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At Last, a Nondopaminergic Agent for the Treatment of Schizophrenia: The Combination of Xanomeline and Trospium (Cobenfy)
Goff, Donald C
PMID: 39913270
ISSN: 1533-712x
CID: 5784242
Dysfunctional activation of the default mode network in response inhibition in schizophrenia
Krakowski, Menahem; Hoptman, Matthew J; Czobor, Pal
The aim of this study was to characterize dysfunctional cerebral activation in patients with schizophrenia while they performed a response inhibition task. To achieve this, performance on the task and functional magnetic resonance imaging (fMRI) were compared between healthy control subjects (HC) and patients with schizophrenia (SZ). We focused on the default mode network (DMN), as there is strong evidence in the literature that lack of DMN suppression in schizophrenia is associated with cognitive impairment including poor response inhibition. fMRI was used to measure blood-oxygen-level-dependent activation in 84 subjects (44 SZ and 40 HC) while they performed a Go NoGo task. The subjects were also evaluated for psychiatric symptoms and immediate visual memory. SZ performed more poorly than HC on the task; they had a higher number of commission errors. On the fMRI, the patients consistently evidenced higher activation than the controls in several areas of the default mode network (DMN) including the precuneus, rostral anterior cingulate, parahippocampus and insula. The higher brain activation in the patients with schizophrenia indicates a failure to deactivate the DMN while they perform the response inhibition task. These findings point to the importance of DMN dysfunction as an underlying cause of impairment in response inhibition in schizophrenia. DMN disruptions play an essential role in the cognitive impairment present in schizophrenia.
PMID: 39536502
ISSN: 1879-1379
CID: 5753192
Dysfunctional activation of the default mode network in response inhibition in schizophrenia
Krakowski, Menahem; Hoptman, Matthew J; Czobor, Pal
The aim of this study was to characterize dysfunctional cerebral activation in patients with schizophrenia while they performed a response inhibition task. To achieve this, performance on the task and functional magnetic resonance imaging (fMRI) were compared between healthy control subjects (HC) and patients with schizophrenia (SZ). We focused on the default mode network (DMN), as there is strong evidence in the literature that lack of DMN suppression in schizophrenia is associated with cognitive impairment including poor response inhibition. fMRI was used to measure blood-oxygen-level-dependent activation in 84 subjects (44 SZ and 40 HC) while they performed a Go NoGo task. The subjects were also evaluated for psychiatric symptoms and immediate visual memory. SZ performed more poorly than HC on the task; they had a higher number of commission errors. On the fMRI, the patients consistently evidenced higher activation than the controls in several areas of the default mode network (DMN) including the precuneus, rostral anterior cingulate, parahippocampus and insula. The higher brain activation in the patients with schizophrenia indicates a failure to deactivate the DMN while they perform the response inhibition task. These findings point to the importance of DMN dysfunction as an underlying cause of impairment in response inhibition in schizophrenia. DMN disruptions play an essential role in the cognitive impairment present in schizophrenia.
PMID: 39536502
ISSN: 1879-1379
CID: 5753202
Dose-dependent effects of transcranial photobiomodulation on brain temperature in patients with major depressive disorder: a spectroscopy study
Weerasekera, Akila; Coelho, David Richer Araujo; Ratai, Eva-Maria; Collins, Katherine Anne; Puerto, Aura Maria Hurtado; De Taboada, Luis; Gersten, Maia Beth; Clancy, Julie A; Hoptman, Matthew J; Irvin, Molly Kennedy; Sparpana, Allison Mary; Sullivan, Elizabeth F; Song, Xiaotong; Adib, Arwa; Cassano, Paolo; Iosifescu, Dan Vlad
This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm2, medium: 300 mW/cm2, high: 850 mW/cm2) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy (1H-MRS). A voxel with a volume of 30 × 30 × 15 mm3 was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing 1H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant temperature differences for any t-PBM-active or sham groups post-irradiation (p-value range = 0.105 and 0.781). We also tested for potential differences in the pre-post variability of brain temperature in each group. As for t-PBM active groups, the lowest fluctuation (variance) was observed for the medium dose (σ2 = 0.29), followed by the low dose (σ2 = 0.47), and the highest fluctuation was for the high dose (σ2 = 0.67). t-PBM sham condition showed the overall lowest fluctuation (σ2 = 0.11). Our 1H-MRS thermometry results showed no significant brain temperature elevations during t-PBM administration.
PMID: 39370461
ISSN: 1435-604x
CID: 5705882
Why Do Veterans Not Respond as Well as Civilians to Trauma-Focused Therapies for PTSD?
Kitaj, Max; Goff, Donald C
This column first reviews evidence that veterans have poorer response to trauma-focused therapies for PTSD compared to civilians. We then consider several explanations for this trend, starting with gender as a possible confounding variable. We also examine other hypotheses, including the effects of the military acculturation process, the unique influences of military traumas, such as combat and military sexual traumas, and the roles of traumatic brain injuries (TBIs) and moral injury. Future research, we conclude, must determine whether gender explains the differences in trauma-focused therapy response. If so, then the underlying reasons must be further explored. If not, then we must determine the unique characteristics of the veteran population that make it more resistant to treatment. Mining these elements will help us adapt our trauma-focused therapies to better help this population and close the response-rate gap.
PMID: 38990904
ISSN: 1465-7309
CID: 5699082
Anti-spike antibody responses to SARS-CoV-2 mRNA vaccines in people with schizophrenia and schizoaffective disorder
Nemani, Katlyn; De Picker, Livia; Dickerson, Faith; Leboyer, Marion; Santacatterina, Michele; Ando, Fumika; Capichioni, Gillian; Smith, Thomas E; Kammer, Jamie; El Abdellati, Kawtar; Morrens, Manuel; Coppens, Violette; Katsafanas, Emily; Origoni, Andrea; Khan, Sabahat; Rowe, Kelly; Ziemann, R Sarah; Tamouza, Ryad; Yolken, Robert H; Goff, Donald C
IMPORTANCE/UNASSIGNED:Individuals with schizophrenia are at higher risk for severe COVID-19 illness and severe breakthrough infection following vaccination. It is unclear whether immune response to vaccination differs in this population. OBJECTIVE/UNASSIGNED:To assess whether anti-SARS-CoV-2 spike antibody titers after vaccination differ in people with a diagnosis of schizophrenia or schizoaffective disorder (SZ) compared to controls without a psychiatric disorder. DESIGN/UNASSIGNED:This cohort study assessed antibody response following the first and second dose of mRNA vaccines at longitudinal timepoints, up to 7 weeks following the first dose of vaccine. SETTING/UNASSIGNED:A multi-center study including psychiatric healthcare settings in the United States and Europe. PARTICIPANTS/UNASSIGNED:205 adults with no history of COVID-19 infection, including 106 individuals with SZ and 99 controls without a psychiatric disorder, who received their first dose of SARS-CoV-2 mRNA vaccine between December 20, 2020 and May 27, 2021. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Mean SARS-CoV-2 anti-Spike IgG antibody levels within 7 weeks after the first dose of vaccination. RESULTS/UNASSIGNED: = 0.96). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of individuals with SZ and a control group without psychiatric disorders, SZ was associated with lower SARS-CoV-2 anti-spike antibody levels following 2 doses of SARS-CoV-2 mRNA vaccination. This highlights the need for further studies assessing vaccine immunogenicity in individuals with schizophrenia.
PMCID:11252076
PMID: 39021438
ISSN: 2666-3546
CID: 5731932
Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication
Tani, Hideaki; Moxon-Emre, Iska; Forde, Natalie J; Neufeld, Nicholas H; Bingham, Kathleen S; Whyte, Ellen M; Meyers, Barnett S; Alexopoulos, George S; Hoptman, Matthew J; Rothschild, Anthony J; Uchida, Hiroyuki; Flint, Alastair J; Mulsant, Benoit H; Voineskos, Aristotle N
BACKGROUND:The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS:Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS:Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS:Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.
PMCID:10844359
PMID: 37917311
ISSN: 1931-7565
CID: 5633052
Emotion-related impulsivity and suicidal ideation and behavior in schizophrenia spectrum disorder: a pilot fMRI study
Hoptman, Matthew J; Evans, Kathryn T; Parincu, Zamfira; Sparpana, Allison M; Sullivan, Elizabeth F; Ahmed, Anthony O; Iosifescu, Dan V
INTRODUCTION/UNASSIGNED:Suicidal ideation and behavior (SIB) are serious problems in people with schizophrenia spectrum disorders (SSD). Nevertheless, relatively little is known about the circuitry underlying SIB in SSD. Recently, we showed that elevated emotional impulsivity (urgency) was associated with SIB in SSD. Here we examined brain activity in people with SSD and elevated SIB. METHODS/UNASSIGNED:We tested 16 people with SSD who had low SIB and 14 people with high SIB on a task in which emotion regulation in response to affective pictures was implicitly manipulated using spoken sentences. Thus, there were neutral pictures preceded by neutral statements (NeutNeut condition), as well as negative pictures preceded by either negative (NegNeg) or neutral (NeutNeg) statements. After each picture, participants rated how unpleasant each picture was for them. The latter two conditions were compared to the NeutNeut condition. We compared the emotion-regulated condition (NeutNeg) to the unregulated condition (NeutNeut). Statistics were threshold using threshold free cluster enhancement (TFCE). RESULTS/UNASSIGNED:People in the low SIB group showed higher activation in this contrast in medial frontal gyrus, right rostral anterior cingulate, bilateral superior frontal gyrus/DLPFC, and right middle cingulate gyrus, as well as right superior temporal gyrus. DISCUSSION/UNASSIGNED:This study provides clues to the neural basis of SIB in SSD as well as underlying mechanisms.
PMCID:11234166
PMID: 38988737
ISSN: 1664-0640
CID: 5732402
Biomarkers for Cognitive Control, Response Inhibition, Aggressivity, Impulsivity, and Violence
Hoptman, Matthew J; Girgis, Ragy R; Javitt, Daniel C
Deficits in cognitive control contribute to behavioral impairments across neuropsychiatric disorders. Cognitive control is captured as a construct in the Research Domain Construct (RDoC) matrix and incorporate subdomains of goal selection, response selection, and performance monitoring. Relevant tasks for these subdomains include the "AX" version of the continuous performance task (goal selection) and the Go/NoGo and Stop-Signal reaction time tasks (response selection). Underlying mechanisms for these domains have been investigated intensively using fMRI and event-related potential (ERP) approaches, which provide candidate biomarkers for translational research. In RDoC, impulsive behaviors are provisionally assigned to the cognitive control/response selection construct, but other factors may also contribute. Impulsivity has gained increased importance over recent years due to its link to aggression and suicidality, which is mediated especially through the constructs of urgency and frustrative nonreward. These constructs, in turn, may be captured through scales such as the Urgency, (Lack of) Premeditation, (Lack of) Perseverance, and Sensation Seeking (UPPS-P) impulsivity scale and the Point Subtraction Aggression Paradigm (PSAP), respectively. At present, no validated biomarkers exist for either urgency or aggressivity. Potential directions for the development of predictive biomarkers for both targets are discussed.
PMID: 39562462
ISSN: 2190-5215
CID: 5758492
Structural-functional connectivity deficits of callosal-white matter-cortical circuits in schizophrenia
Wang, Pan; Jiang, Yuan; Hoptman, Matthew J; Li, Yilu; Cao, Qingquan; Shah, Pushti; Klugah-Brown, Benjamin; Biswal, Bharat B
Schizophrenia is increasingly recognized as a disorder with altered integration between large-scale functional networks and cortical-subcortical pathways. This spatial long-distance information communication must be associated with white matter (WM) fiber bundles. With accumulating evidence that WM functional signals reflect the intrinsic neural activities, how the deep callosal organization modulates cortical functional activities through WM remains unclear in schizophrenia. Using a data-driven method, we identified nine WM and gray matter (GM) functional networks, and then parcellated corpus callosum into distinct sub-regions. Combining functional connectivity and fiber tracking analysis, we estimated the structural and functional connectivity changes of callosal-WM-cortical circuits in schizophrenia. We observed higher structural and functional connectivity between corpus callosum, WM and GM functional networks involving visual network (visual processing), executive control network (executive controls), ventral attention network (processing of salience), and limbic network (emotion processing) in schizophrenia compared to healthy controls. We also found nine abnormal pathways of callosal-WM-cortical circuits involving the above networks and default mode network (self-related thought). These results highlight the role of connectivity deficits in callosal-WM-cortical circuits may play in understanding the delusions, hallucinations and cognitive impairment of schizophrenia.
PMID: 37931478
ISSN: 1872-7123
CID: 5590342