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Microstructural and Microvascular Alterations in Psychotic Spectrum Disorders: A Three-Compartment Intravoxel Incoherent Imaging and Free Water Model

McKenna, Faye; Gupta, Pradeep Kumar; Sui, Yu Veronica; Bertisch, Hilary; Gonen, Oded; Goff, Donald C; Lazar, Mariana
BACKGROUND AND HYPOTHESIS:Microvascular and inflammatory mechanisms have been hypothesized to be involved in the pathophysiology of psychotic spectrum disorders (PSDs). However, data evaluating these hypotheses remain limited. STUDY DESIGN:We applied a three-compartment intravoxel incoherent motion free water imaging (IVIM-FWI) technique that estimates the perfusion fraction (PF), free water fraction (FW), and anisotropic diffusion of tissue (FAt) to examine microvascular and microstructural changes in gray and white matter in 55 young adults with a PSD compared to 37 healthy controls (HCs). STUDY RESULTS:We found significantly increased PF, FW, and FAt in gray matter regions, and significantly increased PF, FW, and decreased FAt in white matter regions in the PSD group versus HC. Furthermore, in patients, but not in the HC group, increased PF, FW, and FAt in gray matter and increased PF in white matter were significantly associated with poor performance on several cognitive tests assessing memory and processing speed. We additionally report significant associations between IVIM-FWI metrics and myo-inositol, choline, and N-acetylaspartic acid magnetic resonance spectroscopy imaging metabolites in the posterior cingulate cortex, which further supports the validity of PF, FW, and FAt as microvascular and microstructural biomarkers of PSD. Finally, we found significant relationships between IVIM-FWI metrics and the duration of psychosis in gray and white matter regions. CONCLUSIONS:The three-compartment IVIM-FWI model provides metrics that are associated with cognitive deficits and may reflect disease progression.
PMID: 36921060
ISSN: 1745-1701
CID: 5590612

Another Step Toward the Prediction of Antipsychotic Treatment Response Using Functional Connectivity [Comment]

Goff, Donald C; Roffman, Joshua; Holt, Daphne J
PMID: 37908095
ISSN: 1535-7228
CID: 5614442

Aberrant resting-state functional connectivity of the globus pallidus interna in first-episode schizophrenia

Qi, Wei; Wen, Zhenfu; Chen, Jingyun; Capichioni, Gillian; Ando, Fumika; Chen, Zhe Sage; Wang, Jijun; Yoncheva, Yuliya; Castellanos, Francisco X; Milad, Mohammed; Goff, Donald C
BACKGROUND:The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS:71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: = 0.486, p < 0.001). CONCLUSIONS:Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.
PMID: 37716202
ISSN: 1573-2509
CID: 5593342

Levetiracetam effects on hippocampal blood flow and symptoms in medication-free individuals with nonaffective first episode psychosis (letter) [Letter]

Goff, Donald C; Santacatterina, Michele; Capichioni, Gillian; Ando, Fumika; Hart, Kamber; Convit, Antonio; Rusinek, Henry
PMID: 37657280
ISSN: 1573-2509
CID: 5618122

Dose Finding for d-Serine Enhancement of Plasticity in Schizophrenia [Comment]

Nemani, Katlyn; Goff, Donald C
PMID: 37380254
ISSN: 1873-2402
CID: 5538682

Hippocampal Subfield Volumes Predict Disengagement from Maintenance Treatment in First Episode Schizophrenia

Qi, Wei; Marx, Julia; Zingman, Michael; Li, Yi; Petkova, Eva; Blessing, Esther; Ardekani, Babak; Sakalli Kani, Ayse; Cather, Corinne; Freudenreich, Oliver; Holt, Daphne; Zhao, Jingping; Wang, Jijun; Goff, Donald C
OBJECTIVES/OBJECTIVE:Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS:FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS:Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS:Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.
PMID: 36370124
ISSN: 1745-1701
CID: 5357702

Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms

Sui, Yu Veronica; McKenna, Faye; Bertisch, Hilary; Storey, Pippa; Anthopolos, Rebecca; Goff, Donald C; Samsonov, Alexey; Lazar, Mariana
Iron deficits have been reported as a risk factor for psychotic spectrum disorders (PSD). However, examinations of brain iron in PSD remain limited. The current study employed quantitative MRI to examine iron content in several iron-rich subcortical structures in 49 young adult individuals with PSD (15 schizophrenia, 17 schizoaffective disorder, and 17 bipolar disorder with psychotic features) compared with 35 age-matched healthy controls (HC). A parametric approach based on a two-pool magnetization transfer model was applied to estimate longitudinal relaxation rate (R1), which reflects both iron and myelin, and macromolecular proton fraction (MPF), which is specific to myelin. To describe iron content, a synthetic effective transverse relaxation rate (R2*) was modeled using a linear fitting of R1 and MPF. PSD patients compared to HC showed significantly reduced R1 and synthetic R2* across examined regions including the pallidum, ventral diencephalon, thalamus, and putamen areas. This finding was primarily driven by decreases in the subgroup with schizophrenia, followed by schizoaffective disorder. No significant group differences were noted for MPF between PSD and HC while for regional volume, significant reductions in patients were only observed in bilateral caudate, suggesting that R1 and synthetic R2* reductions in schizophrenia and schizoaffective patients likely reflect iron deficits that either occur independently or precede structural and myelin changes. Subcortical R1 and synthetic R2* were also found to be inversely related to positive symptoms within the PSD group and to schizotypal traits across the whole sample. These findings that decreased iron in subcortical regions are associated with PSD risk and symptomatology suggest that brain iron deficiencies may play a role in PSD pathology and warrant further study.
PMID: 36071113
ISSN: 1476-5578
CID: 5332512

Association Between the Use of Psychotropic Medications and the Risk of COVID-19 Infection Among Long-term Inpatients With Serious Mental Illness in a New York State-wide Psychiatric Hospital System

Nemani, Katlyn; Williams, Sharifa Z; Olfson, Mark; Leckman-Westin, Emily; Finnerty, Molly; Kammer, Jammie; Smith, Thomas E; Silverman, Daniel J; Lindenmayer, Jean-Pierre; Capichioni, Gillian; Clelland, James; Goff, Donald C
Importance/UNASSIGNED:Individuals with serious mental illness are at increased risk of severe COVID-19 infection. Several psychotropic medications have been identified as potential therapeutic agents to prevent or treat COVID-19 but have not been systematically examined in this population. Objective/UNASSIGNED:To evaluate the associations between the use of psychotropic medications and the risk of COVID-19 infection among adults with serious mental illness receiving long-term inpatient psychiatric treatment. Design, Setting, and Participants/UNASSIGNED:This retrospective cohort study assessed adults with serious mental illness hospitalized in a statewide psychiatric hospital system in New York between March 8 and July 1, 2020. The final date of follow-up was December 1, 2020. The study included 1958 consecutive adult inpatients with serious mental illness (affective or nonaffective psychoses) who received testing for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction or antinucleocapsid antibodies and were continuously hospitalized from March 8 until medical discharge or July 1, 2020. Exposures/UNASSIGNED:Psychotropic medications prescribed prior to COVID-19 testing. Main Outcomes and Measures/UNASSIGNED:COVID-19 infection was the primary outcome, defined by a positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction or antibody test result. The secondary outcome was COVID-19-related death among patients with laboratory-confirmed infection. Results/UNASSIGNED:Of the 2087 adult inpatients with serious mental illness continuously hospitalized during the study period, 1958 (93.8%) underwent testing and were included in the study; 1442 (73.6%) were men, and the mean (SD) age was 51.4 (14.3) years. A total of 969 patients (49.5%) had laboratory-confirmed COVID-19 infection that occurred while they were hospitalized; of those, 38 (3.9%) died. The use of second-generation antipsychotic medications, as a class, was associated with decreased odds of infection (odds ratio [OR], 0.62; 95% CI, 0.45-0.86), whereas the use of mood stabilizers was associated with increased odds of infection (OR, 1.23; 95% CI, 1.03-1.47). In a multivariable model of individual medications, the use of paliperidone was associated with decreased odds of infection (OR, 0.59; 95% CI, 0.41-0.84), and the use of valproic acid was associated with increased odds of infection (OR, 1.39; 95% CI, 1.10-1.76). Clozapine use was associated with reduced odds of mortality in unadjusted analyses (unadjusted OR, 0.25; 95% CI, 0.10-0.62; fully adjusted OR, 0.43; 95% CI, 0.17-1.12). Conclusions and Relevance/UNASSIGNED:In this cohort study of adults hospitalized with serious mental illness, the use of second-generation antipsychotic medications was associated with decreased risk of COVID-19 infection, whereas the use of valproic acid was associated with increased risk. Further research is needed to assess the mechanisms that underlie these findings.
PMID: 35522282
ISSN: 2574-3805
CID: 5213932

Impairment in acquisition of conditioned fear in schizophrenia

Tuominen, Lauri; Romaniuk, Liana; Milad, Mohammed R; Goff, Donald C; Hall, Jeremy; Holt, Daphne J
Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS- SCRs) and responses to CS + and CS- separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.
PMID: 34588608
ISSN: 1740-634x
CID: 5067502

Inverse Relationships Between Basal Ganglia Iron and Positive Psychotic Symptoms in Early Psychotic Spectrum Disorders [Meeting Abstract]

Sui, Yu Veronica; McKenna, Faye; Bertisch, Hilary; Storey, Pippa; Anthopolos, Rebecca; Goff, Donald C.; Samsonov, Alexey; Lazar, Mariana
ISSN: 0006-3223
CID: 5386482