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Article ; Online: Alcohol withdrawal produces changes in excitability, population discharge probability, and seizure threshold.

Alberto, Gregory E / Klorig, David C / Goldstein, Allison T / Godwin, Dwayne W

Alcohol, clinical & experimental research

2023 Volume 47, Issue 2, Page(s) 211–218

Abstract: Background: Alcohol withdrawal syndrome (AWS) results from the sudden cessation of chronic alcohol use and is associated with high morbidity and mortality. Alcohol withdrawal-induced central nervous system (CNS) hyperexcitability results from complex, ... ...

Abstract	Background: Alcohol withdrawal syndrome (AWS) results from the sudden cessation of chronic alcohol use and is associated with high morbidity and mortality. Alcohol withdrawal-induced central nervous system (CNS) hyperexcitability results from complex, compensatory changes in synaptic efficacy and intrinsic excitability. These changes in excitability counteract the depressing effects of chronic ethanol on neural transmission and underlie symptoms of AWS, which range from mild anxiety to seizures and death. The development of targeted pharmacotherapies for treating AWS has been slow, due in part to the lack of available animal models that capture the key features of human AWS. Using a unique optogenetic method of probing network excitability, we examined electrophysiologic correlates of hyperexcitability sensitive to early changes in CNS excitability. This method is sensitive to pharmacologic treatments that reduce excitability and may represent a platform for AWS drug development. Methods: We applied a newly developed method, the optogenetic population discharge threshold (oPDT), which uses light intensity response curves to measure network excitability in chronically implanted mice. Excitability was tracked using the oPDT before, during, and after the chronic intermittent exposure (CIE) model of alcohol withdrawal (WD). Results: Alcohol withdrawal produced a dose-dependent leftward shift in the oPDT curve (denoting increased excitability), which was detectable in as few as three exposure cycles. This shift in excitability mirrored an increase in the number of spontaneous interictal spikes during withdrawal. In addition, Withdrawal lowered seizure thresholds and increased seizure severity in optogenetically kindled mice. Conclusion: We demonstrate that the oPDT provides a sensitive measure of alcohol withdrawal-induced hyperexcitability. The ability to actively probe the progression of excitability without eliciting potentially confounding seizures promises to be a useful tool in the preclinical development of next-generation pharmacotherapies for AWS.
MeSH term(s)	Humans ; Mice ; Animals ; Substance Withdrawal Syndrome/complications ; Alcoholism/complications ; Patient Discharge ; Ethanol/adverse effects ; Seizures/chemically induced ; Alcohol Withdrawal Seizures/complications
Chemical Substances	Ethanol (3K9958V90M)
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2993-7175
ISSN (online)	2993-7175
DOI	10.1111/acer.15004
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Article ; Online: Contextual Effects of Traumatic Brain Injury on the Connectome: Differential Effects of Deployment- and Non-Deployment-Acquired Injuries.

Rowland, Jared A / Stapleton-Kotloski, Jennifer R / Rogers, Emily / Taber, Katherine H / Godwin, Dwayne W / Martindale, Sarah L

The Journal of head trauma rehabilitation

2022 Volume 37, Issue 6, Page(s) E449–E457

Abstract: Objective: To identify differential effects of mild traumatic brain injury (TBI) occurring in a deployment or nondeployment setting on the functional brain connectome.: Setting: Veterans Affairs Medical Center.: Participants: In total, 181 combat- ... ...

Abstract	Objective: To identify differential effects of mild traumatic brain injury (TBI) occurring in a deployment or nondeployment setting on the functional brain connectome. Setting: Veterans Affairs Medical Center. Participants: In total, 181 combat-exposed veterans of the wars in Iraq and Afghanistan ( n = 74 with deployment-related mild TBI, average time since injury = 11.0 years, SD = 4.1). Design: Cross-sectional observational study. Main measures: Mid-Atlantic MIRECC (Mid-Atlantic Mental Illness Research, Education, and Clinical Center) Assessment of TBI, Clinician-Administered PTSD Scale, connectome metrics. Results: Linear regression adjusting for relevant covariates demonstrates a significant ( P < .05 corrected) association between deployment mild TBI with reduced global efficiency (nonstandardized β = -.011) and degree of the K-core (nonstandardized β = -.79). Nondeployment mild TBI was significantly associated with a reduced number of modules within the connectome (nonstandardized β = -2.32). Finally, the interaction between deployment and nondeployment mild TBIs was significantly ( P < .05 corrected) associated with increased mean (nonstandardized β = 9.92) and mode (nonstandardized β = 14.02) frequency at which connections occur. Conclusions: These results demonstrate distinct effects of mild TBI on the functional brain connectome when sustained in a deployment versus nondeployment context. This is consistent with findings demonstrating differential effects in other areas such as psychiatric diagnoses and severity, pain, sleep, and cognitive function. Furthermore, participants were an average of 11 years postinjury, suggesting these represent chronic effects of the injury. Overall, these findings add to the growing body of evidence, suggesting the effects of mild TBI acquired during deployment are different and potentially longer lasting than those of mild TBI acquired in a nondeployment context.
MeSH term(s)	Humans ; Iraq War, 2003-2011 ; Connectome ; Cross-Sectional Studies ; Brain Injuries, Traumatic/diagnostic imaging ; Brain Injuries, Traumatic/psychology ; Veterans/psychology ; Brain Concussion/diagnostic imaging ; Stress Disorders, Post-Traumatic/psychology ; Afghan Campaign 2001-
Language	English
Publishing date	2022-07-20
Publishing country	United States
Document type	Observational Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639221-0
ISSN	1550-509X ; 0885-9701
ISSN (online)	1550-509X
ISSN	0885-9701
DOI	10.1097/HTR.0000000000000803
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Zs.A 2278: Show issues

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Article: Use of magnetic source imaging to assess recovery after severe traumatic brain injury-an MEG pilot study.

Sarma, Anand Karthik / Popli, Gautam / Anzalone, Anthony / Contillo, Nicholas / Cornell, Cassandra / Nunn, Andrew M / Rowland, Jared A / Godwin, Dwayne W / Flashman, Laura A / Couture, Daniel / Stapleton-Kotloski, Jennifer R

Frontiers in neurology

2023 Volume 14, Page(s) 1257886

Abstract: Rationale: Severe TBI (sTBI) is a devastating neurological injury that comprises a significant global trauma burden. Early comprehensive neurocritical care and rehabilitation improve outcomes for such patients, although better diagnostic and prognostic ... ...

Abstract	Rationale: Severe TBI (sTBI) is a devastating neurological injury that comprises a significant global trauma burden. Early comprehensive neurocritical care and rehabilitation improve outcomes for such patients, although better diagnostic and prognostic tools are necessary to guide personalized treatment plans. Methods: In this study, we explored the feasibility of conducting resting state magnetoencephalography (MEG) in a case series of sTBI patients acutely after injury (~7 days), and then about 1.5 and 8 months after injury. Synthetic aperture magnetometry (SAM) was utilized to localize source power in the canonical frequency bands of delta, theta, alpha, beta, and gamma, as well as DC-80 Hz. Results: At the first scan, SAM source maps revealed zones of hypofunction, islands of preserved activity, and hemispheric asymmetry across bandwidths, with markedly reduced power on the side of injury for each patient. GCS scores improved at scan 2 and by scan 3 the patients were ambulatory. The SAM maps for scans 2 and 3 varied, with most patients showing increasing power over time, especially in gamma, but a continued reduction in power in damaged areas and hemispheric asymmetry and/or relative diminishment in power at the site of injury. At the group level for scan 1, there was a large excess of neural generators operating within the delta band relative to control participants, while the number of neural generators for beta and gamma were significantly reduced. At scan 2 there was increased beta power relative to controls. At scan 3 there was increased group-wise delta power in comparison to controls. Conclusion: In summary, this pilot study shows that MEG can be safely used to monitor and track the recovery of brain function in patients with severe TBI as well as to identify patient-specific regions of decreased or altered brain function. Such MEG maps of brain function may be used in the future to tailor patient-specific rehabilitation plans to target regions of altered spectral power with neurostimulation and other treatments.
Language	English
Publishing date	2023-11-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2023.1257886
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Article ; Online: A magnetic rotary optical fiber connector for optogenetic experiments in freely moving animals.

Klorig, David C / Godwin, Dwayne W

Journal of neuroscience methods

2014 Volume 227, Page(s) 132–139

Abstract: Background: Performing optogenetic experiments in a behaving animal presents a unique technical challenge. In order to provide an optical path between a fixed light source and a chronically implanted fiber in a freely moving animal, a typical ... ...

Abstract	Background: Performing optogenetic experiments in a behaving animal presents a unique technical challenge. In order to provide an optical path between a fixed light source and a chronically implanted fiber in a freely moving animal, a typical experimental setup includes a detachable connection between the light source and the head of the animal, as well as a rotary joint to relieve torsional stress during movement. New method: We have combined the functionality of the head mounted connector and the rotary joint into a single integrated device that is inexpensive, simple to build, and easy to use. Results: A typical rotary connector has a transmission efficiency of 80% with a rotational variability of 4%, but can be configured to have a rotational variability of 2% at the expense of a reduced transmission efficiency. Depending on configuration, rotational torque ranges from 14 to 180μNm, making the rotary connector suitable for use with small animals such as mice. Comparison with existing methods: Benchmark tests demonstrate that our connectors perform similarly to commercially available solutions in terms of transmission efficiency, rotational variability, and torque but at a fraction of the cost. Unlike currently available solutions, our unique design requires a single optical junction which significantly reduces overall light loss. In addition, magnets allow the connectors and caps to "snap into place" for quick yet reliable connection and disconnection. Conclusions: Our rotary connector system offers superior performance, reduced cost, and is easily incorporated into existing optogenetic setups.
MeSH term(s)	Acoustic Stimulation ; Animals ; Biophysics ; Electrodes, Implanted ; Equipment Design ; Evoked Potentials, Visual/physiology ; Magnetic Phenomena ; Mice ; Movement/physiology ; Optical Fibers ; Optogenetics/instrumentation ; Optogenetics/methods ; Wakefulness/physiology
Language	English
Publishing date	2014-03-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2014.02.013
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Zs.A 1486: Show issues

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Article: Rich Club Characteristics of Alcohol-Naïve Functional Brain Networks Predict Future Drinking Phenotypes in Rhesus Macaques.

Rowland, Jared A / Stapleton-Kotloski, Jennifer R / Alberto, Greg E / Davenport, April T / Epperly, Phillip M / Godwin, Dwayne W / Daunais, James B

Frontiers in behavioral neuroscience

2021 Volume 15, Page(s) 673151

Abstract: ... ...

Abstract	Purpose
Language	English
Publishing date	2021-06-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2021.673151
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Article ; Online: MEG source imaging detects optogenetically-induced activity in cortical and subcortical networks.

Alberto, Gregory E / Stapleton-Kotloski, Jennifer R / Klorig, David C / Rogers, Emily R / Constantinidis, Christos / Daunais, James B / Godwin, Dwayne W

Nature communications

2021 Volume 12, Issue 1, Page(s) 5259

Abstract: Magnetoencephalography measures neuromagnetic activity with high temporal, and theoretically, high spatial resolution. We developed an experimental platform combining MEG-compatible optogenetic techniques in nonhuman primates for use as a functional ... ...

Abstract	Magnetoencephalography measures neuromagnetic activity with high temporal, and theoretically, high spatial resolution. We developed an experimental platform combining MEG-compatible optogenetic techniques in nonhuman primates for use as a functional brain-mapping platform. Here we show localization of optogenetically evoked signals to known sources in the superficial arcuate sulcus of cortex and in CA3 of hippocampus at a resolution of 750 µm
MeSH term(s)	Animals ; Bacterial Proteins/genetics ; Brain/diagnostic imaging ; Brain/physiology ; Chlorocebus aethiops ; Evoked Potentials/physiology ; Female ; Functional Neuroimaging/methods ; Luminescent Proteins/genetics ; Magnetoencephalography/methods ; Microscopy, Confocal ; Models, Neurological ; Nerve Net ; Optogenetics/methods ; Signal Processing, Computer-Assisted
Chemical Substances	Bacterial Proteins ; Luminescent Proteins ; yellow fluorescent protein, Bacteria
Language	English
Publishing date	2021-09-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25481-y
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Article ; Online: Alterations in the Topology of Functional Connectomes Are Associated with Post-Traumatic Stress Disorder and Blast-Related Mild Traumatic Brain Injury in Combat Veterans.

Rowland, Jared A / Stapleton-Kotloski, Jennifer R / Martindale, Sarah L / Rogers, Emily E / Ord, Anna S / Godwin, Dwayne W / Taber, Katherine H

Journal of neurotrauma

2021 Volume 38, Issue 22, Page(s) 3086–3096

Abstract: Post-traumatic stress disorder (PTSD) is a common condition in post-deployment service members (SM). SMs of the conflicts in Iraq and Afghanistan also frequently experience traumatic brain injury (TBI) and exposure to blasts during deployments. This ... ...

Abstract	Post-traumatic stress disorder (PTSD) is a common condition in post-deployment service members (SM). SMs of the conflicts in Iraq and Afghanistan also frequently experience traumatic brain injury (TBI) and exposure to blasts during deployments. This study evaluated the effect of these conditions and experiences on functional brain connectomes in post-deployment, combat-exposed veterans. Functional brain connectomes were created using 5-min resting-state magnetoencephalography data. Well-established clinical interviews determined current PTSD diagnosis, as well as deployment-acquired mild TBI and history of exposure to blast. Linear regression examined the effect of these conditions on functional brain connectomes beyond covariates. There were significant interactions between blast-related mild TBI and PTSD after correction for multiple comparisons including number of nodes (non-standardized parameter estimate [PE] = -12.47), average degree (PE = 0.05), and connection strength (PE = 0.05). A main effect of blast-related mild TBI was observed on the threshold level. These results demonstrate a distinct functional connectome presentation associated with the presence of both blast-related mild TBI and PTSD. These findings suggest the possibility that blast-related mild TBI alterations in functional brain connectomes affect the presentation or progression of recovery from PTSD. The current results offer mixed support for hyper-connectivity in the chronic phase of deployment TBI.
MeSH term(s)	Adult ; Blast Injuries/complications ; Blast Injuries/pathology ; Blast Injuries/psychology ; Brain Concussion/etiology ; Brain Concussion/pathology ; Brain Concussion/psychology ; Combat Disorders/etiology ; Combat Disorders/pathology ; Connectome ; Female ; Humans ; Magnetoencephalography ; Male ; Middle Aged ; Stress Disorders, Post-Traumatic/etiology ; Stress Disorders, Post-Traumatic/pathology ; Veterans/psychology
Language	English
Publishing date	2021-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	645092-1
ISSN	1557-9042 ; 0897-7151
ISSN (online)	1557-9042
ISSN	0897-7151
DOI	10.1089/neu.2020.7450
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Zs.A 2016: Show issues

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Article ; Online: Expression of channelrhodopsin-2 localized within the deep CA1 hippocampal sublayer in the Thy1 line 18 mouse.

Dobbins, Dorothy L / Klorig, David C / Smith, Thuy / Godwin, Dwayne W

Brain research

2017 Volume 1679, Page(s) 179–184

Abstract: Optogenetic proteins are powerful tools for advancing our understanding of neural circuitry. However, the precision of optogenetics is dependent in part on the extent to which expression is limited to cells of interest. The Thy1-ChR2 transgenic mouse is ... ...

Abstract	Optogenetic proteins are powerful tools for advancing our understanding of neural circuitry. However, the precision of optogenetics is dependent in part on the extent to which expression is limited to cells of interest. The Thy1-ChR2 transgenic mouse is commonly used in optogenetic experiments. Although general expression patterns in these animals have been characterized, a detailed evaluation of cell-type specificity is lacking. This information is critical for interpretation of experimental results using these animals. We characterized ChR2 expression under the Thy1promoter in line 18 in comparison to known expression profiles of hippocampal cell types using immunohistochemistry in CA1. ChR2 expression did not colocalize with parvalbumin or calbindin expressing interneurons. However, we found ChR2 expression to be localized in the deep sublayer of CA1 in calbindin-negative pyramidal cells. These findings demonstrate the utility of the Thy1-ChR2-YFP mouse to study the activity and functional role of excitatory neurons located in the deep CA1 pyramidal cell layer.
MeSH term(s)	Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; CA1 Region, Hippocampal/cytology ; CA1 Region, Hippocampal/metabolism ; Calbindins/genetics ; Calbindins/metabolism ; Channelrhodopsins/genetics ; Channelrhodopsins/metabolism ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Mice ; Mice, Transgenic ; Neurons/metabolism ; Optogenetics ; Parvalbumins/metabolism ; Thy-1 Antigens/genetics ; Thy-1 Antigens/metabolism
Chemical Substances	Bacterial Proteins ; Calbindins ; Channelrhodopsins ; Luminescent Proteins ; Parvalbumins ; Thy-1 Antigens ; yellow fluorescent protein, Bacteria
Language	English
Publishing date	2017-11-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2017.11.025
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Zs.A 161: Show issues

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Article: Magnetoencephalography: Clinical and Research Practices.

Stapleton-Kotloski, Jennifer R / Kotloski, Robert J / Popli, Gautam / Godwin, Dwayne W

Brain sciences

2018 Volume 8, Issue 8

Abstract: Magnetoencephalography (MEG) is a neurophysiological technique that detects the magnetic fields associated with brain activity. Synthetic aperture magnetometry (SAM), a MEG magnetic source imaging technique, can be used to construct both detailed maps of ...

Abstract	Magnetoencephalography (MEG) is a neurophysiological technique that detects the magnetic fields associated with brain activity. Synthetic aperture magnetometry (SAM), a MEG magnetic source imaging technique, can be used to construct both detailed maps of global brain activity as well as virtual electrode signals, which provide information that is similar to invasive electrode recordings. This innovative approach has demonstrated utility in both clinical and research settings. For individuals with epilepsy, MEG provides valuable, nonredundant information. MEG accurately localizes the irritative zone associated with interictal spikes, often detecting epileptiform activity other methods cannot, and may give localizing information when other methods fail. These capabilities potentially greatly increase the population eligible for epilepsy surgery and improve planning for those undergoing surgery. MEG methods can be readily adapted to research settings, allowing noninvasive assessment of whole brain neurophysiological activity, with a theoretical spatial range down to submillimeter voxels, and in both humans and nonhuman primates. The combination of clinical and research activities with MEG offers a unique opportunity to advance translational research from bench to bedside and back.
Language	English
Publishing date	2018-08-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci8080157
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Article ; Online: Selective Blockade of T-Type Ca2+ Channels is Protective Against Alcohol-Withdrawal Induced Seizure and Mortality.

Masicampo, Melissa L / Shan, Hong Qu / Xu, Victoria / Speagle, Merritt / Godwin, Dwayne W

Alcohol and alcoholism (Oxford, Oxfordshire)

2018 Volume 53, Issue 5, Page(s) 526–531

Abstract: Aims: We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we ... ...

Abstract	Aims: We have previously demonstrated that blockade of T-type calcium channels by the non-selective antagonist, ethosuximide (ETX), is effective at reducing electrographical and behavioral correlates of alcohol-withdrawal (WD) seizure. Here, we investigated whether blockade of these calcium channels with the selective antagonist TTA-P2 also reduces alcohol-WD seizure. Short summary: The non-specific T-type calcium channel antagonist, ETX, is protective against alcohol-WD seizure. However, the mechanism of this effect is unclear. Here, we provide evidence that further suggests selective blockade of T-type calcium channels are protective against alcohol-WD seizure and WD-related mortality. Methods: We used an intermittent ethanol exposure model to produce WD-induced hyperexcitability in DBA/2 J mice. Seizure severity was intensified with the chemoconvulsant pentylenetetrazole (PTZ). Results: TTA-P2 (10 mg/kg) reduced seizure severity in mice undergoing alcohol WD with concurrent PTZ treatment (20 mg/kg). Moreover, TTA-P2 (20 and 40 mg/kg) was also protective against PTZ-induced (40 mg/kg) seizure and mortality. Conclusions: These results are consistent with prior results using ETX, and suggest that the protective effects of ETX and TTA-P2 against EtOH WD seizures are mediated by T-type calcium channels.
MeSH term(s)	Alcohol Withdrawal Seizures/chemically induced ; Alcohol Withdrawal Seizures/mortality ; Alcohol Withdrawal Seizures/prevention & control ; Animals ; Benzamides/therapeutic use ; Calcium Channel Blockers/therapeutic use ; Calcium Channels, T-Type/physiology ; Dose-Response Relationship, Drug ; Ethanol/toxicity ; Male ; Mice ; Mice, Inbred DBA ; Pentylenetetrazole/toxicity ; Piperidines/therapeutic use ; Seizures/chemically induced ; Seizures/mortality ; Seizures/prevention & control
Chemical Substances	3,5-dichloro-N-(1-(2,2-dimethyltetrahydropyran-4-ylmethyl)-4-fluoropiperidin-4-ylmethyl)benzamide ; Benzamides ; Calcium Channel Blockers ; Calcium Channels, T-Type ; Piperidines ; Ethanol (3K9958V90M) ; Pentylenetetrazole (WM5Z385K7T)
Language	English
Publishing date	2018-06-18
Publishing country	England
Document type	Journal Article
ZDB-ID	604956-4
ISSN	1464-3502 ; 0309-1635 ; 0735-0414
ISSN (online)	1464-3502
ISSN	0309-1635 ; 0735-0414
DOI	10.1093/alcalc/agy042
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