EEG biomarkers of target engagement, therapeutic effect, and disease process

Featherstone, Robert E.; McMullen, Mary F.; Ward, Katelyn; Bang, Jakyung; Xiao, Jane; Siegel, Steven J.

doi:10.1111/nyas.12745

Cited by 32 publications

(52 citation statements)

References 162 publications

(381 reference statements)

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“…Importantly, EEG can be similarly measured in both rodents and humans, and thus EEG phenotypes have realistic translational relevance [33]. Our EEG findings contrast to some degree with the clinical picture of patients with SHANK3 mutations, as some patients with loss of function SHANK3 mutations have epilepsy and 67% have some EEG abnormality [31].…”

Section: Discussionmentioning

confidence: 99%

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Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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BackgroundAutism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice.MethodsIn vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays.ResultsRelative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory.ConclusionsRobust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong...

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Section: Discussionmentioning

confidence: 99%

“…Importantly, EEG can be similarly measured in both rodent models and in human patients and thus EEG phenotypes have great translational relevance [33]. To evaluate the utility of EEG as a quantitative biomarker, we characterized seizure propensity and oscillatory activity in the Shank3B mutant mice.…”

Section: Introductionmentioning

confidence: 99%

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

et al. 2017

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“…Finally, aberrant neurophysiology related to SZ assessed with EEG is being sought to inform the development of novel therapeutic interventions including identifying changes in oscillatory frequencies such as increased resting state gamma oscillations 76. More work needs to be done to determine if increased resting state gamma oscillations: (1) can be consistently identified in SZ; (2) can be localised to deep brain structures within specific circuitry (measured by both LFP and EEG simultaneously to assess coherence and synchrony); (3) can be associated with specific symptoms; and (4) can be normalised in response to effective therapy.…”

Section: Methodsmentioning

confidence: 99%

Approaches to neuromodulation for schizophrenia

Gault

Davis

Cascella

et al. 2017

J Neurol Neurosurg Psychiatry

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Based on the success of deep brain stimulation (DBS) for treating movement disorders, there is growing interest in using DBS to treat schizophrenia (SZ). we review the unmet needs of patients with SZ and the scientific rationale behind the DBS targets proposed in the literature in order to guide future development of DBS to treat this vulnerable patient population. SZ remains a devastating disorder despite treatment. Relapse, untreated psychosis, intolerable side effects and the lack of effective treatment for negative and cognitive symptoms contribute to poor outcome. Novel therapeutic interventions are needed to treat SZ and DBS is emerging as a potential intervention. Convergent genetic, pharmacological and neuroimaging evidence implicating neuropathology associated with psychosis is consistent with SZ being a circuit disorder amenable to striatal modulation with DBS. Many of the DBS targets proposed in the literature may modulate striatal dysregulation. Additional targets are considered for treating tardive dyskinesia and negative and cognitive symptoms. A need is identified for the concurrent development of neurophysiological biomarkers relevant to SZ pathology in order to inform DBS targeting. Finally, we discuss the current clinical trials of DBS for SZ, and their ethical considerations. we conclude that patients with severe symptoms despite treatment must have the capacity to consent for a DBS clinical trial in which risks can be estimated, but benefit is not known. in addition, psychiatric populations should have access to the potential benefits of neurosurgical advances. CurreNT sTATe of TreATmeNT for sChizophreNiA► Schizophrenia (SZ) remains a devastating disorder despite antipsychotic, psychological and social treatments.

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“…EEG adaptation for rodent models of disease however, first requires prior knowledge of the EEG response dynamics in clinical populations (Featherstone et al, 2015; Gandal et al, 2010). In humans, the extended-sessions 5C-CPT is adapted for EEG studies.…”

Section: Adaptationsmentioning

confidence: 99%

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

Bhakta

Young

2017

Journal of Neuroscience Methods

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Background Neurodevelopmental disorders including Tourette’s syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are characterized by significant impairment in attention and cognitive control. These cognitive deficits persist throughout development, contribute significantly to socio-occupational impairment, and are relatively impervious to available treatment. A critical challenge in pro-cognitive drug discovery is translatability of findings across species, underscoring the need for developing valid and reliable cross-species cognitive tasks. New Method Here we describe a cross-species 5 choice continuous performance task that was developed to measure cognitive control processes of attention, vigilance, and response inhibition, enabling the translation of findings for pro-cognitive drug discovery across species and delineate neural mechanisms underlying cognitive control construct. Results Construct validity of 5C-CPT has been verified by multiple cross-species studies. Several lines of evidence report consistent findings across species including, deficits resulting from 36-hour sleep deprivation studies, engagement of parietal cortex in human brain imaging and rodent lesion studies, and vigilance decrements over time. Comparison with existing method Unlike the widely used rodent 5 choice serial reaction time task (5CSRTT) and the sustained attention task (SAT), the rodent 5C-CPT includes both target and non-target stimuli that allow measuring of cognitive control elements including response inhibition, an ability to inhibit pre-potent response during non-target trials, detect vigilance decrement and calculate signal detection parameters in rodents analogous to human CPT. Conclusion The cross-species 5C-CPT is a robust translational tool to characterize the neurobiological substrates underlying cognitive control deficits in clinical population including, ADHD and TS and develop targeted pro-cognitive therapeutics.

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EEG biomarkers of target engagement, therapeutic effect, and disease process

Cited by 32 publications

References 162 publications

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism

Approaches to neuromodulation for schizophrenia

The 5 choice continuous performance test (5C-CPT): A novel tool to assess cognitive control across species

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