Mihaly Hajós

Yale University | YU · Section of Comparative Medicine

Background The OVERTURE I (NCT03556280) randomized controlled trial (RCT) evaluated Cognito’s non‐invasive device (SpectrisTM) in mild‐moderate Alzheimer’s disease (AD). Composite measures, such as combined statistical tests (CSTs) and iADRS, combine the joint evolution of function and cognition over time in the population of interest when calculat...

Background The OVERTURE (NCT03556280) randomized controlled trial (RCT) evaluated evoked gamma oscillation therapy using Cognito’s medical device (CogTx‐001) in mild‐moderate Alzheimer’s disease (AD). Brain atrophy, as measured by whole brain volume (WBV), is a key indicator of neurodegeneration in AD¹ and may be influenced by baseline covariates s...

Background Recent research by Da et al. (2023) has demonstrated that non‐invasive gamma sensory stimulation can reduce brain white matter atrophy and myelin content loss. The impact on the Corpus Callosum (CC), the brain's largest commissural white matter tract essential for hemispheric connectivity, remains unexplored. Diffusion Tensor Imaging (DT...

Background Preclinical investigations in Alzheimer’s disease (AD) have highlighted the efficacy of gamma sensory stimulation in mitigating AD‐related pathologies. Cognito Therapeutics, Inc. (Cambridge, MA) has designed the Sensory Stimulation System for safe at‐home usage, to induce EEG‐confirmed gamma oscillations as a potential treatment for AD....

Objective To examine the impact of 40Hz gamma stimulation on the preservation of the corpus callosum, a critical structure for interhemispheric connectivity, in people with mild cognitive impairment or Alzheimer's disease. Methods OVERTURE (NCT03556280) participants were randomized 2:1 (Active:Sham) to receive daily, 1-h, 40Hz gamma sensory stimul...

The most common approach for estimating the spatial resolution of PET images in multi-center studies typically uses Hoffman phantom data as a surrogate. Specifically, the phantom-based matching resolution approach assumes that scanned phantom PET images are well approximated by a ground truth, noise-free digital phantom convolved with a Gaussian ke...

Many coronavirus disease 2019 (COVID‐19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting “brain fog” and mild cognitive impairments even months after the acute phase of infection. Resting‐state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An exp...

Background Alzheimer’s Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito’s Evoked Gamma Therapy System provides an innovative approach for AD by...

Background Developing safe and disease modifying therapies for Alzheimer’s disease (AD) is still challenging, in spite of recent advancements in the understanding of AD pathophysiology. A fundamentally different therapeutic approach under development at Cognito Therapeutics targets abnormal neuronal activities using the company’s Gamma Sensory Stim...

Background Previous research has shown that white matter (WM) and gray matter (GM) tissues exhibit regionally selective pathological changes in Alzheimer’s disease (AD). The contrast between WM and GM signal intensities (WM/GM contrast) measured by magnetic resonance imaging (MRI) has previously been proposed as a method for quantifying these chang...

Background Although morphometric changes in Alzheimer’s Disease (AD) occur both in gray and white matter, gray matter changes had been the primary focus of previous work. Recent studies have highlighted the importance of pathological changes in white matter and myelination in AD patients, including early changes to oligodendrocytes and transcriptio...

Background In three prospective clinical trials (Overture: NCT03556280, Etude: NCT03661034, Flicker: NCT03543878) non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation diminished Alzheimer’s disease (AD) symptoms, including a reduction in decline in cognitive and functional symptoms. These trials initiated the design of the Cognito Th...

Background: Patients with Alzheimer’s disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. Objective: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matt...

The α7 nicotinic acetylcholine receptor is a calcium permeable, ligand-gated ion channel that modulates synaptic transmission in the hippocampus, thalamus, and cerebral cortex. Previously disclosed work described PNU-120596 that acts as a powerful positive allosteric modulator of the α7 nicotinic acetylcholine receptor. The initial structure-activi...

Recent experimental findings demonstrate that sensory‐evoked brain gamma oscillation reduces Alzheimer’s disease (AD) pathologies in AD‐related transgenic mice, including decline in synaptic function, neurodegeneration, and brain atrophy (Adaikkan & Tsai, Trends Neurosci. 2020;43:24‐41). Based on these findings, gamma‐frequency sensory stimulation...

Abnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to th...

Although white matter atrophy is observed in normal aging, it is more pronounced in Alzheimer’s Disease (AD) patients. Recently, advanced magnetic resonance imaging (MRI) provided more detailed information which linked changes in white matter to elevated risk and progression of AD. White matter degeneration, myelin loss, and oligodendrocyte damage...

Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Ad...

Background Non‐invasive gamma sensory stimulation has been demonstrated to have beneficial effects on the hallmarks of AD pathophysiology in transgenic mouse models of AD. The Etude clinical trial is a translational clinical study examining dose‐ranging, safety, tolerability, and potential benefits of gamma sensory stimulation as a novel, non‐invas...

Background Alzheimer’s disease (AD) patients exhibit distorted excitatory‐inhibitory balance of neuronal activity, leading to accelerated worsening of functional and cognitive abilities. Improving abnormal neuronal synchrony by long‐term non‐invasive, gamma sensory stimulation at 40 Hz in transgenic mice carrying pathological AD human genes has bee...

Background Daily, at‐home gamma sensory stimulation consisting of EEG‐calibrated auditory and visual stimuli is a new therapeutic approach for the treatment of Alzheimer’s Disease (AD). Based on experimental studies demonstrating that sensory‐evoked gamma oscillation halts or reverses AD‐related pathology, improves cognitive function, and normalize...

Background Preclinical studies in transgenic mice demonstrated that sub‐chronic 40 Hz gamma sensory stimulation effectively halted or reversed AD‐related pathology, increased synaptic density, improved cognitive function, and normalized circadian rhythm. The OVERTURE clinical trial (NCT03556280), funded by Cognito Therapeutics Inc., is a 2‐to‐1 ran...

Background Non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation demonstrates clearance of β‐amyloid plaques and tau tangles, and cognition improvement in preclinical AD models (Iaccarino, 2016, Martorell, 2019). A home‐use gamma sensory stimulation device (Cognito Therapeutics, Inc., Cambridge, MA) was developed to evoke gamma oscill...

Background Accelerated brain atrophy, correlating with cognitive decline and loss of function in Alzheimer’s disease (AD) patients compared to age‐matched healthy subjects is well established. Since recent experimental findings demonstrated that sensory‐evoked brain gamma oscillation reduces brain atrophy and neurodegeneration in AD‐related transge...

Background: Loss of function mutations in gene encoding triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with the risk of developing Alzheimer's disease (AD) and other progressive dementias. In the brain, TREM2 is specifically expressed on microglia suggesting their active involvement in driving disease pathol...

Pathological proteins contributing to Alzheimer’s disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis o...

Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using...

Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer’s disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical sp...

The development of the next generation therapy for Alzheimer’s disease (AD) presents a huge challenge given the number of promising treatment candidates that failed in trials, despite recent advancements in understanding of genetic, pathophysiologic and clinical characteristics of the disease. This review reflects some of the most current concepts...

Significance It is of great importance to elucidate mechanisms underlying the loss or dysfunction of synapses in neurological diseases. The concept that reduced functional synapses in disease reflect aberrant reactivation of pathways mediating synapse elimination in development has yielded candidate mechanisms. Here, we elucidate a role of the cyto...

Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. Here, we present the first syste...

Background Previous work has shown that sleep abnormalities are associated with Alzheimer’s Disease (AD) in multiple ways, including the observation that sleep disruptions precede the onset of cognitive symptoms in AD subjects, and that there is a strong association between disrupted sleep and development and progression of AD (Ju et al, Nat Rev Ne...

Background As a potential neurophysiology‐based biomarker of cortical neuronal network integrity, visually evoked steady‐state oscillations (SSVEPs) are investigated in healthy young and elderly subjects, and mild cognitive impaired (MCI) and Alzheimer’s disease (AD) patients. Based on recent findings from the Li‐Huei Tsai Laboratory (Picower Insti...

Selective activation of dopamine D1 receptors remains a promising pro-cognitive therapeutic strategy awaiting robust clinical investigation. PF-6142 is a key example from a recently disclosed novel series of non-catechol agonists and partial agonists of the dopamine D1/5 receptors (D1R) that exhibit pharmacokinetic (PK) properties suitable for oral...

The brain has evolved in an environment where food sources are scarce and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity/overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences...

Background: Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. Methods: The chronological emergence of neurophysi...

Enhancing remyelination is a key therapeutic strategy for demyelinating diseases such as multiple sclerosis. To achieve this goal, a central challenge is being able to quantitatively and longitudinally track functional remyelination, especially with translatable biomarkers that can be performed in both preclinical models and in the clinic. We devel...

Current findings suggest that accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain disrupt synaptic function in hippocampal-cortical neuronal networks leading to impairment in cognitive and affective functions in Alzheimer's disease (AD). Development of new disease-modifying AD drugs are challenging due to the lack of predictive...

Background Translational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cogni...

Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory ga...

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a pre-clinical candidate targeting cognitive impairment associated with schiz...

Background: Currently available therapies for Alzheimer’s disease (AD) have limited efficacy and do not affect disease progression, while development of new drugs with disease-modifying potential has proven a challenge due to the lack of highly predictive animal models and assays. Objective: In the present study we studied neural network activity i...

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. In order to more fully explore the biology of PDE2A inhibition we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calcula...

Activation of α7 nAChRs has been shown to improve performance in a variety of nonclinical assays of cognitive function. The role of α7 nAChRs in cognitive processes is likely related to their role in modulating synaptic transmission and plasticity that have been reported in cell culture, brain slices, and intact animals. Here we report the effects...

Despite the vast amount of research on schizophrenia and depression in the past two decades, there have been few innovative drugs to treat these disorders. Precompetitive research collaborations between companies and academic groups can help tackle this innovation deficit, as illustrated by the achievements of the IMI-NEWMEDS consortium.

Neural α7 nicotinic acetylcholine receptors (α7 nAChRs) emerged as a potential pharmacologic target for treating cognitive deficits in schizophrenia and Alzheimer's disease. Experiments modeling these dysfunctions, as well as clinical evidence, demonstrate the relatively consistent procognitive effects of α7 nAChR agonists. One preclinical observat...

Amyloid-β (Aβ) peptide overproduction is one of the pathomechanisms contributing to Alzheimer’s disease (AD). Agonists of α7 nicotinic acetylcholine receptors (α7 nAChRs) are under development as symptomatic treatments for AD, and clinical findings suggest that α7 nAChR agonists may improve cognitive functions in AD patients. However, interactions...

Background/purpose: Major psychiatric illnesses, affecting 36% of the world's population, are profound disorders of thought, mood and behavior associated with underlying impairments in synaptic plasticity and cellular resilience. Mitochondria support energy demanding processes like neural transmission and synaptogenesis and are thus points of broa...

Raw data for elevated plus maze and light/dark box figures.DOI: http://dx.doi.org/10.7554/eLife.14120.011

Raw data for fear-potentiated startle and Vogel conflict test figures.DOI: http://dx.doi.org/10.7554/eLife.14120.015

Raw data for peak frequency and stimulation intensity – peak frequency slope figures.DOI: http://dx.doi.org/10.7554/eLife.14120.019

ELife digest Fear and anxiety can be thought of as different but related emotional states. Fear is triggered by specific harmful situations, such as the immediate presence of a predator. Anxiety instead results from the possibility of an obscure threat, such as being in an exposed environment, which increases the chance of being detected by a preda...

Evidence has accumulated over the past several decades suggesting that both exo- and endocannabinoids play a role in the pathophysiology of schizophrenia (SZ). The current paper presents evidence suggesting that one of the mechanisms whereby cannabinoids induce psychosis is through the alteration in synchronized neural oscillations. Neural oscillat...

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotrans...

Development of neurofibrillary tangles in Alzheimer's disease correlates with neuronal loss and dementia. Transgenic Tg4510 mice model the tauopathy of the disease, with these mice exhibiting progressive, region-specific neuronal loss, and behavioral deficits. In the present study, neuronal network activity in the hippocampus of 7-month-old Tg4510...

Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this...

Synchronization of neuronal network oscillations within the cortex and hippocampus has been closely linked to various cognitive domains, including attention, learning, and memory. The frequency, power, and connectivity of hippocampal oscillations provide quantitative measures for examining the modulation of network activity, which influences mnemon...

Pharmacological activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on α7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to...

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a confo...

Schizophrenia patients have cognitive deficits and associated functional impairments. Previous clinical and preclinical studies have validated the rationale for α7 nicotinic acetylcholine receptor (α7R) agonists as a procognitive treatment strategy across CNS disorders. We recently reported that Encenicline-an α7R partial agonist-elicits physiologi...

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA recept...

Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the iden...

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) positive allosteric modulation (i.e. "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator's mechanism-based therapeutic index (TI) and to d...

The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease a...

Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. One of the main obstacles is the poor predictive validity of our preclinical animal models. In the present study the effects of the γ-secretase inh...

Subanesthetic doses of the psychomimetic, ketamine, have been used for many years to elicit behavioral effects reminiscent of schizophrenia in both healthy humans and in animal models of the disease. More recently, there has been a move toward the use of simple neurophysiological measures (event-related potentials, brain oscillations) to assay the...

N-Methyl-D-aspartate receptor (NMDAR) antagonists mimic several symptoms of schizophrenia in healthy subjects, and are used in preclinical disease models. In the present study, the impact of pharmacologically and genetically induced NMDAR hypofunction was assessed in rats and mice, including the NMDAR hypomorphic (Grin1) mice, with respect to neuro...