Publications by authors named "Daphne Holt"

78 Publications

Relationship between cannabis use and psychotic experiences in college students.

Schizophr Res 2021 Apr 19;231:198-204. Epub 2021 Apr 19.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.

Background: Emerging data suggest cannabis use is a component cause of psychotic disorders; however, the sequence of processes accounting for this association is poorly understood. Some clues have come from studies in laboratory settings showing that acute cannabis intoxication is associated with subclinical hallucinations and delusional thinking, i.e., "psychotic experiences". Although psychotic experiences are relatively common, those that are severe and distressing are linked to an increased risk of developing a psychotic disorder. This study aimed to investigate the association between the frequency of cannabis use and psychotic experiences in young adults.

Methods: 1034 U.S. college students completed questionnaires to assess: cannabis use in the past week, delusional ideation (Peters Delusions Inventory), hallucinations (Launay-Slade Hallucinations Scale-Extended), and depression (Beck Depression Inventory).

Results: Participants reporting higher rates of weekly cannabis use were more likely to report hallucinatory experiences and delusional ideation. The relationship between cannabis use and hallucinatory experiences, but not the relationship between cannabis use and delusional ideation, remained significant after controlling for levels of depression. Moreover, those who reported greater amounts of cannabis use had more distressing delusional ideas, that were held with more conviction.

Conclusions: Cannabis use is linked to the presence of subclinical hallucinations and delusional ideation in U.S. college students.
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http://dx.doi.org/10.1016/j.schres.2021.04.004DOI Listing
April 2021

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.

Psychiatry Res Neuroimaging 2021 Apr 7;312:111286. Epub 2021 Apr 7.

Department of Psychiatry, NYU Langone Health, 1 Park Avenue, New York, NY 10016, United States of America; Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States of America. Electronic address:

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.
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http://dx.doi.org/10.1016/j.pscychresns.2021.111286DOI Listing
April 2021

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

J Clin Psychopharmacol 2021 May-Jun 01;41(3):244-249

Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai.

Purpose/background: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation.

Methods/procedures: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2).

Findings/results: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES.

Implications/conclusions: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.
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http://dx.doi.org/10.1097/JCP.0000000000001391DOI Listing
April 2021

Anxious attachment is associated with heightened responsivity of a parietofrontal cortical network that monitors peri-personal space.

Neuroimage Clin 2021 Feb 10;30:102585. Epub 2021 Feb 10.

Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, United States; Harvard Medical School, Boston, MA, United States; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, United States. Electronic address:

Background: Attachment, or affiliative bonding among conspecifics, is thought to involve neural mechanisms underlying behavioral responses to threat and reward-related social signals. However, attachment-oriented responses may also rely on basic sensorimotor processes. One sensorimotor system that may play a role in attachment is the parietofrontal cortical network that responds to stimuli that are near or approaching the body, the peripersonal space (PPS) monitoring system. We hypothesized that this network may vary in responsivity to such potentially harmful stimuli, particularly those with social salience, based on individual differences in attachment styles.

Methods: Young adults viewed images of human faces or cars that appeared to move towards or away from them, while functional magnetic resonance imaging data were collected. Correlations between each of four adult attachment styles, measured using the Relationship Questionnaire, and responses of the PPS network to approaching (versus withdrawing) stimuli were measured.

Results: A region-of-interest (ROI) analysis, focused on six cortical regions of the PPS network that showed significant responses to approaching versus withdrawing face stimuli in an independent sample (n = 80), revealed that anxious attachment style (but not the other 3 attachment styles) was significantly positively correlated with responses to faces (but not to cars) in all six ROIs (r = 0.33-0.49, p = 0.01-0.0001, n = 50).

Conclusions: These findings suggest that anxious attachment is associated with over-responsivity of a sensorimotor network involved in attending to social stimuli near the body.
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http://dx.doi.org/10.1016/j.nicl.2021.102585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024770PMC
February 2021

Neural Abnormalities in Fear Generalization in Schizophrenia and Associations With Negative Symptoms.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jan 29. Epub 2021 Jan 29.

Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts; Harvard Medical School, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning.

Methods: To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging. Skin conductance and neural responses to conditioned (CS+), neutral (CS-), and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected after the scanning, as well as measures of symptom severity.

Results: Compared with healthy control subjects, individuals with nonaffective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the salience and default networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization were associated with higher levels of negative symptoms.

Conclusions: Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that can be investigated further in future human and experimental animal studies.
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http://dx.doi.org/10.1016/j.bpsc.2021.01.006DOI Listing
January 2021

Altered temporal, but intact spatial, features of transient network dynamics in psychosis.

Mol Psychiatry 2021 Jan 18. Epub 2021 Jan 18.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks ("states") in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering "single snapshots" of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = -0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.
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http://dx.doi.org/10.1038/s41380-020-00983-1DOI Listing
January 2021

Air pollution and hippocampal atrophy in first episode schizophrenia.

Schizophr Res 2020 04 10;218:63-69. Epub 2020 Mar 10.

NYU Langone Health Department of Psychiatry, New York, NY, United States of America; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States of America. Electronic address:

Air pollution has recently been linked to central nervous system (CNS) diseases, possibly mediated by inflammation and oxidative stress. Hippocampal atrophy in individuals with first episode schizophrenia (FES) has also been associated with biomarkers of inflammation and oxidative stress, whereas hippocampal atrophy was not observed in matched healthy controls with similar biomarker levels of inflammation and oxidative stress. Fine particulate matter (PM2.5), one component of air pollution, is most strongly implicated in CNS disease. The present study examined the association between PM2.5 and hippocampal volume in individuals with FES who participated in a 52-week placebo-controlled clinical trial of citalopram added to clinician-determined antipsychotic treatment at four sites in the US and China. Left hippocampal volumetric integrity (LHVI; inversely related to atrophy) was measured at baseline and week 52 using an automated highly-reliable algorithm. Mean annual PM2.5 concentrations were obtained from records compiled by the World Health Organization. The relationships between baseline LHVI and PM2.5 and change in LHVI and PM2.5 were evaluated using regression analyses. 89 participants completed imaging at baseline and 46 participants completed imaging at week 52. Mean annual PM2.5 was significantly associated with both baseline LHVI and change in LHVI after controlling for age, sex, baseline LHVI, duration of untreated psychosis and baseline antipsychotic medication dose. Air pollution may contribute to the progression of hippocampal atrophy after a first episode of illness, but these findings should be considered preliminary since other unmeasured factors may have differed between cities and contributed to the observed effect.
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http://dx.doi.org/10.1016/j.schres.2020.03.001DOI Listing
April 2020

Rationale, Methods, Feasibility, and Preliminary Outcomes of a Transdiagnostic Prevention Program for At-Risk College Students.

Front Psychiatry 2019 25;10:1030. Epub 2020 Feb 25.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States.

Purpose: Early adulthood represents one period of increased risk for the emergence of a serious mental illness. The college campus provides a unique opportunity to assess and monitor individuals in this at-risk age group. However, there are no validated early detection programs that are widely implemented on college campuses. In an effort to address this gap, we designed and tested an early detection and prevention program tailored to college students. A transdiagnostic approach was employed because of evidence for shared risk factors across major mental illnesses.

Design: Single arm, prospective study evaluating outcomes following a 4-week intervention.

Method: Three in-person mental health screenings were conducted on the campus of one university. Undergraduate students with at least mildly elevated, self-reported levels of depressive or subclinical psychotic symptoms, who were not receiving treatment for these symptoms, were invited to participate in a 4-session workshop focused on increasing self- and other- awareness and emotion regulation using established mindfulness, self-compassion, and mentalization principles and experiential exercises. Symptoms, resilience-promoting capacities, and aspects of social functioning were assessed pre- and post- intervention.

Results: 416 students were screened and a total of 63 students participated in the workshop. 91% attended at least 3 of the 4 sessions. The majority of participants found the workshop interesting and useful and would recommend it to a friend. Significant pre-to-post reductions in symptoms (depression, anxiety, and subclinical psychotic symptoms, s < 0.004) and improvements in resilience-promoting capacities (self-compassion and self-efficacy, s < 0.006) and indices of social functioning (social motivation, activity, and a measure of comfort with the physical presence of others, s < 0.04) were observed. Moreover, the significant increases in resilience-promoting capacities correlated with the reductions in affective symptoms (s < 0.03).

Conclusions: These findings suggest that an on-campus mental health screening and early intervention program is feasible, acceptable, and may be associated with improvements in resilience-related capacities and symptom reductions in young adults with non-impairing, subclinical symptoms of psychopathology. Follow-up work will determine whether this program can improve both shorter and longer-term mental health and functional outcomes in this at-risk population.
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http://dx.doi.org/10.3389/fpsyt.2019.01030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051934PMC
February 2020

Elevated Amygdala Activity in Young Adults With Familial Risk for Depression: A Potential Marker of Low Resilience.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 02 6;5(2):194-202. Epub 2019 Nov 6.

Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts.

Background: Amygdala overactivity has been frequently observed in patients with depression, as well as in nondepressed relatives of patients with depression. A remaining unanswered question is whether elevated amygdala activity in those with familial risk for depression is related to the presence of subthreshold symptoms or to a trait-level vulnerability for illness.

Methods: To examine this question, functional magnetic resonance imaging data were collected in nondepressed young adults with (family history [FH+]) (n = 27) or without (FH-) (n = 45) a first-degree relative with a history of depression while they viewed images of "looming" or withdrawing stimuli (faces and cars) that varied in salience by virtue of their apparent proximity to the subject. Activation of the amygdala and 2 other regions known to exhibit responses to looming stimuli, the dorsal intraparietal sulcus (DIPS) and ventral premotor cortex (PMv), were measured, as well as levels of resilience, anxiety, and psychotic and depressive symptoms.

Results: Compared with the FH- group, the FH+ group exhibited significantly greater responses of the amygdala, but not the dorsal intraparietal sulcus or ventral premotor cortex, to looming face stimuli. Moreover, amygdala responses in the FH+ group were negatively correlated with levels of resilience and unrelated to levels of subthreshold symptoms of psychopathology.

Conclusions: These findings indicate that elevated amygdala activity in nondepressed young adults with a familial history of depression is more closely linked to poor resilience than to current symptom state.
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http://dx.doi.org/10.1016/j.bpsc.2019.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448615PMC
February 2020

Deficient Hippocampal Habituation in Psychosis: A Manifestation of Hippocampal Overactivity?

Authors:
Daphne J Holt

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 11;4(11):938-939

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, and the Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.bpsc.2019.09.002DOI Listing
November 2019

Are Negative Symptoms Merely the "Real World" Consequences of Deficits in Social Cognition?

Schizophr Bull 2020 02;46(2):236-241

Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA.

Many investigations have demonstrated that negative symptoms and social cognitive deficits in schizophrenia play a large role in determining functional outcomes and ultimately long-term prognosis. Given this, there is increasing interest in understanding the relationship between these two symptom domains, particularly since studies have consistently found moderate to large associations between them. This shared variance raises a key question: to what degree do these two categories of symptoms arise from overlapping or identical changes in brain function? In other words, do some or all negative symptoms represent merely the downstream effects of social cognition deficits on daily functioning? In this commentary, the evidence for and against this possibility, limitations of currently validated empirical measurements of these symptoms, and directions for further investigation of this hypothesis are discussed. Understanding the shared and distinct mechanisms of these disabling deficits will have important implications for the design of novel, personalized treatments for psychotic illness.
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http://dx.doi.org/10.1093/schbul/sbz095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043060PMC
February 2020

The life-course approach to vaccination: Harnessing the benefits of vaccination throughout life.

Vaccine 2019 10 23;37(44):6581-6583. Epub 2019 Sep 23.

The Health Policy Partnership, 68-69 St Martin's Lane, London WC2N 4JS, United Kingdom. Electronic address:

Vaccination beyond childhood brings significant benefits at the individual, community and socio-economic levels. Despite this, immunisation programmes often fail to deliver the vaccines which could protect those at risk of vaccine-preventable diseases. In this commentary, we argue that the benefits of vaccination beyond childhood must be more widely understood and furthermore, that action must be taken by policymakers, healthcare professionals and patient and civil society organisations to ensure that the benefits of vaccination are fully realised. We outline five areas where change is needed to ensure vaccination across the life-course becomes truly embedded in national immunisation programmes. This includes investing in robust data collection and analysis; ensuring coordinated, multidisciplinary leadership from the top; engaging healthcare professionals; changing public perceptions of vaccination; and integrating vaccination into schools and workplaces.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.016DOI Listing
October 2019

Correction: Progressive decline in hippocampal CA1 volume in individuals at ultra-high-risk for psychosis who do not remit: findings from the longitudinal youth at risk study.

Neuropsychopharmacology 2019 Nov;44(12):2144

Neuroscience and Behavioral Disorders Program, Center for Cognitive Neuroscience, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41386-019-0477-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898685PMC
November 2019

Neuroepigenetic signatures of age and sex in the living human brain.

Nat Commun 2019 07 3;10(1):2945. Epub 2019 Jul 3.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior.
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http://dx.doi.org/10.1038/s41467-019-11031-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610136PMC
July 2019

Increased amygdala-visual cortex connectivity in youth with persecutory ideation.

Psychol Med 2020 01 12;50(2):273-283. Epub 2019 Feb 12.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.

Background: Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis.

Methods: A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured.

Results: Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs.

Conclusions: These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.
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http://dx.doi.org/10.1017/S0033291718004221DOI Listing
January 2020

Citalopram in first episode schizophrenia: The DECIFER trial.

Schizophr Res 2019 06 30;208:331-337. Epub 2019 Jan 30.

National Clinical Research Center for Mental Disorders, Mental Health Institute, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan, China.

Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms.
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http://dx.doi.org/10.1016/j.schres.2019.01.028DOI Listing
June 2019

The relationship of perceptual discrimination to neural mechanisms of fear generalization.

Neuroimage 2019 03 18;188:445-455. Epub 2018 Dec 18.

Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.

The generalization of conditioned fear responses has been shown to decrease as a function of perceptual similarity. However, generalization may also extend beyond the perceptual discrimination threshold, ostensibly due to contributions from processes other than perception. Currently the neural mechanisms that mediate perceptual and non-perceptual aspects of fear generalization are unclear. To investigate this question, we conducted a Pavlovian fear conditioning and generalization experiment, collecting functional magnetic resonance imaging (fMRI), skin conductance and explicit shock likelihood ratings, in 37 healthy subjects. Face stimuli were initially paired (CS+) or not paired (CS) with an electrical shock. During the generalization phase, responses were measured to the CS+, CS and a range of CS + -toCS morphs (generalization stimuli), selected for each participant based on that participant's discrimination ability. Across multiple measurements, we found that fear generalization responses were limited to stimuli that could not be distinguished from the CS + stimulus, thus following a gradient closely linked to perceptual discriminability. These measurements, which were correlated with one another, included skin conductance responses, behavioral ratings, and fMRI responses of anterior insula and superior frontal gyrus. In contrast, responses in areas of the default network, including the posterior cingulate gyrus, angular gyrus and hippocampus, showed a negative generalization function extending to stimuli that were more likely to be distinguished from the CS+. In addition, the generalization gradients of the anterior insula and the behavioral ratings showed some evidence for extension beyond perceptual limits. Taken together, these results suggest that distinct brain areas are involved in perceptual and non-perceptual components of fear generalization.
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http://dx.doi.org/10.1016/j.neuroimage.2018.12.034DOI Listing
March 2019

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.

J Clin Invest 2019 01 10;129(1):364-372. Epub 2018 Dec 10.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Background: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET).

Methods: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered.

Results: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.

Conclusions: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.

Funding: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.
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http://dx.doi.org/10.1172/JCI123743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307962PMC
January 2019

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.

J Clin Invest 2019 01 10;129(1):364-372. Epub 2018 Dec 10.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

Background: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET).

Methods: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered.

Results: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls.

Conclusions: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans.

Funding: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.
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http://dx.doi.org/10.1172/JCI123743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307962PMC
January 2019

The Shared Genetic Basis of Educational Attainment and Cerebral Cortical Morphology.

Cereb Cortex 2019 07;29(8):3471-3481

Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Individual differences in educational attainment are linked to differences in intelligence, and predict important social, economic, and health outcomes. Previous studies have found common genetic factors that influence educational achievement, cognitive performance and total brain volume (i.e., brain size). Here, in a large sample of participants from the UK Biobank, we investigate the shared genetic basis between educational attainment and fine-grained cerebral cortical morphological features, and associate this genetic variation with a related aspect of cognitive ability. Importantly, we execute novel statistical methods that enable high-dimensional genetic correlation analysis, and compute high-resolution surface maps for the genetic correlations between educational attainment and vertex-wise morphological measurements. We conduct secondary analyses, using the UK Biobank verbal-numerical reasoning score, to confirm that variation in educational attainment that is genetically correlated with cortical morphology is related to differences in cognitive performance. Our analyses relate the genetic overlap between cognitive ability and cortical thickness measurements to bilateral primary motor cortex as well as predominantly left superior temporal cortex and proximal regions. These findings extend our understanding of the neurobiology that connects genetic variation to individual differences in educational attainment and cognitive performance.
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http://dx.doi.org/10.1093/cercor/bhy216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644848PMC
July 2019

Lessons from an online vaccine communication project.

Vaccine 2018 10 18;36(44):6509-6511. Epub 2018 Jun 18.

University of Florence, Italy.

Most members of the general public use the internet to research health topics. However, the quality of vaccine-related material available online is mixed and internet search engines often bring web users to low-quality anti-vaccine websites. We present a case study of a pro-vaccine information hub launched in 2011. Vaccines Today provides high-quality information about vaccines and diseases, expert interviews, answers to frequently asked questions, parent/patient stories and videos/infographics. Twitter, Facebook, YouTube and Instagram are used to share this content and to engage with various online audiences. This Commentary outlines what works in online communication about vaccines and offers proposals for improving the impact of online vaccine advocacy. The value of networking to boost visibility and search engine ranking is emphasised. Furthermore, we present the case for the sharing and application of best practice in online communication.
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http://dx.doi.org/10.1016/j.vaccine.2018.05.007DOI Listing
October 2018

Regional GABA Concentrations Modulate Inter-network Resting-state Functional Connectivity.

Cereb Cortex 2019 04;29(4):1607-1618

Psychotic Disorders Division, McLean Hospital, Harvard Medical School, Belmont, MA, USA.

Coordinated activity within and differential activity between large-scale neuronal networks such as the default mode network (DMN) and the control network (CN) is a critical feature of brain organization. The CN usually exhibits activations in response to cognitive tasks while the DMN shows deactivations; in addition, activity between the two networks is anti-correlated at rest. To address this issue, we used functional MRI to measure whole-brain BOLD signal during resting-state and task-evoked conditions, and MR spectroscopy (MRS) to quantify GABA and glutamate concentrations, in nodes within the DMN and CN (MPFC and DLPFC, respectively) in 19 healthy individuals at 3 Tesla. We found that GABA concentrations in the MPFC were significantly associated with DMN deactivation during a working memory task and with anti-correlation between DMN and CN at rest and during task performance, while GABA concentrations in the DLPFC weakly modulated DMN-CN anti-correlation in the opposite direction. Highlighting specificity, glutamate played a less significant role related to brain activity. These findings indicate that GABA in the MPFC is potentially involved in orchestrating between-network brain activity at rest and during task performance.
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http://dx.doi.org/10.1093/cercor/bhy059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418388PMC
April 2019

Correlation Between Levels of Delusional Beliefs and Perfusion of the Hippocampus and an Associated Network in a Non-Help-Seeking Population.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 02 13;3(2):178-186. Epub 2017 Jul 13.

Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts. Electronic address:

Background: Delusions are a defining and common symptom of psychotic disorders. Recent evidence suggests that subclinical and clinical delusions may represent distinct stages on a phenomenological and biological continuum. However, few studies have tested whether subclinical psychotic experiences are associated with neural changes that are similar to those observed in clinical psychosis. For example, it is unclear if overactivity of the hippocampus, a replicated finding of neuroimaging studies of schizophrenia, is also present in individuals with subclinical psychotic symptoms.

Methods: To investigate this question, structural and pulsed arterial spin labeling scans were collected in 77 adult participants with no psychiatric history. An anatomical region of interest approach was used to extract resting perfusion of the hippocampus, and 15 other regions, from each individual. A self-report measure of delusional ideation was collected on the day of scanning.

Results: The level of delusional thinking (number of beliefs [r = .27, p = .02]), as well as the associated level of distress (r = .29, p = .02), was significantly correlated with hippocampal perfusion (averaged over right and left hemispheres). The correlations remained significant after controlling for age, hippocampal volume, symptoms of depression and anxiety, and image signal-to-noise ratio, and they were confirmed in a voxelwise regression analysis. The same association was observed in the thalamus and parahippocampal, lateral temporal, and cingulate cortices.

Conclusions: Similar to patients with schizophrenia, non-help-seeking individuals show elevated perfusion of a network of limbic regions in association with delusional beliefs.
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http://dx.doi.org/10.1016/j.bpsc.2017.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854214PMC
February 2018

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

Schizophr Res 2018 05 3;195:306-317. Epub 2017 Oct 3.

The Cognitive Genetics and Cognitive Therapy Group, Department of Psychology, National University of Ireland, Galway, Ireland.

Background: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection.

Methods: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site.

Results: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other.

Conclusions: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2017.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882601PMC
May 2018

Progressive Decline in Hippocampal CA1 Volume in Individuals at Ultra-High-Risk for Psychosis Who Do Not Remit: Findings from the Longitudinal Youth at Risk Study.

Neuropsychopharmacology 2017 May 12;42(6):1361-1370. Epub 2017 Jan 12.

Neuroscience and Behavioral Disorders Program, Center for Cognitive Neuroscience, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.

Most individuals identified as ultra-high-risk (UHR) for psychosis do not develop frank psychosis. They continue to exhibit subthreshold symptoms, or go on to fully remit. Prior work has shown that the volume of CA1, a subfield of the hippocampus, is selectively reduced in the early stages of schizophrenia. Here we aimed to determine whether patterns of volume change of CA1 are different in UHR individuals who do or do not achieve symptomatic remission. Structural MRI scans were acquired at baseline and at 1-2 follow-up time points (at 12-month intervals) from 147 UHR and healthy control subjects. An automated method (based on an ex vivo atlas of ultra-high-resolution hippocampal tissue) was used to delineate the hippocampal subfields. Over time, a greater decline in bilateral CA1 subfield volumes was found in the subgroup of UHR subjects whose subthreshold symptoms persisted (n=40) and also those who developed clinical psychosis (n=12), compared with UHR subjects who remitted (n=41) and healthy controls (n=54). No baseline differences in volumes of the overall hippocampus or its subfields were found among the groups. Moreover, the rate of volume decline of CA1, but not of other hippocampal subfields, in the non-remitters was associated with increasing symptom severity over time. Thus, these findings indicate that there is deterioration of CA1 volume in persistently symptomatic UHR individuals in proportion to symptomatic progression.
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http://dx.doi.org/10.1038/npp.2017.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437892PMC
May 2017

The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection.

Expert Rev Vaccines 2017 04 22;16(4):313-328. Epub 2016 Nov 22.

r Department of Pediatrics , FCM da Santa Casa de São Paulo , São Paulo , Brazil.

Introduction: The 2015 Global Meningococcal Initiative (GMI) meeting discussed the global importance of meningococcal disease (MD) and its continually changing epidemiology. Areas covered: Although recent vaccination programs have been successful in reducing incidence in many countries (e.g. Neisseria meningitidis serogroup [Men]C in Brazil, MenA in the African meningitis belt), new clones have emerged, causing outbreaks (e.g. MenW in South America, MenC in Nigeria and Niger). The importance of herd protection was highlighted, emphasizing the need for high vaccination uptake among those with the highest carriage rates, as was the need for boosters to maintain individual and herd protection following decline of immune response after primary immunization. Expert commentary: The GMI Global Recommendations for Meningococcal Disease were updated to include a recommendation to enable access to whole-genome sequencing as for surveillance, guidance on strain typing to guide use of subcapsular vaccines, and recognition of the importance of advocacy and awareness campaigns.
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http://dx.doi.org/10.1080/14760584.2017.1258308DOI Listing
April 2017

A Pathway to Understanding Emotional Dysfunction in Schizophrenia.

Authors:
Daphne J Holt

JAMA Psychiatry 2016 06;73(6):555-6

Department of Psychiatry, Massachusetts General Hospital, Boston2Harvard Medical School, Boston, Massachusetts3The Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts.

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http://dx.doi.org/10.1001/jamapsychiatry.2016.0172DOI Listing
June 2016

Corrigendum to abnormalities in personal space and parietal-frontal function in schizophrenia.

Neuroimage Clin 2016 3;11:538. Epub 2016 Apr 3.

Harvard Medical School, Boston, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA; Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.nicl.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840402PMC
April 2016

Alterations of lateral temporal cortical gray matter and facial memory as vulnerability indicators for schizophrenia: An MRI study in youth at familial high-risk for schizophrenia.

Schizophr Res 2016 Jan 24;170(1):123-9. Epub 2015 Nov 24.

Harvard Medical School, Department of Psychiatry at Massachusetts General Hospital, Boston, MA 02114, United States; Harvard Medical School, Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA 02115, United States; The HST-MIT Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, United States.

Background: Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness.

Methods: Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphometry. The Wechsler Memory Scale - Third Edition and the Children's Memory Scale - Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory.

Results: Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in relatives.

Conclusion: These results support the hypothesis that smaller middle temporal gyri are related to the genetic liability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs.
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http://dx.doi.org/10.1016/j.schres.2015.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707114PMC
January 2016