Journal Article Annotations
2021, 3rd Quarter

Neuropsychiatry

Annotations by Brandon Francis MD, MPH
September, 2021

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.
Individuals at increased risk for development of bipolar disorder display structural alterations similar to people with manifest disease.
Magnetic resonance imaging of brain anomalies in adult and pediatric schizophrenia patients: Experience of a Romanian tertiary hospital.

PUBLICATION #1 — Neuropsychiatry

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

ENIGMA Clinical High Risk for Psychosis Working Group; Maria Jalbrzikowski, Rebecca A Hayes, Stephen J Wood, Dorte Nordholm, Juan H Zhou, Paolo Fusar-Poli, Peter J Uhlhaas, Tsutomu Takahashi, Gisela Sugranyes, Yoo Bin Kwak, Daniel H Mathalon, Naoyuki Katagiri, Christine I Hooker, Lukasz Smigielski, Tiziano Colibazzi, Esther Via, Jinsong Tang, Shinsuke Koike, Paul E Rasser, Chantal Michel, Irina Lebedeva, Wenche Ten Velden Hegelstad, Camilo de la Fuente-Sandoval, James A Waltz, Romina Mizrahi, Cheryl M Corcoran, Franz Resch, Christian K Tamnes, Shalaila S Haas, Imke L J Lemmers-Jansen, Ingrid Agartz, Paul Allen, G Paul Amminger, Ole A Andreassen, Kimberley Atkinson, Peter Bachman, Inmaculada Baeza, Helen Baldwin, Cali F Bartholomeusz, Stefan Borgwardt, Sabrina Catalano, Michael W L Chee, Xiaogang Chen, Kang Ik K Cho, Rebecca E Cooper, Vanessa L Cropley, Montserrat Dolz, Bjørn H Ebdrup, Adriana Fortea, Louise Birkedal Glenthøj, Birte Y Glenthøj, Lieuwe de Haan, Holly K Hamilton, Mathew A Harris, Kristen M Haut, Ying He, Karsten Heekeren, Andreas Heinz, Daniela Hubl, Wu Jeong Hwang, Michael Kaess, Kiyoto Kasai, Minah Kim, Jochen Kindler, Mallory J Klaunig, Alex Koppel, Tina D Kristensen, Jun Soo Kwon, Stephen M Lawrie, Jimmy Lee, Pablo León-Ortiz, Ashleigh Lin, Rachel L Loewy, Xiaoqian Ma, Patrick McGorry, Philip McGuire, Masafumi Mizuno, Paul Møller, Tomas Moncada-Habib, Daniel Muñoz-Samons, Barnaby Nelson, Takahiro Nemoto, Merete Nordentoft, Maria A Omelchenko, Ketil Oppedal, Lijun Ouyang, Christos Pantelis, Jose C Pariente, Jayachandra M Raghava, Francisco Reyes-Madrigal, Brian J Roach, Jan I Røssberg, Wulf Rössler, Dean F Salisbury, Daiki Sasabayashi, Ulrich Schall, Jason Schiffman, Florian Schlagenhauf, Andre Schmidt, Mikkel E Sørensen, Michio Suzuki, Anastasia Theodoridou, Alexander S Tomyshev, Jordina Tor, Tor G Værnes, Dennis Velakoulis, Gloria D Venegoni, Sophia Vinogradov, Christina Wenneberg, Lars T Westlye, Hidenori Yamasue, Liu Yuan, Alison R Yung, Thérèse A M J van Amelsvoort, Jessica A Turner, Theo G M van Erp, Paul M Thompson, Dennis Hernaus

Abstract: JAMA Psychiatry. 2021 Jul 1;78(7):753-766. doi: 10.1001/jamapsychiatry.2021.0638.

Importance:
The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective:
To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, setting, and participants:
In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main outcomes and measures:
Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results:
Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions and relevance:
This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Annotation

The finding:
This case-control study of structural MRI findings for patients with high risk of psychotic-spectrum disorders found that those with decreased cortical thickness were at increased risk. Specifically, those with decreased cortical thickness in the right fusiform, left superior temporal and bilateral paracentral regions demonstrated increased conversion to a psychotic disorder.

Strength and weaknesses:
This study is the largest (3169 patients) using structural MRI to evaluate cortical thickness in patients having significant clinical risk factors for the development of psychotic disorders. It was an international multisite study, and differences in MRI scanners were controlled by using standard protocols and adjudication methods reported. The study focused on baseline assessments which limits the ability to understand any anatomic changes that may occur leading to or during the conversion to a psychotic disorder. The primary limitation inherent to this type of work relates to the reality that patients with clinical risk factors can have variable outcomes in different areas such as psychosocial functioning and other psychiatric illnesses such as anxiety. This study was not designed to capture the other areas of functioning that might be impacted by neuroanatomic changes such as cortical thickness.

Relevance:
Reduced cortical thickness has been associated with schizophrenia and other psychotic spectrum disorders. Utilizing structural MRI for clinical decision-making is not currently standard of care. However, understanding the potential influences of post-natal brain development may have on the development of psychotic disorders may one day provide a predictive anatomic diagnostic data point. Aligned with previous studies, no correlation was found with respect to subcortical volume changes and psychosis.

PUBLICATION #2 — Neuropsychiatry

Individuals at increased risk for development of bipolar disorder display structural alterations similar to people with manifest disease.

Pavol Mikolas, Kyra Bröckel, Christoph Vogelbacher, Dirk K Müller, Michael Marxen, Christina Berndt, Cathrin Sauer, Stine Jung, Juliane Hilde Fröhner, Andreas J Fallgatter, Thomas Ethofer, Anne Rau, Tilo Kircher, Irina Falkenberg, Martin Lambert, Vivien Kraft, Karolina Leopold, Andreas Bechdolf, Andreas Reif, Silke Matura, Thomas Stamm, Felix Bermpohl, Jana Fiebig, Georg Juckel, Vera Flasbeck, Christoph U Correll, Philipp Ritter, Michael Bauer, Andreas Jansen, Andrea Pfennig

Abstract: Transl Psychiatry. 2021 Sep 20;11(1):485. doi: 10.1038/s41398-021-01598-y.

In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.

Annotation

The finding:
This multisite population-based observational study (no control group) used the EPIBipolar semi-structured interview tool to risk stratify patients into no risk, low risk or high risk for bipolar disorder. T1-weighted (and some functional) sequences were obtained. Patients with diagnosed bipolar disorder, schizophrenia or other psychotic disorders were excluded. They also excluded those with substance-dependence disorders that fully explained the patient’s symptoms. They evaluated 263 patients and found a significant difference in the cortical thickness of the left infero-frontal pars opercularis between high risk and no risk groups. Those with high risk demonstrated a thinner cortex (p = < 0.024).

Strength and weaknesses:
Each of the seven different sites that participated attempted to use similar protocols for each sequence of interest. However, the software and hardware were not identical among sites. This study used a structured tool to stratify patients at risk of development of bipolar disorder. The primary limitation of the study was the lack of follow up to ascertain which patients actually developed bipolar disorder. While the findings are aligned with cortical thickness changes previously reported in patients with bipolar disorder, long-term follow up would be helpful in more clearly demonstrating a functional relationship between cortical thickness and diagnostic outcomes.

Relevance:
The infero-frontal gyrus (pars opercularis) has been implicated in emotional dysregulation and may play an important part in mood disorders. This study highlights the role that neuroimaging may play in assisting the C-L Psychiatrist in identifying patients at risk. While not standard of care, neuroimaging may represent an untapped diagnostic resource for those caring for patients at high risk for bipolar disorder.

PUBLICATION #3 — Neuropsychiatry

Magnetic resonance imaging of brain anomalies in adult and pediatric schizophrenia patients: Experience of a Romanian tertiary hospital.

Floris Petru Iliuta, Mihnea Costin Manea, Magdalena Budisteanu, Emanuela Andrei, Florentina Linca, Florina Rad, Romica Cergan, Adela Magdalena Ciobanu

Abstract: Exp Ther Med. 2021 Oct;22(4):1098. doi: 10.3892/etm.2021.10532. Epub 2021 Aug 2.

Schizophrenia is a severe mental illness with a significant impact on the life of both the patient and the patient’s family. Magnetic resonance imaging has proven a useful tool for studying structural changes of the brain in schizophrenia. However, interpreting the published literature presents several challenges. Despite thorough research in recent years, which has included anatomopathological, imaging, electrophysiological, and genetic studies, the intimate pathophysiological mechanisms of this disease are not yet fully elucidated. The present study included patients with schizophrenia diagnosed in the psychiatric clinics from the ‘Prof. Dr. Alexandru Obregia’ Clinical Psychiatry Hospital between September 2019 and December 2020. Three Tesla magnetic resonance neuroimaging studies were performed. In a significant number of cases, the neuroimaging studies showed association of cerebral modifications such as enlargement of the Virchow spaces, lesions of the white matter with demyelinating appearance, and inflammatory sinus reactions. Cortical atrophy and hemosiderotic spots were present in a statistically significant proportion in the patient group with an age range of 29-61 years. MRI is indicated as a useful technique in the follow-up process of schizophrenia patients. However, whether the anomalies revealed in this disorder can be utilised as diagnostic biomarkers is still being debated.

Annotation

The finding:
This single site, observational study evaluated neuroanatomic changes using a 3 Tesla MRI with 45 patients (from ages 13-, mean 26 years) who have schizophrenia and were admitted to a psychiatric hospital. The investigators found enlargement of Virchow’s spaces (97% of those with schizophrenia), sinusitis (60%) and demyelinating lesions (36%).

Strength and weaknesses:
This study reported a lower rate cortical atrophy (9% of patients) compared to prior studies, which may reflect the high proportion of pediatric patients in the study. They also included patients who were actively taking antipsychotic medications without controlling for the duration of that treatment. The effect of antipsychotic psychopharmacology on MRI brain anatomy has not been fully explored, rendering the data presented in this study difficult to interpret. The study is also relatively small and without any comparative imaging, it is difficult to determine if there were any temporal relationships that need to be considered.

Relevance:
MRI sequences can provide accurate neuroanatomic information in patients with schizophrenia. While not standard of care, in the future, MRI may assist in the differential diagnosis, prognosis and follow up for patients with schizophrenia. More study is needed with respect to effect of pharmacotherapy (and substance use) on these neuroanatomic changes in this population as well as comparative imaging such that longitudinal relationships can be explored.