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The neuropsychopharmacology of acetyl-L-carnitine (LAC): basic, translational and therapeutic implications

Bigio, Benedetta; Azam, Shofiul; Mathé, Aleksander A.; Nasca, Carla
Mitochondrial metabolism can contribute to nuclear histone acetylation among other epigenetic mechanisms. A central aspect of this signaling pathway is acetyl-L-carnitine (LAC), a pivotal mitochondrial metabolite best known for its role in fatty acid oxidation. Work from our and other groups suggested LAC as a novel epigenetic modulator of brain plasticity and a therapeutic target for clinical phenotypes of depression linked to childhood trauma. Aberrant mitochondrial metabolism of LAC has also been implicated in the pathophysiology of Alzheimer"™s disease. Furthermore, mitochondrial dysfunction is linked to other processes implicated in the pathophysiology of both major depressive disorders and Alzheimer"™s disease, such as oxidative stress, inflammation, and insulin resistance. In addition to the rapid epigenetic modulation of glutamatergic function, preclinical studies showed that boosting mitochondrial metabolism of LAC protects against oxidative stress, rapidly ameliorates insulin resistance, and reduces neuroinflammation by decreasing proinflammatory pathways such as NFkB in hippocampal and cortical neurons. These basic and translational neuroscience findings point to this mitochondrial signaling pathway as a potential target to identify novel mechanisms of brain plasticity and potential unique targets for therapeutic intervention targeted to specific clinical phenotypes.
SCOPUS:85181258455
ISSN: 2731-4383
CID: 5628912

The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge

Shalom, Eve S; Kim, Harrison; van der Heijden, Rianne A; Ahmed, Zaki; Patel, Reyna; Hormuth, David A; DiCarlo, Julie C; Yankeelov, Thomas E; Sisco, Nicholas J; Dortch, Richard D; Stokes, Ashley M; Inglese, Marianna; Grech-Sollars, Matthew; Toschi, Nicola; Sahoo, Prativa; Singh, Anup; Verma, Sanjay K; Rathore, Divya K; Kazerouni, Anum S; Partridge, Savannah C; LoCastro, Eve; Paudyal, Ramesh; Wolansky, Ivan A; Shukla-Dave, Amita; Schouten, Pepijn; Gurney-Champion, Oliver J; Jiřík, Radovan; Macíček, Ondřej; Bartoš, Michal; Vitouš, Jiří; Das, Ayesha Bharadwaj; Kim, S Gene; Bokacheva, Louisa; Mikheev, Artem; Rusinek, Henry; Berks, Michael; Hubbard Cristinacce, Penny L; Little, Ross A; Cheung, Susan; O'Connor, James P B; Parker, Geoff J M; Moloney, Brendan; LaViolette, Peter S; Bobholz, Samuel; Duenweg, Savannah; Virostko, John; Laue, Hendrik O; Sung, Kyunghyun; Nabavizadeh, Ali; Saligheh Rad, Hamidreza; Hu, Leland S; Sourbron, Steven; Bell, Laura C; Fathi Kazerooni, Anahita
PURPOSE/OBJECTIVE: METHODS: RESULTS: CONCLUSIONS:
PMID: 38115695
ISSN: 1522-2594
CID: 5612382

Cannabinoid treatments in epilepsy and seizure disorders

Devinsky, Orrin; Jones, Nicholas A; Cunningham, Mark O; Jayasekera, B Ashan P; Devore, Sasha; Whalley, Benjamin J
Cannabis has been used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized controlled clinical trials that led to US Food and Drug Administration approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.
PMID: 37882730
ISSN: 1522-1210
CID: 5628142

Rapid quantitative magnetization transfer imaging: Utilizing the hybrid state and the generalized Bloch model

Assländer, Jakob; Gultekin, Cem; Mao, Andrew; Zhang, Xiaoxia; Duchemin, Quentin; Liu, Kangning; Charlson, Robert W; Shepherd, Timothy M; Fernandez-Granda, Carlos; Flassbeck, Sebastian
PURPOSE/OBJECTIVE:To explore efficient encoding schemes for quantitative magnetization transfer (qMT) imaging with few constraints on model parameters. THEORY AND METHODS/METHODS:We combine two recently proposed models in a Bloch-McConnell equation: the dynamics of the free spin pool are confined to the hybrid state, and the dynamics of the semi-solid spin pool are described by the generalized Bloch model. We numerically optimize the flip angles and durations of a train of radio frequency pulses to enhance the encoding of three qMT parameters while accounting for all eight parameters of the two-pool model. We sparsely sample each time frame along this spin dynamics with a three-dimensional radial koosh-ball trajectory, reconstruct the data with subspace modeling, and fit the qMT model with a neural network for computational efficiency. RESULTS:We extracted qMT parameter maps of the whole brain with an effective resolution of 1.24 mm from a 12.6-min scan. In lesions of multiple sclerosis subjects, we observe a decreased size of the semi-solid spin pool and longer relaxation times, consistent with previous reports. CONCLUSION/CONCLUSIONS:The encoding power of the hybrid state, combined with regularized image reconstruction, and the accuracy of the generalized Bloch model provide an excellent basis for efficient quantitative magnetization transfer imaging with few constraints on model parameters.
PMID: 38073093
ISSN: 1522-2594
CID: 5589482

Target trial emulation for comparative effectiveness research with observational data: Promise and challenges for studying medications for opioid use disorder

Christine, Paul J; Lodi, Sara; Hsu, Heather E; Bovell-Ammon, Benjamin; Yan, Shapei; Bernson, Dana; Novo, Patricia; Lee, Joshua D; Rotrosen, John; Liebschutz, Jane; Walley, Alexander Y; Larochelle, Marc R
Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine-naloxone and extended-release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD.
PMID: 38519819
ISSN: 1360-0443
CID: 5641042

Contribution of the serotonergic system to developmental brain abnormalities in autism spectrum disorder

Wegiel, Jarek; Chadman, Kathryn; London, Eric; Wisniewski, Thomas; Wegiel, Jerzy
This review highlights a key role of the serotonergic system in brain development and in distortions of normal brain development in early stages of fetal life resulting in cascades of abnormalities, including defects of neurogenesis, neuronal migration, neuronal growth, differentiation, and arborization, as well as defective neuronal circuit formation in the cortex, subcortical structures, brainstem, and cerebellum of autistic subjects. In autism, defects in regulation of neuronal growth are the most frequent and ubiquitous developmental changes associated with impaired neuron differentiation, smaller size, distorted shape, loss of spatial orientation, and distortion of cortex organization. Common developmental defects of the brain in autism include multiregional focal dysplastic changes contributing to local neuronal circuit distortion, epileptogenic activity, and epilepsy. There is a discrepancy between more than 500 reports demonstrating the contribution of the serotonergic system to autism's behavioral anomalies, highlighted by lack of studies of autistic subjects' brainstem raphe nuclei, the center of brain serotonergic innervation, and of the contribution of the serotonergic system to the diagnostic features of autism spectrum disorder (ASD). Discovery of severe fetal brainstem auditory system neuronal deficits and other anomalies leading to a spectrum of hearing deficits contributing to a cascade of behavioral alterations, including deficits of social and verbal communication in individuals with autism, is another argument to intensify postmortem studies of the type and topography of, and the severity of developmental defects in raphe nuclei and their contribution to abnormal brain development and to the broad spectrum of functional deficits and comorbid conditions in ASD.
PMID: 38500252
ISSN: 1939-3806
CID: 5640252

Clinical outcomes among initial survivors of cryptogenic new-onset refractory status epilepsy (NORSE)

Costello, Daniel J; Matthews, Elizabeth; Aurangzeb, Sidra; Doran, Elisabeth; Stack, Jessica; Wesselingh, Robb; Dugan, Patricia; Choi, Hyunmi; Depondt, Chantal; Devinsky, Orrin; Doherty, Colin; Kwan, Patrick; Monif, Mastura; O'Brien, Terence J; Sen, Arjune; Gaspard, Nicolas
OBJECTIVE:New-onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%-50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well-phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. METHODS:Well-characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005-2019. Treating epileptologists reported on post-NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post-discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. RESULTS:Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow-up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. SIGNIFICANCE/CONCLUSIONS:Among survivors of cryptogenic NORSE, longer-term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies.
PMID: 38498313
ISSN: 1528-1167
CID: 5640142

Impact of PTSD treatment on postconcussive symptoms in veterans: A comparison of sertraline, prolonged exposure, and their combination

Porter, Katherine E; Stein, Murray B; Grau, Peter P; Kim, H Myra; Powell, Corey; Hoge, Charles W; Venners, Margaret R; Smith, Erin R; Martis, Brian; Simon, Naomi M; Liberzon, Israel; Rauch, Sheila A M; ,
Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms.
PMID: 38503135
ISSN: 1879-1379
CID: 5640422

On multi-path longitudinal spin relaxation in brain tissue

Assländer, Jakob; Mao, Andrew; Beck, Erin S; Rosa, Francesco La; Charlson, Robert W; Shepherd, Timothy M; Flassbeck, Sebastian
The purpose of this paper is to confirm previous reports that identified magnetization transfer (MT) as an inherent driver of longitudinal relaxation in brain tissue by asserting a substantial difference between the $T_1$ relaxation times of the free and the semi-solid spin pools. Further, we aim to identify an avenue towards the quantification of these relaxation processes on a voxel-by-voxel basis in a clinical imaging setting, i.e. with a nominal resolution of 1mm isotropic and full brain coverage in 12min. To this end, we optimized a hybrid-state pulse sequence for mapping the parameters of an unconstrained MT model. We scanned 4 people with relapsing-remitting multiple sclerosis (MS) and 4 healthy controls with this pulse sequence and estimated $T_1^f \approx 1.90$s and $T_1^s \approx 0.327$s for the free and semi-solid spin pool of healthy WM, respectively, confirming previous reports and questioning the commonly used assumptions $T_1^s = T_1^f$ or $T_1^s = 1$s. Further, we estimated a fractional size of the semi-solid spin pool of $m_0^s \approx 0.202$, which is larger than previously assumed. An analysis of $T_1^f$ in normal appearing white matter revealed statistically significant differences between individuals with MS and controls. In conclusion, we confirm that longitudinal spin relaxation in brain tissue is dominated by MT and that the hybrid state facilitates a voxel-wise fit of the unconstrained MT model, which enables the analysis of subtle neurodegeneration.
PMCID:9882584
PMID: 36713253
ISSN: 2331-8422
CID: 5473602

Psychiatric risks for worsened mental health after psychedelic use

Marrocu, Alessia; Kettner, Hannes; Weiss, Brandon; Zeifman, Richard J; Erritzoe, David; Carhart-Harris, Robin L
BACKGROUND/UNASSIGNED:Resurgent psychedelic research has largely supported the safety and efficacy of psychedelic therapy for the treatment of various psychiatric disorders. As psychedelic use and therapy increase in prevalence, so does the importance of understanding associated risks. Cases of prolonged negative psychological responses to psychedelic therapy seem to be rare; however, studies are limited by biases and small sample sizes. The current analytical approach was motivated by the question of whether rare but significant adverse effects have been under-sampled in psychedelic research studies. METHODS/UNASSIGNED: = 807). We define "negative response" by a clinically meaningful decline in a generic index of mental health, that is, one standard error from the mean decrease in psychological well-being 4 weeks post-psychedelic use (vs pre-use baseline). We then assessed whether a history of diagnosed mental illness can predict negative responses. RESULTS/UNASSIGNED: < 0.05). CONCLUSION/UNASSIGNED:We infer that the presence of a personality disorder may represent an elevated risk for psychedelic use and hypothesize that the importance of psychological support and good therapeutic alliance may be increased in this population.
PMCID:10944581
PMID: 38491857
ISSN: 1461-7285
CID: 5639872