppressed gamma oscillations. Second, to directly probe the effects of neuromodulation on different stages of spatial learning, I acutely activated or inactivated cholinergic or dopaminergic neurons during various behavioural tasks. My findings suggested that cholinergic activation, solely during the reward phase of a long-term spatial memory task, slowed place learning, highlighting the importance of temporally-precise neuromodulation. Moreover, dopaminergic stimulation may enhance place learning of a food rewarded task, supporting a role for dopamine in spatial learning. In addition, I tested the effects of cholinergic and dopaminergic modulation on reversal learning and found that cholinergic inactivation and dopaminergic activation appear to impair this process. Together, these findings emphasise the importance of cholinergic and dopaminergic modulation in learning and memory. They suggest that precise timing of neuromodulator action is critical for optimal learning and memory performance, and that acetylcholine and dopamine support complementary processes that allow for effective learning and adaptation to changing environments.Gulbenkian Yuval Cambridge Studentshi

Doctor of Philosophy

dissertationHippocampal network oscillations are important for learning and memory. Theta rhythms are involved in attention, navigation, and memory encoding, whereas sharp wave-ripple complexes (ripples) are involved in memory consolidation. Cholinergic neurons in the medial septum-diagonal band of Broca (MS-DB) influence both types of hippocampal oscillations, promoting theta rhythms and suppressing ripples. They also receive frequency-dependent hyperpolarizing feedback from hippocamposeptal connections, potentially affecting their role as neuromodulators in the septohippocampal circuit. However, little is known about how the integration properties of cholinergic MS-DB neurons change with hyperpolarization. By potentially altering firing behavior in cholinergic neurons, hyperpolarizing feedback from the hippocampal neurons may, in turn, change hippocampal network activity. To study how hyperpolarizing inputs change in membrane integration properties, we used whole-cell patch-clamp recordings targeting genetically labeled, choline acetyltransferase-positive neurons in mouse medial septal brain slices. Hyperpolarization of cholinergic MS-DB neurons resulted in a long-lasting decrease in spike firing rate and input-output gain. Additionally, voltage-clamp measures implicated a slowly inactivating, 4-AP-insensitive, outward K+ conductance. Using a conductance-based model of cholinergic MS-DB neurons, we show that the ability of this conductance to modulate firing rate and gain depends on the expression of an experimentally verified shallow intrinsic spike frequency-voltage relationship. Finally, we show that cholinergic suppression of hippocampal ripples can be achieved through an imbalance in drive, caused by cholinergic modulation, to hippocampal excitatory and inhibitory neurons. Together, these findings show possible mechanisms through which cholinergic MS-DB neurons may both influence and be influenced by hippocampal rhythms