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1.
Front Psychiatry ; 14: 1218321, 2023.
Article in English | MEDLINE | ID: mdl-38025437

ABSTRACT

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

2.
Schizophrenia (Heidelb) ; 8(1): 118, 2022 Dec 30.
Article in English | MEDLINE | ID: mdl-36585407

ABSTRACT

Childhood sexual abuse (CSA) is a potentially unique risk factor for auditory hallucinations (AH), but few studies have examined the moderating effects of sex or the association of CSA with limbic gray matter volume (GMV) in transdiagnostic samples of people with psychotic disorders. Here we found that people with psychotic disorders reported higher levels of all surveyed maltreatment types (e.g., physical abuse) than healthy controls, but people with psychotic disorders with AH (n = 41) reported greater CSA compared to both those without AH (n = 37; t = -2.21, p = .03) and controls (n = 37; t = -3.90, p < .001). Among people with psychosis, elevated CSA was most pronounced among females with AH (sex × AH status: F = 4.91, p = .009), held controlling for diagnosis, medications, and other maltreatment (F = 3.88, p = .02), and correlated with the current severity of AH (r = .26, p = .03) but not other symptoms (p's > .16). Greater CSA among patients related to larger GMV of the left amygdala accounting for AH status, diagnosis, medications, and other maltreatment (t = 2.12, p = .04). Among people with psychosis, females with AH may represent a unique subgroup with greater CSA. Prospective high-risk studies integrating multiple measures of maltreatment and brain structure/function may help elucidate the mechanisms linking CSA with amygdala alterations and AH.

3.
Neuroimage Clin ; 32: 102893, 2021.
Article in English | MEDLINE | ID: mdl-34911197

ABSTRACT

BACKGROUND: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis. METHODS: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis. RESULTS: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH. CONCLUSIONS: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders.


Subject(s)
Psychotic Disorders , Schizophrenia , Brain , Brain Mapping , Cerebellum/diagnostic imaging , Hallucinations/diagnostic imaging , Hallucinations/etiology , Humans , Magnetic Resonance Imaging , Psychotic Disorders/diagnostic imaging , Schizophrenia/diagnostic imaging , Temporal Lobe/diagnostic imaging
4.
Schizophr Bull ; 47(1): 138-148, 2021 01 23.
Article in English | MEDLINE | ID: mdl-32572485

ABSTRACT

Imaging studies in psychotic disorders typically examine cross-sectional relationships between magnetic resonance imaging (MRI) signals and diagnosis or symptoms. We sought to examine changes in network connectivity identified using resting-state functional MRI (fMRI) corresponding to divergent functional recovery trajectories and relapse in early-stage psychosis (ESP). Prior studies have linked schizophrenia to hyperconnectivity in the default mode network (DMN). Given the correlations between the DMN and behavioral impairments in psychosis, we hypothesized that dynamic changes in DMN connectivity reflect the heterogeneity of outcomes in ESP. Longitudinal data were collected from 66 ESP patients and 20 healthy controls. Longitudinal cluster analysis identified subgroups of patients with similar trajectories in terms of symptom severity and functional outcomes. DMN connectivity was measured in a subset of patients (n = 36) longitudinally over 2 scans separated by a mean of 12 months. We then compared connectivity between patients and controls, and among the different outcome trajectory subgroups. Among ESP participants, 4 subgroups were empirically identified corresponding to: "Poor," "Middle," "Catch-up," and "Good" trajectory outcomes in the complete dataset (n = 36), and an independent replication (n = 30). DMN connectivity changes differed significantly between functional subgroups (F3,32 = 6.06, P-FDR corrected = .01); DMN connectivity increased over time in the "Poor" outcome cluster (ß = +0.145) but decreased over time in the "Catch-up" cluster (ß = -0.212). DMN connectivity is dynamic and correlates with a change in functional status over time in ESP. This approach identifies a brain-based marker that reflects important neurobiological processes required to sustain functional recovery.


Subject(s)
Affective Disorders, Psychotic/physiopathology , Connectome , Default Mode Network/physiopathology , Psychotic Disorders/physiopathology , Schizophrenia/physiopathology , Adult , Affective Disorders, Psychotic/diagnostic imaging , Default Mode Network/diagnostic imaging , Disease Progression , Female , Functional Status , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Outcome Assessment, Health Care , Psychotic Disorders/diagnostic imaging , Schizophrenia/diagnostic imaging , Severity of Illness Index , Young Adult
5.
Harv Rev Psychiatry ; 28(4): 255-270, 2020.
Article in English | MEDLINE | ID: mdl-32692089

ABSTRACT

BACKGROUND: The prevalence of severe mental illness (SMI) in correctional settings is alarmingly high. Some correctional facilities have developed mental health units (MHUs) to treat incarcerated individuals with SMI. OBJECTIVE: To identify existing MHUs in the United States and collate information on these units. DATA SOURCES: A systematic review using Criminal Justice Abstracts, ERIC, PsycINFO, PubMed, and SocINDEX, plus an exploratory review using the Google search engine were conducted. MHUs were included if they were located within an adult correctional facility in the United States, specifically catered to SMI populations, and were in active operation as of June 2019. RESULTS: Eleven articles were identified through the peer-reviewed literature, but there were still major gaps in the information on MHUs. The Google search identified 317 MHUs. The majority of units were located within prisons (79.5%) and served only men (76%). The Google search found information indicating that 169 (53.3%) offered groups or programming to inmates; 104 (32.8%) offered individual therapy; and 89 (23%) offered both. One hundred sixty-six units (52.4%) had dedicated mental health staff, and 75 (23.7%) provided mental health training to correctional officers. Information on funding and outcomes of the MHUs is presented. LIMITATIONS: Use of the Google search engine and sources that have not been peer reviewed limits the robustness of conclusions about the MHUs. CONCLUSIONS: Standards for developing and implementing MHUs are not widespread. The shortcomings of current MHUs are discussed in the context of desired criteria for size, staffing, and programming.


Subject(s)
Correctional Facilities , Mental Health Services/organization & administration , Mental Health Services/standards , Prisoners , Humans , Mental Disorders/diagnosis , Mental Disorders/therapy , Mental Health/education , United States
6.
Front Psychiatry ; 10: 1011, 2019.
Article in English | MEDLINE | ID: mdl-32153431

ABSTRACT

Voice hearing (VH) can occur in trauma spectrum disorders (TSD) such as posttraumatic stress disorder (PTSD) and dissociative disorders. However, previous estimates of VH among individuals with TSD vary widely. In this study, we sought to better characterize the rate and phenomenology of VH in a sample of 70 women with TSD related to childhood abuse who were receiving care in a specialized trauma program. We compared the rate of VH within our sample using two different measures: 1) the auditory hallucination (AH) item in the Structured Clinical Interview for DSM-IV-TR (SCID), and 2) the thirteen questions involving VH in the Multidimensional Inventory of Dissociation (MID), a self-report questionnaire that comprehensively assesses pathological dissociation. We found that 45.7% of our sample met threshold for SCID AH, while 91.4% met criteria for MID VH. Receiver operating characteristics (ROC) analyses showed that while SCID AH and MID VH items have greater than chance agreement, the strength of agreement is only moderate, suggesting that SCID and MID VH items measure related but not identical constructs. Thirty-two patients met criteria for both SCID AH and at least one MID VH item ("unequivocal VH"), 32 for at least one MID VH item but not SCID AH ("ambiguous VH"), and 6 met criteria for neither ("unequivocal non-VH"). Relative to the ambiguous VH group, the unequivocal VH group had higher dissociation scores for child voices, and higher mean frequencies for child voices and Schneiderian voices. Our findings suggest that VH in women with TSD related to childhood abuse is common, but that the rate of VH depends on how the question is asked. We review prior studies examining AH and/or VH in TSD, focusing on the measures used to ascertain these experiences, and conclude that our two estimates are consistent with previous studies that used comparable instruments and patient samples. Our results add to growing evidence that VH-an experience typically considered psychotic or psychotic-like-is not equivalent to having a psychotic disorder. Instruments that assess VH apart from psychotic disorders and that capture their multidimensional nature may improve identification of VH, especially among patients with non-psychotic disorders.

7.
Breast Cancer Res ; 15(5): R91, 2013.
Article in English | MEDLINE | ID: mdl-24074261

ABSTRACT

INTRODUCTION: The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis. METHODS: We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays. RESULTS: Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes. CONCLUSIONS: These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis.


Subject(s)
Gene Expression , Mammary Glands, Animal/metabolism , Mammary Glands, Animal/pathology , cdc42 GTP-Binding Protein/genetics , Animals , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line , Cell Movement/genetics , Cell Proliferation , Cell Survival/genetics , Cell Transformation, Neoplastic/genetics , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , MAP Kinase Signaling System , Mice , Mice, Transgenic , Stromal Cells/metabolism , rac1 GTP-Binding Protein/metabolism , rhoA GTP-Binding Protein/metabolism
8.
Cancers (Basel) ; 4(2): 475-89, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22582143

ABSTRACT

Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP) deficiency inhibits ErbB2-induced mammary tumor formation in mice. Here we describe a novel role for p190B as a regulator of mitosis. We found that p190B localized to centrosomes during interphase and mitosis, and that it is differentially phosphorylated during mitosis. Knockdown of p190B expression in MCF-7 and Hela cells increased the incidence of aberrant microtubule-kinetochore attachments at metaphase, lagging chromosomes at anaphase, and micronucleation, all of which are indicative of aneuploidy. Cell cycle analysis of p190B deficient MCF-7 cells revealed a significant increase in apoptotic cells with a concomitant decrease in cells in G1 and S phase, suggesting that p190B deficient cells die at the G1 to S transition. Chemical inhibition of the Rac GTPase during mitosis reduced the incidence of lagging chromosomes in p190B knockdown cells to levels detected in control cells, suggesting that aberrant Rac activity in the absence of p190B promotes chromosome segregation defects. Taken together, these data suggest that p190B regulates chromosome segregation and apoptosis in cancer cells. We propose that disruption of mitosis may be one mechanism by which p190B deficiency inhibits tumorigenesis.

9.
J Immunol ; 179(9): 5829-38, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17947656

ABSTRACT

CD4(+) T cells are known to provide support for the activation and expansion of primary CD8(+) T cells, their subsequent differentiation, and ultimately their survival as memory cells. However, the importance of cognate memory CD4(+) T cells in the expansion of memory CD8(+) T cells after re-exposure to Ag has been not been examined in detail. Using bone marrow-derived dendritic cells pulsed with cognate or noncognate MHC class I- and class II-restricted peptides, we examined whether the presence of memory CD4(+) T cells with the same Ag specificity as memory CD8(+) T cells influenced the quantity and quality of the secondary CD8(+) T cell response. After recombinant vaccinia virus-mediated challenge, we demonstrate that, although cognate memory CD4(+) T cells are not required for activation of secondary CD8(+) T cells, their presence enhances the expansion of cognate memory CD8(+) T cells. Cognate CD4(+) T cell help results in an approximate 2-fold increase in the frequency of secondary CD8(+) T cells in secondary lymphoid tissues, and can be accounted for by enhanced proliferation in the secondary CD8(+) T cell population. In addition, cognate memory CD4(+) T cells further selectively enhance secondary CD8(+) T cell infiltration of tumor-associated peripheral tissue, and this is accompanied by increased differentiation into effector phenotype within the secondary CD8(+) T cell population. The consequence of these improvements to the magnitude and phenotype of the secondary CD8(+) T cell response is substantial increase in control of tumor outgrowth.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Cell Movement , Dendritic Cells/immunology , Immunologic Memory/immunology , Neoplasms/immunology , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Line , Cross-Priming/immunology , Dendritic Cells/cytology , Disease Progression , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Neoplasms/pathology
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