Tellurium occurs as TeIV, TeV, and TeVI in these phases which demonstrate the high chemical flexibility of the system. Uranium VI) adopts a variety of coordinations, namely, UO6 in K2  and Sr [(UO2) (TeO3)2], and UO8 in Sr [(UO2) (TeO5)]. The structure of K2 [(UO2) (Te2O7)] is featured with one dimensional (1D) [Te2O7]4- chains along the c-axis. The Te2O7 chains are further linked by UO6 polyhedra, forming the 3D [(UO2) (Te2O7)]2- anionic frameworks. In Mg [(UO2) (TeO3)2], TeO4 disphenoids share common corners with each other resulting in infinite 1D chains of [(TeO3)2]4- propagating along the a-axis. These chains link the uranyl bipyramids by edge sharing along two edges of the disphenoids, resulting in the 2D layered structure of [(UO2) (Te2O6)]2-. The structure of Sr [(UO2) (TeO3)2] is based on 1D chains of [(UO2) (TeO3)2]∞2− propagating into the c-axis. These chains are formed by edge-sharing uranyl bipyramids which are additionally fused together by two TeO4 disphenoids, which also share two edges. The 3D framework structure of Sr [(UO2) (TeO5)] is composed of 1D [TeO5]4− chains sharing edges with UO7 bipyramids. Three tunnels based on 6-Membered rings (MRs) are propagating along [001] [010] and [100] directions. The HT/HP synthetic conditions for the preparation of single crystalline samples and their structural aspects are discussed in this work.The study of phase formation in the U-Te-O systems with mono and divalent cations under high-temperature high-pressure (HT/HP) conditions has resulted in four new inorganic compounds: K BesidesO2)TeO6) . MoctezuO2)TeO6) .VI. Hereby, uranium is present as almost linear trans dioxo-cations  both in solid state as well as in solution. Within the solid state, the typical coordination environment surrounding the dioxo-cations is a bipyramid, in which the uranyl forms the central axis and additional four to six oxygen atoms occupy sites within the equatorial plane, leading to tetragonal, pentagonal or hexagonal bipyramids  in which all three coordination geometries of Te are present  typically adopts trigonal bipyramidal, distorted octahedral or tetrahedral coordination in oxygen phases. A few ditellurates contain mixed valent tellurium, TeIV and TeVI, ACuTe2O7  and BaMTe2O7 (M = Mg or Zn) have been previously reported . These phases are of interest for potential applications in the fields of second harmonic generation (SHG) as well as ferro- and piezo-and pyroelectricity . This acnt years . Howevernt years .A-U-Te-O  system under extreme conditions (HT/HP). Our goal is to further understand the different chemical behavior of actinide-tellurium oxo-phases from extreme conditions compared to conventional ones and to develop a methodology of how these phases crystallize under the extreme environment. As a result of this study, a series of quaternary oxide tellurium materials, K2 [(UO2) (Te2O7)], Mg [(UO2) (TeO3)2], Sr [(UO2) (TeO3)2] and Sr [(UO2) (TeO5)] have been prepared by the HT/HP solid state reaction method. In which, K2 [(UO2) (Te2O7)] is a very rare example of a TeV bearing phase. The detailed HT/HP synthetic routes, high-temperature and high-pressure behavior, and topology of the structures are discussed.We have recently systematically studied the Caution!The UO2(NO3)2⋅6H2O used in this work contained natural uranium; nevertheless the standard precautions for handling radioactive materials must be followed. The γ-UO3was formed simply by heating the uranyl nitrate and analyzing it with powder XRD  (Te2O7)]. Uranium trioxide UO3 , KNO3 , TeO2 , and H6TeO6  in a molar ratio of UO3: KNO3: TeO2: H6TeO6 = 1 : 3: 2 : 4 were mixed together and finely ground. Then, the mixture was filled into a platinum capsule . The capsule was sealed on both sides with an impulse micro welding device (Lampert PUK U4) and placed into the center of a 1/2-inch piston cylinder talc-pyrex assembly. After this, the capsule was inserted into a 6 mm diameter MgO spacer and positioned in the center of a tapered graphite furnace. The final run pressure of 3.5 GPa was applied within 30 min, then the temperature program was started. With a heating rate of 100 K min-1 the temperature was increased to the maximum temperature of 1173 K. After 1 h of annealing, the temperature was decreased to 570 K over a time period of 106 h (cooling rate 0.11 K min-1). At 570 K, the experiment was automatically quenched to room temperature. After decompression for 20 min, the capsule was extracted out of the high-pressure assembly and broken. The product of yellow crystals were picked up for further analysis. The yield was impossible to be determined due to the similarity of broken glass pieces and obtained crystals.Mg[(UO2) (TeO3)2]. For the synthesis of Mg [(UO2) (TeO3)2], UO3 , Mg(NO3)2 , TeO2 , and H6TeO6  were weighed with a molar ratio of 1:3:1:2 and subsequently thoroughly ground before being filled into platinum capsule. The operations of sealing the platinum capsule and opening it after the reactions are same as mentioned above for the synthesis of K2 [(UO2) (Te2O7)]. The pressure of 3.5 GPa was used within 30 min, then the temperature program was started. It was heated up to 1373 K with a heating rate of 100 K min-1. After a holding time of 4 h at 1373 K, the temperature was decreased to 1173 K in 1h, and then cooled to 623 K over a time period of 90 h (cooling rate 0.10 K min-1). At 623 K, the experiment was automatically quenched to room temperature. After decompression for 20 min, the capsule was extracted out of the high-pressure assembly and broken. The product containing small yellow crystals were picked up for further analysis.Sr[(UO2) (TeO3)2] and Sr[(UO2) (TeO5)]. Both phases co-precipitated using a finely ground mixture of UO3 , Sr(CO3) , TeO2 , and H6TeO6  with a molar ratio of 1:1:1:1. The pressure of 3.5 GPa was applied within 30 min, then the temperature program was started. It was heated up to 1273 K with a heating rate of 100 K min-1. After a holding time of 4 h at 1273 K, the temperature was cooled down to 1073 K in 1h, and then decreased to 573 K over a time period of 50 h (cooling rate 0.17 K min-1). At 573 K, the experiment was automatically quenched to room temperature. After decompression for 20 min, the capsule was extracted out of the high-pressure assembly and broken. The product containing small yellow crystals together with colorless remains of the educts, mainly consisting of SrCO3. The small yellow crystals were picked up for further analysis.α radiation (λ = 0.71073 Å) at room temperature. All data sets were corrected for Lorentz and polarization factors as well as for absorption by the multi-scan method (F2 by SHELX (2 [(UO2) (Te2O7)], Mg [(UO2) (TeO3)2], Sr [(UO2) (TeO3)2] and Sr [(UO2) (TeO5)], respectively.Single crystal X-ray diffraction data for all four compounds were collected on an Agilent Technologies SuperNova diffractometer with Mo-Kn method . The strby SHELX . Their sby SHELX . CrystalAs a semi-empirical method for the approximate determination of valence states, BVS of all atoms in both phases were calculated. The bond-valence parameters for U(VI)-O, K(I)-O, Mg(II)-O, Sr(II)-O, Te(IV)-O, Te(V)-O and Te(VI)-O were used according to Burns , Brese aA-U-Te-O  system under extreme HT/HP conditions  yielded four novel compounds: K2 [(UO2) (Te2O7)], Mg [(UO2) (TeO3)2], Sr [(UO2) (TeO3)2] and Sr [(UO2) (TeO5)]. K2 [(UO2) (Te2O7)] was obtained through the usage of UO3: KNO3: TeO2: H6TeO6 in a ratio of 1 : 3: 2 : 4. Although analytical-grade TeⅠVO2 and H6TeVⅠO6 were used as an initial reagent, interestingly, tellurium occurs as TeV with a 5+ oxidation state in K2 [(UO2) (Te2O7)]. We concluded that TeⅠVO2 and H6TeVⅠO6 undergo an oxidation-reduction chemical reaction opposite to the disproportionation of TeV under the extreme conditions . Attempts were made to synthesize K2 [(UO2) (Te2O7)] through high temperature solid state reaction at ambient pressure, however this was unsuccessful. This suggests the high pressure is an essential factor for this redox reaction. For the synthesis of Mg [(UO2) (TeⅠVO3)2]: UO3, Mg(NO3)2, TeO2 and H6TeO6 were taken in molar ratios of 1 : 2: 3:1. Whereas both phases of Sr [(UO2) (TeⅠVO3)2] and Sr [(UO2) (TeVⅠO5)] co-precipitated using a finely ground mixture of UO3, Sr(CO3), TeO2 and H6TeO6 with a molar ratio of 1:1:1:1. We presumed that the ratios of TeO2 and H6TeO6 were used in the original reagents has also played a key role for the final oxidation states of tellurium in the compounds. The obtained materials have been found in the form of relatively small single crystals (up to 1 mm size). We presume that they grow up within so called self-flux which is usual for the materials crystallization from multicomponent high-temperature solid-state systems (The investigation of the  systems .2 [(UO2) (Te2O7)] crystallizes in the monoclinic space group C2/c. The structure of K2 [(UO2) (Te2O7)] can be described as a 3D open framework composed of uranium and tellurium polyhedra  sharing linkage along the c-axis  (Te2O7)]2- anionic framework  (Te2O7)], respectively. Corner-shared TeO6 octahedra form a one-dimensional double-chain along the c-axis, and these chains are further connected by UO6 polyhedra along the b-axis, resulting in the 3D network  to two TeO6 octahedra and edge-shared (O2-O3) to two TeO6 octahedra. The Te-O bond distances in TeO6 octahedra range between 1.888(4) and 1.979(4) Å, whereas the U-O bond distances are in the range of [1.992(4)-2.031(4) Å]. Potassium cations are 10-oxygen coordinated and K-O bond distances range from 2.676(5) to 3.304(5) Å. All the bond angles and bond lengths in K2 [(UO2) (Te2O7)] are as shown in There is one crystallographically unique tellurium site Te (1), one uranium site U (1), one potassium site K (1) and five oxygen sites O (1)-O (5) in the structures of K network . The UO62 [(UO2) (Te2O7)] with the series of A [CuTe2O7]  and Ba [MTe2O7] (M = Mg or Zn)  (Te2O7)], A [CuTe2O7]  and Ba [MTe2O7] (M = Mg or Zn) have same stoichiometries, the structure of K2 [(UO2) (Te2O7)] is different from that series. In K2 [(UO2) (Te2O7)], Te atoms occur as TeV as TeO6 polyhedra, whereas in A [CuTe2O7]  and Ba [MTe2O7] (M = Mg or Zn) they are mixed valent tellurium, Te4+ and Te6+. SrCuTe2O7 and PbCuTe2O7 are isostructural, and their two-dimensional crystal structure consists of 2D layers based upon corner-sharing CuO5 square pyramids, TeO6 octahedra, and TeO4 dispheniods. BaMTe2O7 (M = Mg2+ and Zn2+) are iso-structural with BaCuTe2O7, and exhibit a crystal structure composed of layers of corner-shared MO5 (M = Mg2+ or Zn2+) square pyramids, TeO6 octahedra, and TeO4 polyhedra. The [MTe2O7]2− anionic layers (M = Mg2+ and Zn2+) stack along the b-axis, and are separated by Ba2+ cations. Comparing these phases we can presume that high-pressure conditions applied in our study not only condensed the final structures (from 2D towards 3D), but also influenced the redox stability of Te with stabilization of the rare TeV cation.It is noteworthy to compare the structure of Kg or Zn) , due to 2 [(UO2) (Te2O7)], we simplify the anionic uranyl tellurium framework [(UO2)Te2O7]2-, by removing the oxygen atoms, whilst the UO6 and TeO6 polyhedra were viewed as single nodes. As shown in 2 [(UO2) (Te2O7)] can be described as a 2-nodal net topological type with a point symbol of {32.42.52.63.7}2{32.62.72} (c net with stoichiometry (4-c) (5-c)2. Natural tiling is an efficient approach to represent a network proposed by Blatov et al. (2 [(UO2) (Te2O7)] is built from a novel composite building unit (CBU) [102:6:4:32]  (TeO5)] (see below).In order to reveal the complex topological network of K2.62.72} , which iv et al. , which c:6:4:32] , with thque CBU. ,  (TeO3)2] crystallizes in the orthorhombic space group Cmca. Mg, U and Te occupy one crystallographically independent position each and for oxygen three crystallographically independent positions are occupied. As shown in Mg [ to 2.042(3) Å. This coordination is found to be common within Teructures .2) (TeO3)2], TeO4 disphenoids share common corners with each other resulting in infinite onedimensional chains of [(TeO3)2]4− propagating along the a-axis. These chains link the uranyl bipyramids by edge sharing along two edges of the disphenoids. This results in two-dimensional sheets of [(UO2) (Te2O6)]2− ]2− . Within 2+ are located within the rings of UO8 and TeO4 mentioned above. It is coordinated by six oxygen atoms in distances ranging from 2.051(5) to 2.284(6) Å leading to a rectangular bipyramid. Mg2+ acts as a counter charge for the [(UO2) (Te2O6)]2− layers-resulting in a neutrally charged phase. Bond valence sum calculations for all positions  yield values in accordance to the assumed oxidation states.Mg2) (TeO3)2] most resemble the layers found in Tl3 ((UO2)2 (Te2O5(OH)) (Te2O6))·2(H2O) 2 (Te2O5(OH)) (Te2O6))·2(H2O) in comparison to their absence in Mg [(UO2) (TeO3)2]. In the former, two different chains of corner-sharing disphenoidal coordinated Te are present [(Te2O5(OH)]3- and [(TeO3)2]4-. In Mg [(UO2) (TeO3)2] only chains of [(TeO3)2]4- are present. This leads to constant edge-sharing connections between tellurite disphenoids and uranyl bipyramids in Mg [(UO2) (TeO3)2], whereas edge-sharing connections are only found along the [(TeO3)2]4--chains in Tl3 ((UO2)2 (Te2O5(OH)) (Te2O6))·2(H2O) and corner-sharing positions along the [(Te2O5(OH)]3− chains. The difference of the resulting layers can also clearly be seen, whilst comparing the topology graphs for both structures. (The layers found in Mg [(UO)·2(H2O) . The layuctures. .3 ((UO2)2 (Te2O5(OH)) (Te2O6))·2(H2O) are only pentagonal whereas they are hexagonal in Mg [(UO2) (TeO3)2]. This is the first report of hexagonal bipyramids in two-dimensional phases containing U and Te. Otherwise, these are only found in three-dimensional phases, such as within UTe3O9 (2)Te6O13(OH)] (2) (TeO3)2] only two layers are stacked until the original layer is repeated (ABAB stacking), whereas four layers are necessary in Tl3 ((UO2)2 (Te2O5(OH)) (Te2O6))·2(H2O) (ABCDABCD stacking) ] . It is atacking) .2) (TeO3)2] crystallizes in the orthorhombic space group Pbam. U, Sr and Te each are present on one independent position. As U and Sr lie on special positions  and Te lies on a general position in respect to x and y , the multiplicity results in a U:Te molar ratio of 1:2. Oxygen is present on four independent positions, each of them are general positions. The structure of Sr [(UO2) (TeO3)2] is depicted in Sr 2− propagating into the [001] direction. These chains are formed by edge-sharing uranyl bipyramids which are additionally fused together by two TeO4 disphenoids, edge-sharing along two edges. Such a chain is depicted in 2+ cations. The apparent additional void space is filled by the electron-lone pairs from the tetravalent Te. These are directed along the [010].The structure is based on one-dimensional chains of [(UO2) (TeO3)2] and Sr [(UO2) (TeO3)2]. In Mg [(UO2) (TeO3)2], TeO4 disphenoids share common corners with each other resulting in infinite 1D chains of [(TeO3)2]4- propagating along the a-axis. These chains link the uranyl bipyramids by edge sharing along two edges of the disphenoids, resulting in the 2D layered structure of [(UO2) (Te2O6)]2-. Mg2+ counter cations are located between the inter-layers to balance the anionic layered charge. The structure of Sr [(UO2) (TeO3)2] features a 1D chain structure [(UO2) (TeO3)2]2-, propagating into the c-axis. These chains are formed by edge-sharing uranyl bipyramids which are additionally fused together by two TeO4 disphenoids, which also share two edges. We can see that with the counter cations radii increasing from Mg2+ to Sr2+ this results in the structure of materials changing from a 2D to a 1D structural type. In this case we can speak of a morphotropic transition within AII [(UO2) (TeO3)2] .It is worth comparing the structures of chemical analogues Mg [(UO2) (TeO5)] crystallizes in the orthorhombic space group Pbam. The crystallographic data is given in 7 and TeO6 polyhedra with Sr2+ cations filling the voids to achieve charge neutrality.Sr  direction.Te only adopts a single position and is coordinated by six oxygen atoms to form distorted octahedral polyhedra . Hereby,2) (TeO5)]. All three positions are shown in 2) (TeO5)], it is best to divide the structure into simpler one and two-dimensional units. This is shown in 5]4− chains. Two opposite edges of the TeO6 octahedron are involved in edge-sharing with U2O7 and U1O7 bipyramids and the two remaining oxygen positions each corner-share with a U1O7 and a U2O7 (2 [(UO2) (TeO5)] ] .2) (TeO5)] has a multi-intersecting channel system as shown in a- and b-axis with diameters of ca. 6.6 Å × 4.7 Å and ca. 6.3 Å × 4.7 Å (distances are based on two opposite O atoms), respectively. (c-axis with diameters of ca. 6.5 Å × 5.7 Å and ca. 6.9 Å × 5.8 Å (2) (TeO5)], we also simplified the anionic uranyl tellurium framework [(UO2) (TeO5)]2-, by removal of the oxygen anions, whilst the UO7 and TeO6 polyhedra were viewed as single nodes. As shown in 2) (TeO5)] can be described as a 2-nodal net topological type with a point symbol of {32.62.72}{34.42.64.75}; which is a 4, 6-c net with stoichiometry of (4-c) (6-c) (2) (TeO5)] is shown in 2) (TeO5)] is built from a novel CBU of [64⋅34]  (6-c) . Natural [64⋅34] , with th2 [(UO2) (Te2O7)], Mg [(UO2) (TeO3)2], Sr [(UO2) (TeO3)2] and Sr [(UO2) (TeO5)], featured 1D-chain to 3D-framework structures. Surprisingly, tellurium is occurs as TeV in one of the obtained materials, K2 [(UO2) (Te2O7)], which is a rare case in tellurium bearing inorganic phases. Under the same pressure (3.5 GPa) three novel alkaline Earth metal uranyl tellurites/tellurate, Mg [(UO2) (TeO3)2], Sr [(UO2) (TeO3)2] and Sr [(UO2) (TeO5)], were obtained. Mg [(UO2) (TeO3)2] and Sr [(UO2) (TeO3)2] have the same chemical formulas, but they are not iso-structures. This indicates that with the larger Sr2+counter cation the dimensionality of the structure upon the ratio of U:Te = 1:2 decreases. It is noteworthy to consider the HT/HP role in generating these unique 1D to 3D structures, particularly in comparison to other actinide and non-actinide tellurium bearing compounds. Especially, HT/HP plays an important role in the stabilization of the less stable TeV which we were not able to reproduce under normal conditions. This study further demonstrates how subtle adjustments to counter cations can reveal dramatic changes to structural type and topology. Further investigation ofthe A-U-Te-O system under similar synthetic conditions will lead towards obtaining different unique types of structures. This will help in achieving a deeper understanding of the influence of extreme conditions on the chemically complex tellurium bearing oxo-phases.We have shown that by using extreme synthetic conditions (high-temperature high-pressure) novel single crystalline phases in the U-Te-O system can be obtained. Four new uranyl tellurium complex oxides obtained in this study, K


This cohort study evaluates the association between psychiatric comorbidities and schizophrenia in children and adolescents with attention-deficit/hyperactivity disorder. Are psychiatric comorbidities in youths with attention-deficit/hyperactivity disorder (ADHD) who are followed up longitudinally associated with higher rates of schizophrenia?In this cohort study involving 211 705 children and adolescents with ADHD, patients with psychiatric comorbidities had an approximately 2.1-fold higher risk of being diagnosed with schizophrenia compared with those without comorbidities. The higher risk of subsequent schizophrenia was associated with both a greater number of comorbidities and a variety of individual psychiatric disorders.These findings suggest that many people with ADHD who receive schizophrenia diagnoses have various psychiatric comorbidities at the time of diagnosis and experience various disorders preceding the diagnosis. The association between attention-deficit/hyperactivity disorder (ADHD) and schizophrenia has received increased attention; however, evidence on the association between psychiatric comorbidities and subsequent schizophrenia in patients with ADHD is limited.To investigate the risk of being diagnosed with schizophrenia in children and adolescents with ADHD considering the presence of psychiatric comorbidity.This was a population-based, retrospective cohort study using the Health Insurance Review and Assessment claims database from January 1, 2007, to December 31, 2019. Participants were children and adolescents aged 5 to 19 years who received an ADHD diagnosis between January 1, 2010, and December 31, 2018, in the nationwide claims data of Korea. Data were analyzed from January 2010 to December 2019.The presence of psychiatric comorbidity was assessed from diagnosis records within 1 year before ADHD diagnosis. Comorbidities were further categorized according to the number of comorbidities and specific comorbid disorders.Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs, examining the association between psychiatric comorbidities and the risk of being diagnosed with schizophrenia. Furthermore, the occurrence of psychiatric comorbidity during the follow-up period was explored among patients without psychiatric comorbidity at baseline.A total of 211 705 patients with newly diagnosed ADHD were included. A total of 157 272 patients (74.3%) were male, and the age of 5 to 9 years showed the highest distribution (115 081 patients [54.4%]). Patients with psychiatric comorbidity had a significantly higher risk of being diagnosed with schizophrenia than those without . The association between schizophrenia and psychiatric comorbidity became progressively greater with the increasing number of comorbidities. Several individual psychiatric disorders showed an association with development of schizophrenia, with ASD, intellectual disability, tic disorder, depression, and bipolar disorder being the top 5 disorders most associated. Furthermore, 3244 patients (73.8%) without psychiatric comorbidities experienced the emergence of other psychiatric disorders before schizophrenia occurrence.In this retrospective cohort study involving children and adolescents with ADHD, the presence of psychiatric comorbidity in patients with ADHD was associated with an increased risk of being diagnosed with schizophrenia, with an increased risk observed in multiple comorbidities and a wide variety of comorbidities. These findings highlight the significance of assessing and managing psychiatric comorbidities in patients with ADHD to decrease subsequent schizophrenia risk and allow for early intervention. Since schizophrenia negatively influences quality of life, including academic functioning, social functioning, and mortality,7 early detection and intervention for schizophrenia for children and adolescents with ADHD have long been considered important.5Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and adolescents, characterized by impulsivity, hyperactivity, and poor attention.8 and shared genetic susceptibility.11 However, studies investigating the influence of psychiatric comorbidity on diagnosis of schizophrenia in patients with ADHD are limited. Psychiatric comorbidity is commonly observed in patients with ADHD.13 Although the prevalence rate was varied, approximately 50% to 90% of patients with ADHD have at least 1 other psychiatric comorbid disorder, including depression, bipolar disorder, anxiety, and autism spectrum disorder (ASD).18 The presence of psychiatric comorbidity in patients with ADHD has significant implications for symptom severity, functional impairment, and treatment outcomes.13 Furthermore, these psychiatric disorders were independently associated with an increased risk of schizophrenia.22 Moreover, most patients exhibited several clinical symptoms of other psychiatric disorders before schizophrenia occurrence. Therefore, the notion that the presence of psychiatric comorbidity may further be associated with being diagnosed with schizophrenia in this population is plausible. Thus, we aimed to explore the association between ADHD and subsequent schizophrenia and patterns of diagnosis of schizophrenia in children and adolescents with ADHD, focusing on comorbidity.To control the risk of developing subsequent schizophrenia among patients with ADHD, understanding the mechanisms and risk factors associated with these 2 disorders is essential. Several previous studies explored the relationship between ADHD and schizophrenia regarding environmental risk factorsInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]), prescriptions, procedures, and devices. This study was approved by the institutional review board of Jeju National University, and the requirement for informed consent was waived as the HIRA database was anonymized. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort study.We conducted a nationwide population-based retrospective cohort study using the Health Insurance Review and Assessment Service (HIRA) database of South Korea . HIRA is a government-operated agency that evaluates the reimbursement system, which is mandatory for all Korean populations. In this study, we used information about pediatric patients with psychiatric disorders from the HIRA database from 2007 to 2019. The HIRA database contains individual characteristics, including age, sex, and economic vulnerability . Clinical data include information billed by health care practitioners, including diagnoses (according to the ICD-10: F90) between January 1, 2010, and December 31, 2018. The index date for individual patients was defined as the first date of ADHD diagnosis. We excluded patients with a history of ADHD diagnosis or prescription of stimulants and nonstimulants for ADHD for at least 3 years before the index date to restrict the cohort for new incident cases of ADHD. We subsequently only included those who had no diagnosis record of schizophrenia or psychosis for at least 3 years before the index date. The time frame of 3 years was selected according to previous studies that reported the recovery of schizophrenia or psychosis, measured for at least 2 years after treatment.25 The detailed codes of diagnosis and medications were summarized in eTable 1 in Initially, we identified patients aged 5 to 19 years with at least 1 diagnosis record of ADHD , whichever occurred earlier. Schizophrenia development was defined according to the ICD-10 codes of psychiatric comorbidities are shown in eTable 2 in 27We defined depression, anxiety disorder, intellectual disability, nonorganic sleep disorder, tic disorder, bipolar disorder, ASD, conduct disorder, obsessive-compulsive disorder, and substance use disorder (SUD) as psychiatric comorbid disorders of ADHD. The detailed In this study, we classified patients into 2 groups according to the presence of psychiatric comorbidity within 1 year before the index date. Patients who had at least 1 diagnosis record of these psychiatric disorders within 1 year before the index date belonged to the group with psychiatric comorbidities, and others were categorized into the group without psychiatric disorders. Among those with underlying psychiatric comorbidities, further categorization was conducted according to the number of psychiatric comorbidities and specific psychiatric disorders. The number of psychiatric comorbidities was divided into the following 3 groups: 1 comorbidity, 2 comorbidities, and 3 or more comorbidities. For each psychiatric disorder, patients who had at least 1 diagnostic record of that specific disorder were considered as having that particular disorder. To simultaneously investigate the outcomes of both multiple comorbidities and a specific disorder, patients were additionally categorized into the following 3 groups: 1 comorbidity for each psychiatric disorder, 2 comorbidities, and 3 or more comorbidities.To estimate hazard ratios (HRs) along with 95% CIs for the association of being diagnosed with schizophrenia with psychiatric comorbidity in patients with ADHD, Cox proportional hazard models (Cox PH models) were used. We considered several potential confounders in schizophrenia development, including sex, age , insurance type , psychiatric hospitalization, and psychotropic medication use. Age, sex, insurance type, and psychiatric hospitalization were assessed at the index date. The use of psychotropic medications  was assessed during the 1-year period before the index date  during the follow-up period. Additionally, we conducted subgroup analyses according to presence of bipolar disorder, ASD, and intellectual disability at baseline period. Third, to further address uncontrolled confounding effects, we performed an analysis using a propensity score (PS)–matched cohort. We used logistic regression to estimate the PS for the probability of having psychiatric comorbidities by including sex, age, health insurance, and health care utilization . Patients with psychiatric comorbidities and those without were matched 1:1 using the estimated PS with a caliper width of 0.2 on the PS scale.During the follow-up period, individuals with ADHD might experience various psychiatric comorbidities before the subsequent incidence of schizophrenia. However, in the association analysis, it is difficult to capture the comprehensive longitudinal diagnosis pattern from ADHD to schizophrenia due to the complex trajectories of these disorders. To address this, we used trajectory analysis to examine the progression of psychotic disorders to a schizophrenia diagnosis in patients with ADHD.We assessed the occurrence of psychiatric comorbid disorders during the period between the index date of ADHD and subsequent schizophrenia to explore the patterns of diagnosis from ADHD to schizophrenia. This analysis exclusively focused on patients who received schizophrenia diagnoses without any preexisting psychiatric comorbidities (patients belonging to the group without psychiatric comorbidities), ensuring that the diagnostic progression was not influenced by prior cumulative diagnoses. During the follow-up period, the first date of diagnosis record for each psychiatric disorder was considered the occurrence of psychiatric comorbidities. The investigation of diagnostic patterns from ADHD to schizophrenia was presented as frequency and incidence rate per 100 person-years. When 2 or more psychiatric disorders occurred simultaneously on the same day, we adjusted weight of incidence by dividing the number of psychiatric comorbid disorders. The diagnostic flow was depicted using a Sankey diagram.2 tests with significance set at less than .05. Data were analyzed from January 2010 to December 2019.SAS Enterprise Guide 6.1 (SAS Institute) and R software V.3.6.1  were used for data analyses. The baseline demographics of the patients were presented as numbers and proportions for the 2 groups according to the presence of psychiatric comorbidities. The comparison between these groups was performed using 2-sided χWe identified a total of 211 705 patients to be involved in our study cohort. The majority were male (157 272 patients [74.3%]), and 115 081 patients (54.4%) were aged 5 to 9 years. Among them, 77 880 (36.8%) had at least 1 diagnosis record of psychiatric disorders within 1 year before the index date, whereas 133 825 (63.2%) did not exhibit any comorbidities ,38 this finding might be associated with the use of antipsychotics. Therefore, further study is needed to investigate the association between anticholinergic use and schizophrenia in patients with ADHD.Moreover, we examined other schizophrenia-associated factors in patients with ADHD. Male sex, older age, and Medicaid were robust factors associated with risk for the incidence of schizophrenia in this population, which was consistent with previous findings.ICD Z code) due to the social stigma surrounding mental health problems.39 Furthermore, owing to using the claims database, we could not consider the severity or symptoms of ADHD. Instead, psychiatric hospitalization was used as an indirect proxy for assessing symptom severity. Second, despite considering several potential confounders, completely controlling all potential effects of confounders is challenging. However, when adjusting several confounders in Cox PH models and conducting several sensitivity analyses, we observed robust results regarding the associations between psychiatric comorbidities and being diagnosed with schizophrenia. Lastly, psychiatric comorbidities were assessed at baseline, and patients developing signs of these comorbidities during the follow-up period remained in the noncomorbidity group in the analysis. To address this limitation, we analyzed diagnosis trajectories to schizophrenia in patients without psychiatric comorbidities at baseline.Several limitations should be considered when interpreting these findings. First, since the diagnosis of ADHD, schizophrenia, and other psychiatric comorbidities were based on diagnosis codes, the possibility of underdiagnosis or overdiagnosis could not be ruled out. Some patients with ADHD have chosen the general health consultation (This study suggests that the presence of psychiatric comorbidities was associated with an increased risk of being diagnosed with schizophrenia in children and adolescents with ADHD. Interestingly, although patients had no psychiatric comorbidities during ADHD diagnosis, the occurrence of these disorders was frequently observed before the schizophrenia diagnosis. These findings highlighted the significance of carefully monitoring psychiatric comorbidities in patients with ADHD to effectively mitigate the burden of schizophrenia.


Autism Spectrum Disorder (ASD) and Attention‐Deficit/Hyperactivity Disorder (ADHD) are both associated with differences in Executive Functioning (EF). There is lack of clarity around the specificity or overlap of EF differences in early childhood when both disorders are first emerging.This systematic review aims to delineate preschool EF profiles by examining studies comparing the EF profiles of children with and without ASD or ADHD. Five electronic databases were systematically searched (last search in May 2022) to identify published, quantitative studies of global and specific EF , Planning and Attentional Control), comparing children aged 2‐6 with a diagnosis of ASD or ADHD to peers without ASD or ADHD.Thirty‐one empirical studies (10 ADHD and 21 ASD studies) met criteria for inclusion. EF profiles in preschool ASD were characterised by consistent Shifting, and, in most cases, Inhibition impairments. ADHD studies consistently reported impairments in Inhibition and Planning, and in most cases WM. Findings with regards to sustained Attention and Shifting in ADHD and WM and Planning in ASD were mixed.Overall, current evidence indicates overlap but also some specificity in EF impairments in preschool ASD and ADHD. There were differences in the degree to which individual domains were impaired, with Shifting more consistently impaired in ASD, and Inhibition, WM and Planning in ADHD. Methodological issues and differences in methods of outcome measurement could potentially underlie mixed findings, as informant‐based measures revealed more robust EF impairments than laboratory‐based tasks. Both Autism Spectrum Disorder (ASD) and ADHD have been associated with impairments in Executive Functioning (EF), but the profiles of those impairments during early childhood are not well established.Preschoolers with ASD and preschoolers with ADHD over 4 years of age demonstrate robust impairments in global EF.Preschoolers with ASD appear to be consistently impaired mainly in Shifting, while preschoolers with ADHD are more consistently impaired in Inhibition, Planning and Working Memory.Early interventions addressing those domains in young children with ASD and ADHD might be beneficial in preventing further impairments in executive skills which are crucial for everyday functioning, attainment, as well as mental and emotional wellbeing.Autism Spectrum Disorder/ASD and Attention Deficit Hyperactivity Disorder/ADHD are neurodevelopmental conditions that typically emerge in childhood . The review was carried out in line with the PRISMA guidelines  Published, peer‐reviewed studies written in English; (2) Empirical studies comparing two or more groups of participants; (3) Studies include a clinical group with a diagnosis of either ASD or ADHD. The diagnosis must have been made using a standardised diagnostic instrument or based on established diagnostic criteria  Grey literature, book chapters, commentaries, letters or conference abstracts; (2) Qualitative studies; (3) Studies published in a different language/not available in English. (4) Longitudinal/prospective studies that do not include cross‐sectional comparisons between the different groups; (5) Studies measuring only “hot” EF (e.g. Emotion Control) or studies focusing on EF‐related temperament constructs . (6) Studies of participants without a diagnosis of ASD/ADHD .Studies were primarily identified by searching electronic databases . The reference lists of included articles were also checked. Where possible, searches were restricted to child populations and to studies published in peer‐reviewed journals in the English language  of full‐texts. The agreement rate at this stage was 98% (kappa 0.95). Article key information  was extracted from the full text versions of articles and stored in an Excel spreadsheet. Second rater (PW) checked data extraction for errors.After initial database searches, duplicates were removed. The remaining records were imported into Excel for screening. The titles and abstracts were screened by the first author according to inclusion and exclusion criteria. Where the abstract was not available or did not provide enough information to guide decision, the full‐text version was retrieved. A random sample of 100 articles was independently screened by a second rater (PW) based on the title and abstract. The agreement rate was 92% (kappa 0.71) and all disagreements were resolved by discussion. Full‐text articles were retrieved and screened by the first author against the eligibility criteria. The second rater independently screened a randomly chosen sample (The Joanna Briggs Institute (JBI) ‐ Critical Appraisal Checklist for Analytical Cross Sectional Studies Moola et al., A narrative synthesis was used to describe the data from included studies. The synthesis was organised by the different domains of EF as outlined in prior literature , Medium  and Small , according to prior literature  met criteria for inclusion. Most control groups consisted of typically developing (TD) children, matched on chronological age (CA) and/or mental age. The majority of studies were conducted in Western countries, particularly the US and UK. Supplementary materials Table Table Two studies  as well as informant ratings, though three studies out of the total of ten did not report effect sizes. Lacerda et al.  did not Seven studies that used set‐shifting tasks, such as card sort and flexible item selection, and one study that used informant ratings found significant, medium‐large impairments for the ASD group compared to a TD group. Only one of these studies , two of which found the ADHD group to be significantly more impaired than the TD group. Çak et al.  also repFive ASD studies used multi‐component EF tasks, which usually require maintenance of information over a delay, updating this with new information, inhibiting a pre‐potent response, and switching to a different response or search strategy. In most cases, those were administered to younger preschoolers (below the age of 5). Studies failed to find any significant differences between the ASD group and either a TD or a developmentally delayed control group. Yerys et al.  and GrifFour ADHD studies measured Global EF through informant ratings and reported significant, large impairments for the ADHD group. Most studies apart from Sjöwall and Thorell  controllTable There was agreement among studies that both ASD and ADHD preschoolers are markedly impaired in global EF, when that was rated by parents or teachers. This reported impairment was robust and not dependent on factors like parental education, gender and IQ. When considering individual domains, Inhibition was significantly impaired in both ASD and ADHD in comparison to a TD group, though more consistently in ADHD. Shifting was more consistently impaired in ASD preschoolers, as ADHD preschoolers were impaired on informant ratings but not laboratory tasks. Working Memory yielded mixed findings in ASD, while most ADHD studies reported large impairments on tasks as well as informant ratings. ASD preschoolers were impaired in Planning compared to TD children on informant ratings and the Tower of London task, but not on simplified or age‐adapted tasks; there was a clear Planning impairment in ADHD, mainly on informant ratings but also a simple planning task. Different types of attention were measured in ASD and ADHD studies. ASD studies failed to find any group differences in attention shifting, though the studies were generally of lower quality. ADHD studies on sustained attention yielded mixed findings. Taken together, EF difficulties are prevalent in both preschoolers with ASD and ADHD, but may show slightly distinct profiles in the two conditions.The findings of this review are similar to Visser et al. , who revMost studies that measured specific EF domains in the current review recruited older preschoolers (over the age of four). Studies that recruited younger preschoolers typically used multi‐component EF tasks and failed to find any significant group differences. This was mostly the case in ASD studies, where some authors concluded that EF impairments do not emerge until later in life and are only secondary to ASD . It is possible that the consistency in assessment methodology might account for the large effects and the relatively higher agreement among ADHD studies in comparison to ASD studies. The only discrepancies observed in the ADHD studies were for domains assessed through laboratory tests . This discrepancy in findings corresponding to laboratory versus informant based methods was reported in the broad EF/self‐regulation field  and may tap multiple EFs and other cognitive processes, such as attention, short‐term memory, language ability, spatial/visual processing and processing speed. Given the differential impairments found in early and middle childhood  for each condition. This further highlights the importance of assessing and addressing EF in preschoolers with ASD and ADHD. Shifting in ASD and inhibition in ADHD are promising early intervention targets, as they may form the basis of later‐emerging higher‐order functions Diamond, . WorkingBased on the studies reviewed, informant reports provide robust evidence of a global EF impairment in both ASD and ADHD from the fourth year of life. EF profiles in preschool ASD and ADHD overlap to some extent, but there are indications of differences in the consistency of domain‐specific impairments: Shifting seems to be more consistently impaired in ASD compared to ADHD, while WM, Planning and Inhibition are more consistently impaired in ADHD. The EF profile of ADHD preschoolers seems to comprise robust impairments in a larger number of EF domains in comparison to that of ASD preschoolers. However, due to methodological limitations and the different methods of measuring EF, it is still unclear whether these differences are robust enough to reflect different underlying EF profiles and distinct developmental processes in the pathways to ASD and ADHD. Further research on early executive impairments in neurodevelopmental conditions may identify fruitful targets for intervention at a very crucial stage in development.Marina Christoforou: Conceptualization; Methodology; Resources; Software; Writing – original draft; Writing – review & editing. Emily J. H. Jones: Methodology; Supervision; Writing – original draft; Writing – review & editing. Philippa White: Validation; Writing – review & editing. Tony Charman: Conceptualization; Supervision; Writing – review & editing.Emily J. H. Jones is a Joint Editor for JCPP Advances. Tony Charman has served as a paid consultant to F. Hoffmann‐La Roche Ltd. and Servier; and has received royalties from Sage Publications and Guilford Publications. The remaining authors have declared that they have no competing or potential conflicts of interest.Not applicable.Supporting Information S1Click here for additional data file.


Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by hyperactivity, impulsivity, and inattention. Neuroanatomical anomalies such as the volume reduction in the neocortex and hippocampus and the abnormal dendritic spine pruning during postnatal development are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. This review presents recent evidence focused on the molecular mechanisms involved in dendritic spine remodeling in the context of synaptic plasticity and learning. The impairment in synaptic plasticity, working memory and spine phenotype in a murine model of ADHD are also discussed.Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines’ maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines. Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a high incidence in children associated with decreased levels of dopamine and norepinephrine in the brain. The current pharmacotherapy uses mainly inhibitors of dopamine and norepinephrine transporters such as the psychostimulants methylphenidate and amphetamine and the non-stimulant atomoxetine. ADHD is considered a neurodevelopmental disorder in a similar manner to autism spectrum disorder (ASD) and intellectual disability (ID). Early studies of postmortem brain samples of patients with ASD and ID showed an abnormal density of dendritic spines in cortical neurons associated with a putative defective or enhanced spine pruning during postnatal development ,2.It is well known that the molecular machinery involved in synaptic transmission is enriched in the dendritic spines, that appear as small protuberances emerging from the dendritic shaft. These structures are remodeled during Hebbian and homeostatic plasticity events that modify the synaptic strength . The onsADHD is a neurodevelopmental disorder with high prevalence (around 5%) among children worldwide characterized by hyperactivity, inattention and/or impulsivity affecting learning and sociability at school . SeveralSeveral neuroanatomical studies support the view that ADHD is a neurodevelopmental disorder. A significantly lower cortical thickness  in children with ADHD as evaluated by brain MRI has been reported. The fitting of curves of thickness values obtained from sequential brain scanning in children diagnosed with ADHD and healthy controls show a delay of ≈3 years to attain the peak of cortical thickness during childhood, supporting a delay in cortical maturation in ADHD .Meta-analysis of neuroimaging data obtained in children, adolescents and adults with ADHD show a statistically significant reduction (compared to control groups) in cortical thickness, cortical surface area and volume of subcortical areas such as the accumbens, amygdala, caudate, putamen and hippocampus, in children with ADHD. Interestingly, the only brain area significantly reduced in adolescents is the hippocampus . InteresFOXP2), glutamate receptor trafficking and anchorage to postsynaptic density (SORCS3), regulation of dopamine transporter trafficking (DUSP6) and axon guidance (SEMA6D) [FOXP1 and FOXP2 (encoding transcription factors) previously involved in cannabis use disorder and intellectual disability [CDH2 gene, coding for the adhesion protein N-cadherin involved in synaptogenesis, has been recently described [Extensive evidence supporting a polygenic origin of ADHD with additional environmental risk factors has been reported . A recen(SEMA6D) . The sam(SEMA6D) . Among tsability ,22. By aescribed . Knock-iSNAP-25 KO mice, DAT KO mice, LPHN-3 KO mice and rats, and those induced by exposure to environmental chemicals such as lead and pesticides, and by prenatal exposure to nicotine or alcohol [ADHD is associated with a dysfunction of dopamine and noradrenergic systems involving cortical areas such as the PFC , cingulate cortex and basal ganglia  affecting neural networks driving executive control, motor function, reward processing and decision-making . The pha alcohol . The pre alcohol ,32,33,342+-permeable N-methyl-D-aspartate receptors (NMDAR), inducing postsynaptic depolarization [2+-impermeable. By contrast, receptors lacking GluA2 subunit are Ca2+-permeable and exhibit inward rectifying currents due to the block by intracellular polyamines at positive potentials [Excitatory transmission at glutamatergic synapses involves the activation of two types of glutamate-gated ionotropic receptors that produce excitatory post synaptic currents (EPSCs). Glutamate released into the synaptic space activates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) present at the postsynaptic membrane, allowing the influx of sodium and calcium ions which shift the resting potential to a more positive value. This change in membrane potential relieves the magnesium block of the highly Carization . High frrization . AMPARs tentials . During tentials . The photentials ,39. Aftetentials . The curtentials .N) at the postsynaptic membrane, a novel mechanism involving a PKA-dependent increase in unitary conductance of AMPARs (LTPγ) has been recently reported [Analyzing the effect of MPH on learning and hippocampal LTP at the molecular level, it has been reported that a single oral administration of MPH enhances hippocampal LTP and improves visuo-spatial learning  in rats. At the molecular level, this effect was associated with increased levels of GluA1-containing AMPARs at the cell surface, and higher levels of phosphorylated receptors at S845 and S831 residues. In addition, whole-cell recordings in CA1 neurons show higher EPSC amplitudes and enhanced short-term plasticity associated with a lower decay time of currents elicited by 20 Hz stimulation protocols . Considereported .Among symptoms associated with ADHD are the working memory impairments in children . HoweverSeveral human neurodevelopmental and neuropsychiatric disorders such as ASD, SCZ and ADHD are correlated with abnormal development and maturation of dendritic spines in the neocortex including changes in the pruning phase occurring during late childhood and early adolescence . DendritSingle spine stimulation with uncaged glutamate in hippocampal slices cultured and transfected with enhanced green fluorescent protein (EGFP) and whole-cell patch clamp recordings have shown that spine volume and AMPA currents are directly correlated. Small new spines contain low AMPA-dependent EPSCs and bigger persistent spines exhibit higher AMPA-EPSCs. In this cell model, NMDA-dependent EPSCs are not significantly different in spines of different size and lifetime . A recenThe intracellular cascade involved in the structural and functional remodeling of dendritic spines during processes of synaptic plasticity has been studied mainly by investigating the effect of knock-out or block of specific proteins during the induction of LTP or long-term depression (LTD) . In basaStudies focused on the maturation, homeostasis, and regulation of dendritic spines in the mammalian brain have been performed mainly in the neocortex, due to the limited resolution of microscopic tools for imaging of deep brain structures such as the hippocampus. Early studies were focused on mapping the sensitivity to uncaged glutamate of CA1 pyramidal neurons contained in slices and suggest that mushroom-type spine structures are correlated to a high density of AMPAR-dependent EPSCs—by whole-cell recording—reflecting functionally mature spines . Later, The recent development of improved tools of two photon (2p)-microscopy has allowed the study of the spine dynamics in vivo in long-term imaging in the hippocampus, supporting a higher turnover compared to the neocortex. The mathematical modeling of spine kinetics in CA1 pyramidal neurons supports a single spine population with a medium lifetime of ~10 days in the hippocampus, in contrast to the long  and short (~4 days) lifetime populations described in somatosensory and motor neocortices . In addi2+, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation, Ras/RhoA/Rac1/Cdc42 activation, phosphorylation of cofilin, and polymerization of actin filaments that determine the spine head enlargement. Analysis of single spine dynamics in CA1 neurons show that the repetitive glutamate uncaging induces an increase in spine head volume, which exhibits an initial transient component followed by a long-lasting component. Both phases are inhibited by AP5 (a selective NMDAR antagonist) and only the sustained phase by KN62 (a selective CaMKII inhibitor), but fully abolished by latrunculin A (an inhibitor of actin polymerization), supporting the role of NMDAR-dependent calcium influx, the late activation of CaMKII, and the downstream remodeling of the F-actin network in spine remodeling [2+/calmodulin-dependent phosphatase), dephosphorylation of cofilin and depolymerization of actin filaments that induces the spine shrinkage  in cultured hippocampal slices, it has been reported that 2P glutamate uncaging-induced spine enlargement enhances presynaptic exocytosis .PirB (paired immunoglobulin receptor B) knock-out mice [Several studies demonstrate a significant spine enlargement and formation of new spines in cortical neurons induced by motor skill learning in mice ,63. Fu aout mice . This efout mice .Several studies report mechanisms of spine remodeling induced by growth factors, hormones and drugs . AnalyziThe effect of ketamine as an antidepressant has been proposed to be caused by disinhibition of glutamate synapses by block of the NMDAR in inhibitory GABAergic interneurons. The restored glutamatergic transmission would activate the autocrine BDNF signaling in the postsynaptic neurons by the downstream activation of the mammalian target of rapamycin (mTOR), inducing the local translation of synaptic proteins and spine growth . AdditioThe psychedelic drug psilocybin has been also proposed as pharmacotherapy for depression. It increases spine density and spine size in frontal cortex pyramidal neurons, as evaluated in vivo using 2p-microscopy in Thy1-YFP mice. This effect persists for as long as one month . RecentlTsc2+/− mice defective in mTOR-dependent neuronal autophagy has revealed a deficit in synaptic pruning similar to that found in ASD patients [Several neuroanatomic studies at the cellular level suggest a common neurodevelopmental basis for neuropsychiatric disorders such as ADHD, ASD and schizophrenia, including increased or decreased spine density due to abnormal spine pruning during development . Post-mopatients .Until now there are no reports focused on the analysis of spinogenesis during the childhood and adolescence stages in ADHD patients. The analysis of dendritic spine density and morphology in CA1 pyramidal neurons contained in Golgi-stained brain sections of PNE mice has demonstrated that hippocampal CA1 neurons from these animals exhibit lower spine density compared to control animals. In addition, there is a significant increase in the fraction of thin spines (immature) and a decreased fraction of mushroom ones (mature) compared to the percentage of types of spines in control mice . These rSHANK3. Patch-clamp recordings show that SHANK3-deficient organoids exhibit neuronal hyperexcitability and whole RNA-seq analysis supports that protocadherin and cadherin-dependent pathways are downregulated. The previous evidence pointing to a role of PCDHA (coding for protocadherin α) as a susceptibility gene for ASD [The recent efforts to elucidate the neurobiological basis of the neuropsychiatric and neurodevelopmental disorders such as ADHD have been focused on the meta-analysis of worldwide data of brain imaging from patients and analyzing the effects of mutations and the identification of risk loci associated with the disorders. On the other hand, basic research in animal models of these disorders serves to improve our understanding of the mechanisms underlying these pathological states, and their use in preclinical studies for testing drug efficacy continues to be fruitful. However, the remarkable differences of neurocytological organization of the neocortex and neuronal cytoarchitecture between mice and humans, restricts the studies of neurodevelopmental and neuropsychiatric disorders in murine models in terms of effective translation ,86. Comp for ASD , validat for ASD .CLBN2 gene contains multiple cis regulation sites of repression mediated by Sox5 (a transcription factor), explaining the reduced spinogenesis in PFC neurons in rodents. The CLBN2 gene in humans lacks Sox5 binding sites (in two gene enhancers) making the expression of this organizer insensitive to inhibition by Sox5, allowing a higher spine density in the human PFC. These findings would support a structural basis for higher cognitive functions in humans [A relevant unsolved question in Neuroscience is to determine the neuroanatomical cues involved in the acquisition of higher cognitive functions during the evolution of mammals. Recently, the presence of an anterior–posterior gradient of retinoic acid in primate brain during development, enriched in PFC and involved in neocortex fetal development, has been reported. Interestingly, the gradient of retinoic acid is absent in the mouse brain . Among tn humans .These results contribute to uncovering the neuroanatomical cues involved in the acquisition of higher cognitive functions in humans during primate evolution. In this context, recent studies focused on the development of the neocortex during the recent evolution of Hominidae have been reported. Comparative analysis of genomes of modern humans and Neanderthals identified a single amino acid substitution in the transketolase-like 1 (TLTK1) protein, an enzyme required for fatty acid synthesis. The variant found in modern humans determines the proliferation and growth of basal radial glial cells, progenitors localized in the subventricular zone, mainly promoting cortical neurogenesis in the frontal lobe . Future It is well documented that some neuropsychiatric and neurodevelopmental disorders such as SCZ, ASD and ID exhibit abnormal spine density in the brain associated with abnormal spinogenesis or pruning during postnatal development. However, neuroanatomical studies focused on the development of dendritic spines in ADHD patients are missing. Morphological analysis of dendritic spines in hippocampal CA1 neurons in the PNE murine model of ADHD suggests an impairment in postnatal spine maturation. Further studies using in vivo spine imaging in CA1 pyramidal neurons of PNE mice are required to confirm the correlations between spine remodeling, impairment in hippocampal LTP and defective working memory.DAT gene has been proposed as an epigenetic marker of ADHD [Recent results that have emerged from GWAS using data from worldwide cases to identify risk loci for ADHD and brain MRI meta-analyses show that shared and unique neuroanatomical features will be relevant in the context of defining biomarkers for the disorder to improve early diagnosis, the identification of ADHD subtypes  as well as personalized drug therapy . In addi of ADHD . Future


Professional background and workplace explained only a small part of variance in these attitudes.Prevalence and medication rates of ADHD vary geographically, both between and within countries. No absolute cutoff exists between ADHD and normal behavior, making clinician attitudes  a potential explanation for the observed variation in diagnosis and medication rates. The objective of this study was to describe variation in attitudes toward diagnosis and medication of ADHD among clinicians working in child and adolescent mental health services (CAMHS). We hypothesized that attitudes would vary along a spectrum from “restrictive” to “liberal”. We also explored whether differences in attitudes between clinicians were related to professional background and workplace (clinic). A survey in the form of a web-based questionnaire was developed. All CAMHS outpatient clinics in Norway were invited. Potential respondents were all clinicians involved in diagnosing and treating children and adolescents with ADHD. To investigate the existence of attitudes toward diagnosis and medication as latent constructs, we applied confirmatory factor analysis (CFA). We further examined how much of variance in attitudes could be ascribed to profession and clinics by estimating intraclass correlation coefficients. In total, 674 respondents representing 77 (88%) of the clinics participated. We confirmed variation in attitudes with average responses leaning toward the “restrictive” end of the spectrum. CFA supported “attitude toward diagnosis” and “attitude toward medication” as separate, and moderately correlated (The online version contains supplementary material available at 10.1007/s00787-022-02110-7. Attention-deficit/hyperactivity disorder (ADHD) is characterized by symptoms of inattention and/or hyperactivity and impulsivity that are inappropriate for the individual’s age and developmental level . With anReported rates of ADHD vary considerably between studies from different countries , and eveADHD symptoms exist on a continuum, with no absolute cutoff between clinical diagnosis and “normal” functioning , 13. MorUnnecessarily receiving a diagnosis and medication or being deprived of an appropriate diagnosis and possibly beneficial treatment both have potential detrimental effects in a life course perspective –20. The Variation in medical practice, both at the individual and group level , is a well-documented phenomenon . Some prThe objective of the current study was to describe variation in attitudes toward diagnosis and medication of ADHD among clinicians working in the Norwegian child and adolescent mental health services (CAMHS) outpatient clinics. Further, we wanted to explore if differences in attitudes between clinicians were related to professional background or workplace (clinic). We hypothesized that attitudes vary on a spectrum from “restrictive” to “liberal”. We proposed that such differences might influence the management of children on the margin of ADHD diagnosis, and might help explain the geographical variance in rates of diagnosis and medication of ADHD.To investigate our objective, we developed a survey aimed at measuring clinicians’ attitudes toward diagnosis and medication of ADHD as latent constructs. A team consisting of two clinical psychologists  and two psychiatrists with extensive clinical experience with ADHD patients  designed the questionnaire. To further improve validity and reliability of the items, five external clinicians with special interest in ADHD tested the survey during its development and were interviewed to collect feedback on points of improvement. In addition, the survey was piloted in one clinic.The survey was developed as a one-time, self-administered, web-based questionnaire. Questions were closed-ended with four or six Likert-scaled, forced choice options . Items were developed assuming variation from restrictive to liberal attitudes toward ADHD diagnosis and medication.Comment boxes for optional supplementary comments were provided for each item. All except for two background questions were possible to skip. To maximize response rate, we aimed for a survey that was quick to complete (< 10 min). The survey also included some items as part of a broader investigation of ADHD practice in the clinics that are not relevant to the objective in this article and thus not presented here. The complete, translated survey can be found in Appendix A.profession/educational background, work experience, and frequency of contact with ADHD patients, Table certainty when diagnosing, hypothetical prevalence in an ideal world, Table await making a diagnostic decision, Table medication, Table over/undertreatment in Norway today, Table await, medication) consisted of a question followed by several statements (“sub-items”) to which respondents indicated to which extent they agreed. See Tables To explore variation in clinician attitudes, eight items were used in analyses. To ease communication of results, all items have been given labels that are indicated in italics throughout the text. Three survey items covered background information about respondents .The survey was accessible from September to December 2020. A reminder was sent to all heads of clinics two weeks after initial distribution. Clinics that still had not returned any responses a few weeks after the reminder received personalized follow-up emails or a call.Answers to survey items concerning attitudes were scored along the hypothesized dimension with low scores representing restrictive and high scores liberal attitudes. To estimate response rate, we used the coverage of clinicians per 1,000 children in some catchment areas (made available to us by coauthor IB), which should be roughly generalizable to other regions.Structural equation modeling (SEM) was applied to estimate and examine the relationships between our hypothesized attitude variables. A two-factor confirmatory factor analysis (CFA) was used to estimate the latent constructs of clinicians’ attitude toward diagnosis (DA) and attitude toward medication (MA).D8/other; Table certainty: ideal: await .MA was estimated by seven sub-items of the item over/undertreatment (Table The item nt Table  was not Standardized factor scores for DA and MA were extracted from the two-factor CFA model. The extent of variation in attitudes attributable to profession and clinic level was examined by intraclass correlation coefficients (ICC) in variance-components models, based on factor scores extracted from the factor models. Separate partially latent structural regression models were used to examine associations between experience and frequency (as single exogenous indicators) with DA and MA.Models were estimated using maximum likelihood with missing values (MLMV) . Model fit was assessed by odel fit . Focal sThe online survey was constructed in Corporater Surveyor, an online survey tool pre-approved by the Data Protection Officer of Haukeland University Hospital. Analysis and data visualization was performed in Stata SE 17, except WLSMV estimated in Mplus v8.1.In total, 674 respondents representing 77 (88%) of the 88 outpatient clinics in the Norwegian CAMHS completed the survey. Among these, 484 (72%) of respondents were physicians (including child and adolescent psychiatrists) or licensed clinical psychologists, the two professional groups that are authorized to diagnose patients in Norway. The majority (60%) indicated that they have worked in the CAMHS for 5 years of more, and 84% estimated that they see ADHD patients at least weekly , describing situations/conditions that might make clinicians hold back in the decision-making process of diagnosing patients with ADHD. Model fit statistics for the one-factor model for DA (MLMV) were considered acceptable . Attitude toward medication (MA) was comprised of seven sub-items consisting of statements about the treatment of ADHD (medication). Fit statistics indicated good model fit p < 0.001, CFI 0.95, RMSEA 0.051). All factor loadings were significant.In the final SEM model, attitude toward diagnosis (DA) was estimated by seven sub-items of the item r = 0.4). Model fit statistics for the two-factor model were good . Main results were consistent across model specifications.Overall, DA and MA seemed to reflect separate latent constructs, that are moderately correlated  indicated that respondents’ professional background constituted 5.2% (95% CI 1.4–17.3) of variation in DA and 1.6% (95% CI 0.2–10.1) in MA. For clinic, ICCs showed that 2.7% (95% CI 0.5–13.7) of variation in DA and 9.8% (95% CI 0.49–18.7) in MA was attributable to the clinic level. Figure experience was associated with somewhat more liberal scores on DA , while it did not affect MA scores . There was no support for an association between frequency and DA , while lower frequency of contact with ADHD patients led to slightly more restrictive MA scores .Partially latent structural regression models indicated that longer Our results are based on answers from 674 respondents from the entire population of clinicians working with ADHD in the Norwegian CAMHS outpatient clinics, representing 88% of the clinics in the country. Responses indicated that attitudes toward ADHD diagnosis and medication vary considerably among individual clinicians. Generally, respondents tended to lean toward the restrictive end of the continuum, while a strong liberal attitude was seldom expressed. Only small proportions of variation could be ascribed to professional background or clinic level.certainty and ideal signify that our final DA model became somewhat more narrowly defined than originally planned, consisting only of the sub-items of await. Interestingly, when responding to the item certainty, many respondents commented that other circumstances must be taken into consideration and mentioned specifically the topics covered in await, the subsequent item in the survey. Several respondents commented that they answered on behalf of their team, and that they do not necessarily personally agree with every decision. This could help explain why the items certainty and await correlated less than expected even if respondents seem to consider them related. The items in the final model were considered an adequate measure of attitude toward diagnosis, indicative of practical diagnostic decision-making. With regard to the MA model, several aspects of attitude toward medication are covered, including beliefs about effect, side effects, and relation to alternative forms of treatment.Our CFA supported the hypothesis that attitudes toward diagnosis (DA) and medication (MA) of ADHD can be conceptualized as two separate, but related constructs. The exclusion of the items Partitioning the total variance into individual and group level revealed that most variance occurred between individuals, and only small proportions (< 10%) of variance could be ascribed to the group level. Clinic affiliation explained considerably more variance in MA than in DA, suggesting that attitude toward medication is more sensitive to the development of local practice cultures than attitude toward diagnosis. In summary, there seems to be large differences in attitudes between individual clinicians, which is likely to be of consequence to their clinical practice. However, as little variance was attributable to the clinic level, the hypothesis that these attitudes influence local practice cultures and cause the geographic variation in ADHD diagnosis and medication rates was not supported by these results.To our knowledge, this is the first study aiming to estimate and compare clinician attitudes toward ADHD diagnosis and medication by a comprehensive nationwide survey, and that uses statistical analyses that account for potential variation due to clinic affiliation. Our results are in line with the main findings of related previous studies. Using qualitative methods, Kovshoff et al. (2012) found that clinicians describe the process of making decisions in relation to ADHD as challenging, and that they include in their clinical decision a [subjective] consideration of whether the label will be in the best interest of the child . In a foWhile relevant, the abovementioned studies all include physicians only, albeit of different specialties. To the extent that we can compare our results to studies that include a respondent group including clinicians of diverse educational backgrounds, there seems not to be consistent patterns of group differences in attitudes related to the background variables we have collected. An ambitious international survey , althougThe survey used in this study was designed specifically to extract variation in our hypothesized “restrictive to liberal” attitude dimension. The results, showing large differences between individuals, suggest that we succeeded in this regard. To maximize validity and reliability, the survey was constructed with the involvement of several experienced clinicians, both internal and external to the research group, and was piloted before distribution. The main strength of the study is that we were able to reach out to the entire population of clinicians, and that we achieved a high number of respondents, a satisfactory response rate, and very high geographical, clinic-wise coverage. We have also gathered background variables enabling us to investigate group differences in responses between several relevant groups.Regarding limitations, we do not know if there are shared characteristics within the group of respondents or non-respondents. It is possible that those heads of clinics and clinicians who chose to invest time in the survey represent those particularly concerned about overdiagnosis and overtreatment of ADHD. Interestingly, despite being of high professional relevance, the topic of this survey seems to be considered sensitive by many. This can potentially have lowered the response rate or skewed answers in a direction considered more socially acceptable by respondents.Another possible threat to the validity of any survey pertains to the wording and order of questions and options, as this will shape the collected information. As a specific example, the abstract wording of the options of the item certainty seemed to anchor respondents to the first, most restrictive alternatives. If we had reworded to emphasize that 50% certainty corresponds to “finding it more likely that ADHD is the correct diagnosis than not”, the response distribution would likely have been different.Lastly, we cannot know for certain how much of the actual variation we have succeeded in extracting with our items, and we do not know how respondents would truly act in practical situations. It may be that clinicians who consider themselves similarly restrictive or liberal according to our scale will still make different decisions when faced with comparable cases in clinical practice.Together, these challenges may explain why our findings did not show clear associations between clinicians’ individual attitudes and group affiliation, leaving the question about clinical practice cultures as a reason for geographical variation in rates of ADHD still unsettled.This survey has succeeded in measuring attitudes toward ADHD diagnosis and medication among Norwegian clinicians. We have demonstrated large variation in attitudes between clinicians working in the field, which in turn suggests that clinical practice varies between individual clinicians. However, we did not find large group differences based on clinic affiliation or other background variables. Our results thus do not point to variation in individual attitudes as a main reason for the geographic variation in diagnosis and medication rates. While this alone does not rule out local practice cultures as a reason for the variation, it suggests that any existing practice cultures are driven by forces other than conscious or idealistic differences that we have studied in this survey. As this is an explorative study, its results must be interpreted with some caution. There is need for further research on the potential influence of practice culture on the observed geographic variations in prevalence and treatment of ADHD.Supplementary file1 (PDF 206 KB)Supplementary file2 (PDF 148 KB)Below is the link to the electronic supplementary material.