Persistent Firing Research Articles

Presubicular VIP expressing interneurons receive facilitating excitation from anterior thalamus

The presubiculum is part of the parahippocampal cortex and plays a fundamental role for orientation in space. Many principal neurons of the presubiculum signal head direction, and show persistent firing when the head of an animal is oriented in a specific preferred direction. GABAergic neurons of the presubiculum control the timing, sensitivity and selectivity of head directional signals from the anterior thalamic nuclei. However, the role of vasoactive intestinal peptide (VIP) expressing interneurons in the presubicular microcircuit has not yet been addressed. Here, we examined the intrinsic properties of VIP interneurons as well as their input connectivity following photostimulation of anterior thalamic axons. We show that presubicular VIP interneurons are more densely distributed in superficial than in deep layers. They are highly excitable. Three groups emerged from the unsupervised cluster analysis of their electrophysiological properties. We demonstrate a frequency dependent recruitment of VIP cells by thalamic afferences and facilitating synaptic input dynamics. Our data provide initial insight into the contribution of VIP interneurons for the integration of thalamic head direction information in the presubiculum.

Cholinergic stimulation stabilizes TRPM4 in the plasma membrane of cortical pyramidal neurons.

TRPM4 is a calcium activated non-selective cation channel, impermeable to Ca2+, in neurons it has been implicated in the regulation of the excitability and in the persistent firing. Cholinergic stimulation is also implicated in changes in excitability that leads neurons to an increased firing frequency, however it is not clear whether TRPM4 is involved in the cholinergic-induced increase in firing frequency. Here using a combination of patch clamp electrophysiology, Ca2+ imaging, immunofluorescence, fluorescence recovery after photobleaching (FRAP) and pharmacological approach, we demonstrate that carbachol (Cch) increases firing frequency, intracellular Ca2+ and that TRPM4 inhibition using 9-Ph and CBA reduces firing frequency and decreases the peak in intracellular Ca2+ induced by Cch in cortical pyramidal neurons in culture. Moreover, we determined that cholinergic stimulation reduces TRPM4 recycling and stabilizes TRPM4 in the plasma membrane. Together our results indicate that cholinergic stimulation increases firing in a TRPM4 dependent manner, and also increases the TRPM4 stability in the membrane, suggesting that TRPM4 is locked in microdomains in the membrane, possibly signaling or cytoskeleton proteins complexes.

Cell-type-specific cholinergic control of granular retrosplenial cortex with implications for angular velocity coding across brain states.

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

Neuronal activation sequences in lateral prefrontal cortex encode visuospatial working memory during virtual navigation

Working memory (WM) is the ability to maintain and manipulate information ‘in mind’. The neural codes underlying WM have been a matter of debate. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of male macaque monkeys during a visuospatial WM task that required navigation in a virtual 3D environment. Here, we demonstrate distinct neuronal activation sequences (NASs) that encode remembered target locations in the virtual environment. This NAS code outperformed the persistent firing code for remembered locations during the virtual reality task, but not during a classical WM task using stationary stimuli and constraining eye movements. Finally, blocking NMDA receptors using low doses of ketamine deteriorated the NAS code and behavioral performance selectively during the WM task. These results reveal the versatility and adaptability of neural codes supporting working memory function in the primate lateral prefrontal cortex.

Layer 1 NDNF interneurons are specialized top-down master regulators of cortical circuits

Diverse types of inhibitory interneurons (INs) impart computational power and flexibility to neocortical circuits. Whereas markers for different IN types in cortical layers 2-6 (L2-L6) have been instrumental for generating a wealth of functional insights, only the recent identification of a selective marker (neuron-derived neurotrophic factor [NDNF]) has opened comparable opportunities for INs in L1 (L1INs). However, at present we know very little about the connectivity of NDNF L1INs with other IN types, their input-output conversion, and the existence of potential NDNF L1IN subtypes. Here, we report pervasive inhibition of L2/3 INs (including parvalbumin INs and vasoactive intestinal peptide INs) by NDNF L1INs. Intersectional genetics revealed similar physiology and connectivity in the NDNF L1IN subpopulation co-expressing neuropeptide Y. Finally, NDNF L1INs prominently and selectively engage in persistent firing, a physiological hallmark disconnecting their output from the current input. Collectively, our work therefore identifies NDNF L1INs as specialized master regulators of superficial neocortex according to their pervasive top-down afferents.

Neural Activity in the Anterior Insula at Drinking Onset and Licking Relates to Compulsion-Like Alcohol Consumption.

Much remains unknown about the etiology of compulsion-like alcohol drinking, where consumption persists despite adverse consequences. The role of the anterior insula (AIC) in emotion, motivation, and interoception makes this brain region a likely candidate to drive challenge-resistant behavior, including compulsive drinking. Indeed, subcortical projections from the AIC promote compulsion-like intake in rats and are recruited in heavy-drinking humans during compulsion for alcohol, highlighting the importance of and need for more information about AIC activity patterns that support aversion-resistant responding. Single-unit activity was recorded in the AIC from 15 male rats during alcohol-only and compulsion-like consumption. We found three sustained firing phenotypes, sustained-increase, sustained-decrease, and drinking-onset cells, as well as several firing patterns synchronized with licking. While many AIC neurons had session-long activity changes, only neurons with firing increases at drinking onset had greater activity under compulsion-like conditions. Further, only cells with persistent firing increases maintained activity during pauses in licking, suggesting roles in maintaining drive for alcohol during breaks. AIC firing was not elevated during saccharin drinking, similar to lack of effect of AIC inhibition on sweet fluid intake in many studies. In addition, we observed subsecond changes in AIC neural activity tightly entrained to licking. One lick-synched firing pattern (determined for all licks in a session) predicted compulsion-like drinking, while a separate lick-associated pattern correlated with greater consumption across alcohol intake conditions. Collectively, these data provide a more integrated model for the role of AIC firing in compulsion-like drinking, with important relevance for how the AIC promotes sustained motivated responding more generally.

Interaction Between HCN and Slack Channels Regulates mPFC Pyramidal Cell Excitability in Working Memory Circuits.

The ability of monkeys and rats to carry out spatial working memory tasks has been shown to depend on the persistent firing of pyramidal cells in the prefrontal cortex (PFC), arising from recurrent excitatory connections on dendritic spines. These spines express hyperpolarization-activated cyclic nucleotide-gated (HCN) channels whose open state is increased by cAMP signaling, and which markedly alter PFC network connectivity and neuronal firing. In traditional neural circuits, activation of these non-selective cation channels leads to neuronal depolarization and increased firing rate. Paradoxically, cAMP activation of HCN channels in PFC pyramidal cells reduces working memory-related neuronal firing. This suggests that activation of HCN channels may hyperpolarize rather than depolarize these neurons. The current study tested the hypothesis that Na+ influx through HCN channels activates Slack Na+-activated K+ (KNa) channels to hyperpolarize the membrane. We have found that HCN and Slack KNa channels co-immunoprecipitate in cortical extracts and that, by immunoelectron microscopy, they colocalize at postsynaptic spines of PFC pyramidal neurons. A specific blocker of HCN channels, ZD7288, reduces KNa current in pyramidal cells that express both HCN and Slack channels, but has no effect on KNa currents in an HEK cell line expressing Slack without HCN channels, indicating that blockade of HCN channels in neurons reduces K+ current indirectly by lowering Na+ influx. Activation of HCN channels by cAMP in a cell line expressing a Ca2+ reporter results in elevation of cytoplasmic Ca2+, but the effect of cAMP is reversed if the HCN channels are co-expressed with Slack channels. Finally, we used a novel pharmacological blocker of Slack channels to show that inhibition of Slack in rat PFC improves working memory performance, an effect previously demonstrated for blockers of HCN channels. Our results suggest that the regulation of working memory by HCN channels in PFC pyramidal neurons is mediated by an HCN-Slack channel complex that links activation HCN channels to suppression of neuronal excitability.

Reclusive chandeliers: Functional isolation of dentate axo-axonic cells after experimental status epilepticus

Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.

Effect of short-term plasticity on working memory

The way in which persistent firing activity and synaptic plasticity are orchestrated to underlie working memory in recurrent neural networks is not fully understood. Here, we build a continuous attractor network of pyramidal cells and interneurons to simulate an oculomotor delayed response task. Both short-term facilitation (STF) and short-term depression (STD) manifest at synapses between pyramidal cells. The efficacy of individual synapses depends on the time constants of STF and STD as well as the presynaptic firing rate. Self-sustained firing activity (i.e., a bump attractor) during the delay period encodes the cue position. The bump attractor becomes more robust against random drifts and distractions with enhancing STF or reducing STD. Keeping STF and STD at appropriate levels is crucial for optimizing network performance. Our results suggest that, besides slow recurrent excitation and strong global inhibition, short-term plasticity plays a prominent role in facilitating mnemonic behavior.

Mechanisms underlying the prolonged activation of the genioglossus following arousal from sleep.

Transient arousal from sleep has been shown to elicit a prolonged increase in genioglossus muscle activity that persists following the return to sleep and which may protect against subsequent airway collapse. We hypothesized that this increased genioglossal activity following return to sleep after an arousal is due to persistent firing of inspiratory-modulated motor units (MUs) that are recruited during the arousal. Thirty-four healthy participants were studied overnight while wearing a nasal mask with pneumotachograph to measure ventilation and with 4 intramuscular genioglossus EMG electrodes. During stable N2 and N3 sleep, auditory tones were played to induce brief (3-15s) AASM arousals. Ventilation and genioglossus MUs were quantified before the tone, during the arousal and for 10 breaths after the return to sleep. A total of 1089 auditory tones were played and gave rise to 239 MUs recorded across arousal and the return to sleep in 20 participants (aged 23 ± 4.2 years and BMI 22.5 ± 2.2 kg/m2). Ventilation was elevated above baseline during arousal and the first post-arousal breath (p < .001). Genioglossal activity was elevated for five breaths following the return to sleep, due to increased firing rate and recruitment of inspiratory modulated MUs, as well as a small increase in tonic MU firing frequency. The sustained increase in genioglossal activity that occurs on return to sleep after arousal is primarily a result of persistent activity of inspiratory-modulated MUs, with a slight contribution from tonic units. Harnessing genioglossal activation following arousal may potentially be useful for preventing obstructive respiratory events.

Interrogating the Etiology of Sporadic Alzheimer's Disease Using Aging Rhesus Macaques: Cellular, Molecular, and Cortical Circuitry Perspectives.

Aging is the most significant risk factor for neurodegenerative disorders such as Alzheimer's disease (AD) associated with profound socioeconomic and personal costs. Consequently, there is an urgent need for animal models that recapitulate the age-related spatial and temporal complexity and patterns of pathology identical to human AD. Our research in aging nonhuman primate models involving rhesus macaques has revealed naturally occurring amyloid and tau pathology, including the formation of amyloid plaques and neurofibrillary tangles comprising hyperphosphorylated tau. Moreover, rhesus macaques exhibit synaptic dysfunction in association cortices and cognitive impairments with advancing age, and thus can be used to interrogate the etiological mechanisms that generate neuropathological cascades in sporadic AD. Particularly, unique molecular mechanisms (eg, feedforward cyclic adenosine 3',5'-monophosphate [cAMP]-Protein kinase A (PKA)-calcium signaling) in the newly evolved primate dorsolateral prefrontal cortex are critical for persistent firing required for subserving higher-order cognition. For example, dendritic spines in primate dorsolateral prefrontal cortex contain a specialized repertoire of proteins to magnify feedforward cAMP-PKA-calcium signaling such as N-methyl-d-aspartic acid receptors and calcium channels on the smooth endoplasmic reticulum (eg, ryanodine receptors). This process is constrained by phosphodiesterases (eg, PDE4) that hydrolyze cAMP and calcium-buffering proteins (eg, calbindin) in the cytosol. However, genetic predispositions and age-related insults exacerbate feedforward cAMP-Protein kinase A-calcium signaling pathways that induce a myriad of downstream effects, including the opening of K+ channels to weaken network connectivity, calcium-mediated dysregulation of mitochondria, and activation of inflammatory cascades to eliminate synapses, thereby increasing susceptibility to atrophy. Therefore, aging rhesus macaques provide an invaluable model to explore novel therapeutic strategies in sporadic AD.

Persistent Firing in Hippocampal CA1 Pyramidal Cells in Young and Aged Rats.

Persistent neuronal firing is often observed in working memory and temporal association tasks both in humans and animals, and is believed to retain necessary information in these tasks. We have reported that hippocampal CA1 pyramidal cells are able to support persistent firing through intrinsic mechanisms in the presence of cholinergic agonists. However, it still remains largely unknown how persistent firing is affected by the development of animals and aging. Using in vitro patch-clamp recordings from CA1 pyramidal cells in rat brain slices, we first show that the cellular excitability of these aged rats was significantly lower than the young rats, responding with fewer spikes to current injection. In addition, we found age-dependent modulations of input resistance, membrane capacitance, and spike width. However, persistent firing in aged (~2 years old) rats was as strong as that in young animals, and the properties of persistent firing were very similar among different age groups. In addition, spike after-hyperpolarization potential (AHP), was not increased by aging and did not correlate with the strength of persistent firing. Lastly, we estimated the depolarization current induced by the cholinergic activation. This current was proportional to the increased membrane capacitance of the aged group and was inversely correlated with the intrinsic excitability of cells. These observations indicate that robust persistent firing can be maintained in aged rats despite reduced excitability, due to the increased amount of cholinergically induced positive current.Significant statement:In an aging society, it is crucial to understand neural mechanisms underlying age-dependent cognitive impairments. In recent years, the importance of intrinsic cellular properties in cognitive functions such as memory has increasingly been recognized. However, research examining age-dependent alteration of intrinsic cellular mechanisms of persistent firing, which is believed to support working memory function, has so far been very scarce. In this study, we demonstrate that the ability to support persistent firing is kept intact in neurons from old rats, despite changes in other properties such as intrinsic excitability. These results identify the ability to support persistent firing as one potential cellular mechanism of rescued cognitive functions under cholinergic enhancement used in Alzheimer's disease and other dementias.

A NETWORK PHARMACOLOGICAL INVESTIGATION INTO THE TREATMENT OF PERIMENOPAUSAL DEPRESSION WITH A WARMING AND TONIFYING KIDNEY-YANG RECIPE

We examine the mechanism of warming and tonifying kidney-yang recipe (WTKYR) in treating perimenopausal depression (PMD) using a network pharmacological approach. We identified the active ingredients and targets of WTKYR using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. PMD targets were extracted from the Online Mendelian Inheritance in Man (OMIM), DisGeNET, and GeneCards databases. Venn diagrams were created with Venny to identify common WTKYR and PMD targets. A network diagram of WTKYR targets in PMD was created with Cytoscape to examine its core active ingredients. A protein–protein interaction (PPI) network of WTKYR’s targets was constructed using the STRING database, and its primary targets were evaluated using Network Analyzer and MCODE. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of essential WTKYR target genes were performed with Bioconductor. The LibDock program was applied to molecularly dock the core active ingredients of the WTKYR and the critical targets of PMD. The core WTKYR components for PMD identified were as oleic acid, beta-sitosterol, and phytodolor. The core WTKYR targets identified were the Jun proto-oncogene AP-1 transcription factor subunit (JUN), peroxisome proliferator-activated receptor gamma (PPARG), brain-derived neurotrophic factor (BDNF), caspase 3 (CASP3), and estrogen receptor 1 (ESR1) proteins and the neurotrophin, estrogen, serotonergic synapse, and cyclic adenosine monophosphate (cAMP) signaling pathways. The primary functions of these pathways include extensive neuroprotective and regenerative effects, regulation of 5-hydroxytryptamine (5-HT) metabolism, and participation in regulating the physiological functions of endogenous substances. These improve synaptic sensitivity, promote neuronal cell excitability, and enhance persistent firing in the medial and lateral entorhinal cortex. Molecular docking results show good affinity between the core active ingredients of WTKYR and the critical targets of PMD. This study predicted the essential WTKYR components and its primary targets and pathways for PMD treatment, and found that improving synaptic plasticity, participating in neuroelectrophysiological processes, and regulating related signaling pathways enhance PMD, which require confirmation by future cell or animal validation experiments.

Spike Afterhyperpolarizations Govern Persistent Firing Dynamics in Rat Neocortical and Hippocampal Pyramidal Cells.

Persistent firing is commonly reported in both cortical and subcortical neurons under a variety of behavioral conditions. Yet the mechanisms responsible for persistent activity are only partially resolved with support for both intrinsic and synaptic circuit-based mechanisms. Little also is known about physiological factors that enable epochs of persistent firing to continue beyond brief pauses and then spontaneously terminate. In the present study, we used intracellular recordings in rat (both sexes) neocortical and hippocampal brain slices to assess the ionic mechanisms underlying persistent firing dynamics. Previously, we showed that blockade of ether-á-go-go-related gene (ERG) potassium channels abolished intrinsic persistent firing in the presence of low concentrations of muscarinic receptor agonists and following optogenetic activation of cholinergic axons. Here we show the slow dynamics of ERG conductance changes allows persistent firing to outlast the triggering stimulus and even to initiate discharges following ∼7 s poststimulus firing pauses. We find that persistent firing dynamics is regulated by the interaction between ERG conductance and spike afterhyperpolarizations (AHPs). Increasing the amplitude of spike AHPs using either SK channel activators or a closed-loop reactive feedback system allows persistent discharges to spontaneously terminate in both neocortical neurons and hippocampal CA1 pyramidal cells. The interplay between ERG and the potassium channels that mediate spike AHPs grades the duration of persistent firing, providing a novel, generalizable mechanism to explain self-terminating persistent firing modes observed behaving animals.SIGNIFICANCE STATEMENT Many classes of neurons generate prolonged spiking responses to transient stimuli. These discharges often outlast the stimulus by seconds to minutes in some in vitro models of persistent firing. While recent work has identified key synaptic and intrinsic components that enable persistent spiking responses, less is known about mechanisms that can terminate and regulate the dynamics of these responses. The present study identified the spike afterhyperpolarizations as a potent mechanism that regulates the duration of persistent firing. We found that amplifying spike afterpotentials converted bistable persistent firing into self-terminating discharges. Varying the spike AHP amplitude grades the duration of persistent discharges, generating in vitro responses that mimic firing modes associated with neurons associated with short-term memory function.

P477. Anatomical Evaluation of Calcium-Related Schizophrenia Risk Genes in Rhesus Macaque Dorsolateral Prefrontal Cortex

The dorsolateral prefrontal cortex (dlPFC) mediates high-order cognition, and is profoundly afflicted in schizophrenia, including loss of dendritic spines from deep layer III, the microcircuits that generate persistent firing needed for working memory. Studies in monkeys show that these dendritic spines contain the molecular machinery for cAMP to magnify internal calcium release, where moderate levels sustain neuronal firing, but high levels weaken connectivity via opening nearby potassium channels. Genetic studies have linked schizophrenia risk with gain of function alterations in the Cav1.2 calcium channel encoded by CACNA1C, and a duplication in VIPR2, which increases cAMP intracellular signaling. The current research examined the localization of these key signaling proteins in layer III of the rhesus monkey dlPFC.

Persistent neuronal firing in the medial temporal lobe supports performance and workload of visual working memory in humans

The involvement of the medial temporal lobe (MTL) in working memory is controversially discussed. Recent findings suggest that persistent neural firing in the hippocampus during maintenance in verbal working memory is associated with workload. Here, we recorded single neuron firing in 13 epilepsy patients (7 male) while they performed a visual working memory task. The number of colored squares in the stimulus set determined the workload of the trial. Performance was almost perfect for low workload (1 and 2 squares) and dropped at high workload (4 and 6 squares), suggesting that high workload exceeded working memory capacity. We identified maintenance neurons in MTL neurons that showed persistent firing during the maintenance period. More maintenance neurons were found in the hippocampus for trials with correct compared to incorrect performance. Maintenance neurons increased and decreased firing in the hippocampus and increased firing in the entorhinal cortex for high compared to low workload. Population firing predicted workload particularly during the maintenance period. Prediction accuracy of workload based on single-trial activity during maintenance was strongest for neurons in the entorhinal cortex and hippocampus. The data suggest that persistent neural firing in the MTL reflects a domain-general process of maintenance supporting performance and workload of multiple items in working memory below and beyond working memory capacity. Persistent neural firing during maintenance in the entorhinal cortex may be associated with its preference to process visual-spatial arrays.

Aging-Related Alterations to Persistent Firing in the Lateral Entorhinal Cortex Contribute to Deficits in Temporal Associative Memory.

With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.

Target-specific control of olfactory bulb periglomerular cells by GABAergic and cholinergic basal forebrain inputs.

The olfactory bulb (OB), the first relay for odor processing in the brain, receives dense GABAergic and cholinergic long-range projections from basal forebrain (BF) nuclei that provide information about the internal state and behavioral context of the animal. However, the targets, impact, and dynamic of these afferents are still unclear. How BF synaptic inputs modulate activity in diverse subtypes of periglomerular (PG) interneurons using optogenetic stimulation and loose cell-attached or whole-cell patch-clamp recording in OB slices from adult mice were studied in this article. GABAergic BF inputs potently blocked PG cells firing except in a minority of calretinin-expressing cells in which GABA release elicited spiking. Parallel cholinergic projections excited a previously overlooked PG cell subtype via synaptic activation of M1 muscarinic receptors. Low-frequency stimulation of the cholinergic axons drove persistent firing in these PG cells, thereby increasing tonic inhibition in principal neurons. Taken together, these findings suggest that modality-specific BF inputs can orchestrate synaptic inhibition in OB glomeruli using multiple, potentially independent, inhibitory or excitatory target-specific pathways.

Focused Neuroregulation in the Treatment and Prevention of Mental and Physical Illness

Despite the enormous strides that have been made in neuroscience, the pathophysiology of psychiatric disorders remains unclear. Consequently, various forms of psychotherapy, pharmacotherapy, and neuromodulatory therapy continue to be applied without a clear understanding of what pathological process is being treated. However, an emerging hypothesis contends that psychiatric symptoms are the consequence of pathological hyperactivity in symptom-related circuits in the brain. According to the Multi-Circuit Neuronal Hyperexcitability (MCNH) Hypothesis of Psychiatric Disorders, persistent firing in anxiety circuits causes persistent feelings of anxiety; persistent firing in depressive circuits causes persistent feelings of depression; persistent firing in cognitive circuits causes ruminative and obsessive thoughts; etc… This pathological circuit-specific hyperactivity is believed to be caused by an inherent failure of the neurological system to self-regulate when perturbed by a psychological, emotional, or biological stressor. Based on this hypothesis, it would not be unreasonable to think that psychiatric symptoms, irrespective of which disorder was being treated, would respond favorably to any natural or medicinal intervention that reduces the excitability of the neurological system. Although the use of brain-calming drugs in psychiatry is not new, what is new is the idea of focusing their use on correcting a specific physiological abnormality that is believed to underlie the symptoms. This technique, which could be called “Focused Neuroregulation,” would differ from standard pharmacotherapy in that if one anticonvulsant failed to alleviate or only partially alleviated symptoms, another anticonvulsant would be substituted or added rather than turning to an off-target class of drugs. This approach is clinically valid because each anticonvulsant is structurally different, and there are multiple mechanisms (and receptors) through which the excitability of the neurological system can be therapeutically regulated. Also, anticonvulsants, unlike other classes of psychotropic drugs, tend to bring the system back into balance; hence the term “mood stabilizers.” Yet another benefit of Focused Neuroregulation is that it could help prevent or slow the progression of the many chronic health conditions that have been linked to an inherent hyperexcitability of the neurological system. In recognition of these potential benefits, and in an effort to avoid the many problems that are associated with the symptom-based treatment of psychiatric and related functional symptoms, the aim of this article is to incentivize the study of a more targeted approach to the treatment of mental illness and the prevention of chronic disease.

New Hypothesis on the Pathophysiology of Psychiatric Disorders Illuminates Shared Mechanism of Past and Emergent Treatment Strategies

Although psychotherapy and pharmacotherapy continue to be first-line treatments for a wide range of mental and emotional disorders, a high percentage of patients are ultimately considered to be treatment-resistant. For more than half a century, electroconvulsive therapy had been the gold-standard for such patients. However, in recent years a variety of alternative treatment modalities have been developed for these patients, including deep brain stimulation, vagus nerve stimulation, repetitive transcranial magnetic stimulation, stellate ganglion block, and sub-anesthetic doses of the dissociative drug ketamine. Although these alternative treatments have offered new hope for many patients, there is a great deal of individual variability in their degree of effectiveness, and their mechanisms of action, like standard treatments, remain unclear. However, an emerging hypothesis contends that psychiatric symptoms are driven by pathological hyperactivity in symptom-related circuits in the brain. According to the Multi-Circuit Neuronal Hyperexcitability (MCNH) Hypothesis of Psychiatric Disorders, persistent firing in anxiety circuits causes persistent feelings of anxiety; persistent firing in depressive circuits causes persistent feelings of depression; persistent firing in cognitive circuits causes ruminative and obsessive thoughts; etc... The aim of this review is twofold: the first is to discuss the new hypothesis in relation to the aforementioned treatment strategies; and the second is to tease out the shared neurophysiological effects of past and present treatment strategies to determine whether they support or refute the new hypothesis. Clarifying the cause of mental illness is of critical importance to curbing the escalating mental health crisis, as new medications and emergent treatment strategies are failing to keep up with the steady rise in domestic disputes, suicides, homicides, and mass shootings that are driving the disintegration of individuals, families, and communities.