Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

Neurobiological markers predicting treatment response in anxiety disorders: A systematic review and implications for clinical application.

Anxiety disorders constitute the largest group of mental disorders with a high individual and societal burden. Neurobiological markers of treatment response bear potential to improve response rates by informing stratified medicine approaches. A systematic review was performed on the current evidence of the predictive value of genetic, neuroimaging and other physiological markers for treatment response (pharmacological and/or psychotherapeutic treatment) in anxiety disorders. Studies published until March 2015 were selected through search in PubMed, Web of Science, PsycINFO, Embase, and CENTRAL. Sixty studies were included, among them 27 on genetic, 17 on neuroimaging and 16 on other markers. Preliminary evidence was found for the functional 5-HTTLPR/rs25531 genotypes, anterior cingulate cortex function and cardiovascular flexibility to modulate treatment outcome. Studies varied considerably in methodological quality. Application of more stringent study methodology, predictions on the individual patient level and cross-validation in independent samples are recommended to set the next stage of biomarker research and to avoid flawed conclusions in the emerging field of "Mental Health Predictomics".

Predominant polarity in bipolar disorder and validation of the polarity index in a German sample.

BACKGROUND: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339-346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample. METHODS: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP. RESULTS: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment. CONCLUSION: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.

Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus--a DTI study in major depressive disorder.

BACKGROUND: Depression is commonly conceptualized as corticolimbic dysregulation. Due to insufficient studies in normal aged populations especially subcortical sources of disconnection are unclear in contrast to potentially general parietal white matter (WM) deficits. This may be due to important influences of variable patient characteristics, most importantly episode severity. Especially thalamic disconnections have been functionally revealed, however, their structural correlates have not been distinctly investigated for its highly diverse subnuclei. METHODS: We compared 20 major depressive disorder (MDD) patients with mixed Hamilton depression rating scale (HAMD) severity to matched controls in fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Robust acquisition of 4 repetitions restricted to twelve directions, also to match the same parameters used by Eckert et al. (2011) who described a preferential architecture of centromedian (CM) and mediodorsal (MD) thalamic connections. Second to whole brain analysis, we tested for group differences within the preferred structural network of these two nuclei using a tract of interest (TOI) approach. RESULTS: Significant FA deficits in a whole brain analysis were only found in right parietal WM (p<0.05, corrected). Effects of severity were found for increasing thalamic FA. Post hoc analysis revealed this effect to be restricted to CM specific tracts. In contrast, we found MD to dorsolateral prefrontal cortex (DLPFC) tracts to be decreased in FA. Unspecific decreases between MD and CM towards amygdala were paralleled by primary amygdala FA reductions. LIMITATIONS: Specificity of the TOI approach and heterogenous sample. CONCLUSIONS: Robust parietal FA reductions, controlled for age effects were found in MDD. Further we revealed subcortical disease state dependency of FA in thalamic tracts, specific to predescribed preferential connections.

Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia.

Abnormalities of the hippocampus are intricately involved in the pathophysiology of schizophrenia. Hippocampal volume decrease is present at disease onset and has mainly been observed in the anterior and posterior part of the hippocampus. Nevertheless, an association between regionally specific hippocampal shape deformities putatively affecting a pathophysiologically crucial region, i.e. cornu ammonis field 1 (CA1), and symptomatology as well as required maintenance medication has not been observed. The aim of this study was to characterize the relationship between CA1-specific hippocampal surface deformations and symptom severity. Furthermore, we aimed to explore whether such specific morphological hippocampus abnormalities statistically predict the maintenance dosage of antipsychotic medication. Hippocampal shape and volume were determined by manual segmentation of high resolution, whole brain, three-dimensional structural magnetic resonance imaging scans. Associations between hippocampal volume, specific shape deformities in CA1, and positive and negative symptoms were assessed in 32 patients with schizophrenia and compared with 34 healthy control subjects. In addition to volume reductions of the left hippocampus, patients with schizophrenia displayed specific shape deformities in the left anterior and posterior CA1 subfield. Overall, the severity of positive symptoms was closely associated to these morphological deformities, specifically delusions and hallucinations. In addition, CA1 deformity was linked to the required antipsychotic dosage. Findings were replicated in a second, independent sample. Hippocampal CA1 deformity, possibly reflecting shrinkage, might result from a specific hyperactivity, leading to a circumscribed volume loss. Owing to its physiological function, deficits in CA1 may be directly involved in the pathogenesis of hallucinations and delusions, core symptoms in schizophrenia.

Distinct structural alterations independently contributing to working memory deficits and symptomatology in paranoid schizophrenia.

Schizophrenia is considered a brain disease with a quite heterogeneous clinical presentation. Studies in schizophrenia have yielded a wide array of correlations between structural and functional brain changes and clinical and cognitive symptoms. Reductions of grey matter volume (GMV) in the prefrontal and temporal cortex have been described which are crucial for the development of positive and negative symptoms and impaired working memory (WM). Associations between GMV reduction and positive and negative symptoms as well as WM impairment were assessed in schizophrenia patients (symptomatology in 34, WM in 26) and compared to healthy controls (36 total, WM in 26). GMV was determined by voxel-based morphometry and its relation to positive and negative symptoms as well as WM performance was assessed. In schizophrenia patients, reductions of GMV were evident in anterior cingulate cortex, ventrolateral prefrontal cortex (VLPFC), superior temporal cortex, and insula. GMV reductions in the superior temporal gyrus (STG) were associated with positive symptom severity as well as WM impairment. Furthermore, the absolute GMV of VLPFC was strongly related to negative symptoms. These predicted WM performance as well as processing speed. The present results support the assumption of two distinct pathomechanisms responsible for impaired WM in schizophrenia: (1) GMV reductions in the VLPFC predict the severity of negative symptoms. Increased negative symptoms in turn are associated with a slowing down of processing speed and predict an impaired WM. (2) GMV reductions in the temporal and mediofrontal cortex are involved in the development of positive symptoms and impair WM performance, too.

The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans.

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing-independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal-cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long-term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory.

The role of hippocampus dysfunction in deficient memory encoding and positive symptoms in schizophrenia.

BACKGROUND: Declarative memory disturbances, known to substantially contribute to cognitive impairment in schizophrenia, have previously been attributed to prefrontal as well as hippocampal dysfunction. AIMS: To characterize the role of prefrontal and mesolimbic/hippocampal dysfunction during memory encoding in schizophrenia. METHOD: Neuronal activation in schizophrenia patients and controls was assessed using functional magnetic resonance imaging (fMRI) during encoding of words in a deep (semantic judgement) and shallow (case judgment) task. A free recall (no delay) and a recognition task (24h delay) were performed. RESULTS: Free recall, but not recognition performance was reduced in patients. Reduced performance was correlated with positive symptoms which in turn were related to increased left hippocampal activity during successful encoding. Furthermore, schizophrenia patients displayed a hippocampal hyperactivity during deep encoding irrespective of encoding success along with a reduced anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (DMPFC) activity in successful encoding but an intact left inferior frontal cortex (LIFC) activity. CONCLUSIONS: This study provides the first evidence directly linking positive symptoms and memory deficits to dysfunctional hippocampal hyperactivity. It thereby underscores the pivotal pathophysiological role of a hyperdopaminergic mesolimbic state in schizophrenia.

Glutamatergic and resting-state functional connectivity correlates of severity in major depression - the role of pregenual anterior cingulate cortex and anterior insula.

Glutamatergic mechanisms and resting-state functional connectivity alterations have been recently described as factors contributing to major depressive disorder (MDD). Furthermore, the pregenual anterior cingulate cortex (pgACC) seems to play an important role for major depressive symptoms such as anhedonia and impaired emotion processing. We investigated 22 MDD patients and 22 healthy subjects using a combined magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (fMRI) approach. Severity of depression was rated using the 21-item Hamilton depression scale (HAMD) and patients were divided into severely and mildly depressed subgroups according to HAMD scores. Because of their hypothesized role in depression we investigated the functional connectivity between pgACC and left anterior insular cortex (AI). The sum of Glutamate and Glutamine (Glx) in the pgACC, but not in left AI, predicted the resting-state functional connectivity between the two regions exclusively in depressed patients. Furthermore, functional connectivity between these regions was significantly altered in the subgroup of severely depressed patients (HAMD > 15) compared to healthy subjects and mildly depressed patients. Similarly the Glx ratios, relative to Creatine, in the pgACC were lowest in severely depressed patients. These findings support the involvement of glutamatergic mechanisms in severe MDD which are related to the functional connectivity between pgACC and AI and depression severity.

Changes in cortical blood oxygenation during arithmetical tasks measured by near-infrared spectroscopy.

Solving arithmetical problems is a core skill which is learned starting early in childhood and has been shown to involve a temporo-parietal network. In this study, we investigated hemodynamic concentration changes in oxygenated (O(2)Hb) and deoxygenated hemoglobin (HHb) within cortical brain regions by means of near-infrared spectroscopy (NIRS). Ten healthy subjects had to calculate or just read two-digit addition tasks that were either presented as numeric formulas or embedded in text. We found higher increases for O(2)Hb in parietal brain regions of both hemispheres for the calculation compared to the reading-only condition. Furthermore, these increases were more pronounced during text-embedded tasks than during numeric tasks. Corresponding decreases of HHb could also be detected. These first NIRS findings on that topic confirm that parietal regions are involved in the processing of arithmetic tasks while the amount of activation seems to depend on task modalities like difficulty or complexity.

Brain pathology in pedophilic offenders: evidence of volume reduction in the right amygdala and related diencephalic structures.

CONTEXT: Pedophilic crime causes considerable public concern, but no causative factor of pedophilia has yet been pinpointed. In the past, etiological theories postulated a major impact of the environment, but recent studies increasingly emphasize the role of neurobiological factors, as well. However, the role of alterations in brain structures that are crucial in the development of sexual behavior has not yet been systematically studied in pedophilic subjects. OBJECTIVE: To examine whether pedophilic perpetrators show structural neuronal deficits in brain regions that are critical for sexual behavior and how these deficits relate to criminological characteristics. DESIGN: Amygdalar volume and gray matter of related structures that are critical for sexual development were compared in 15 nonviolent male pedophilic perpetrators (forensic inpatients) and 15 controls using complementary morphometric analyses (voxel-based morphometry and volumetry). Psychosocial adjustment and sexual offenses were also assessed. RESULTS: Pedophilic perpetrators showed a significant decrease of right amygdalar volume, compared with healthy controls (P = .001). We observed reduced gray matter in the right amygdala, hypothalamus (bilaterally), septal regions, substantia innominata, and bed nucleus of the striae terminalis. In 8 of the 15 perpetrators, enlargement of the anterior temporal horn of the right lateral ventricle that adjoins the amygdala could be recognized by routine qualitative clinical assessment. Smaller right amygdalar volumes were correlated with the propensity to commit uniform pedophilic sexual offenses exclusively (P = .006) but not with age (P = .89). CONCLUSIONS: Pedophilic perpetrators show structural impairments of brain regions critical for sexual development. These impairments are not related to age, and their extent predicts how focused the scope of sexual offenses is on uniform pedophilic activity. Subtle defects of the right amygdala and closely related structures might be implicated in the pathogenesis of pedophilia and might possibly reflect developmental disturbances or environmental insults at critical periods.