Kerstin J. Plessen

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce.

An fMRI Study of the Effects of Psychostimulants on Default-Mode Processing During Stroop Task Performance in Youths With ADHD

OBJECTIVE The authors examined the effect of psychostimulants on brain activity in children and adolescents with ADHD performing the Stroop Color and Word Test. METHOD The authors acquired 52 functional MRI scans in 16 youths with ADHD who were known responders to stimulant medication and 20 healthy comparison youths. Participants with ADHD were scanned on and off medication in a counterbalanced design, and comparison subjects were scanned once without medication. RESULTS Stimulant medication significantly improved suppression of default-mode activity in the ventral anterior cingulate cortex in the ADHD group. When off medication, youths with ADHD were unable to suppress default-mode activity to the same degree as comparison subjects, whereas when on medication, they suppressed this activity to comparison group levels. Greater activation of the lateral prefrontal cortex when off medication predicted a greater reduction in ADHD symptoms when on medication. Granger causality analyses demonstrated that activity in the lateral prefrontal and ventral anterior cingulate cortices mutually influenced one another but that the influence of the ventral anterior cingulate cortex on the lateral prefrontal cortex was significantly reduced in youths with ADHD off medication relative to comparison subjects and increased significantly to normal levels when ADHD youths were on medication. CONCLUSIONS Psychostimulants in youths with ADHD improved suppression of default-mode activity in the ventral anterior cingulate and posterior cingulate cortices, components of a circuit in which activity has been shown to correlate with the degree of mind-wandering during attentional tasks. Stimulants seem to improve symptoms in youths with ADHD by normalizing activity within this circuit and improving its functional interactions with the lateral prefrontal cortex.

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 (Cohens 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 (Cohens 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.

Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome

BACKGROUND Tourette syndrome (TS) is a disorder of chronic motor and vocal tics that begins in childhood. METHODS A systematic Medline search was conducted to identify existing anatomical imaging studies in persons with TS. RESULTS Thirty studies were identified, and their methods and findings were reviewed. Findings of reduced caudate volumes across the life span and thinning of sensorimotor cortices that is proportional with tic severity in children with TS implicate these regions in the genesis of tics. Hypertrophy of limbic and prefrontal cortices and a smaller corpus callosum accompany fewer symptoms in children with TS, likely representing an activity-dependent plasticity within these regions that help to modulate tic severity. CONCLUSION Although existing studies differ with respect to sample size, gender composition, quality of clinical characterization, pulse sequences, and methods of image analysis, the preponderance of evidence suggests that disturbances in the development of the motor portions of cortical-subcortical circuits likely predispose to the development TS and that neuroplastic changes in control systems of the brain help to modulate the severity of symptom expression. These findings from cross-sectional studies require confirmation in more representative populations within longitudinal studies.

Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study

BACKGROUND Children with Tourette syndrome generally experience improvement of tics by age 18 years, but psychosocial and comorbidity outcomes at this age are unclear. AIMS To compare psychosocial outcomes and lifetime comorbidity rates in older adolescents with Tourette syndrome and controls. We hypothesised a priori that individuals with Tourette syndrome would have lower Childrens Global Assessment Scale (CGAS) scores. METHOD A total of 65 individuals with Tourette syndrome, identified in childhood, and 65 matched community controls without tic or obsessive-compulsive disorder (OCD) symptoms were assessed around 18 years of age regarding psychosocial functioning and lifetime psychiatric disorders. RESULTS Compared with controls, individuals with Tourette syndrome had substantially lower CGAS scores (P = 10(-8)) and higher rates of attention-deficit hyperactivity disorder (ADHD), major depression, learning disorder and conduct disorder (P< or =0.01). In the participants with Tourette syndrome, poorer psychosocial outcomes were associated with greater ADHD, OCD and tic severity. CONCLUSIONS Clinically ascertained children with Tourette syndrome typically have impaired psychosocial functioning and high comorbidity rates in late adolescence.

Neuroimaging of Developmental Psychopathologies: The Importance of Self‐Regulatory and Neuroplastic Processes in Adolescence

Abstract: Normal brain maturational and developmental processes, together with plastic reorganization of the brain in response to experiential demands, contribute to the acquisition of improved capacities for self‐regulation and impulse control during adolescence. The frontal lobe is a main focus for these developmental and plastic processes during the transition from adolescence into adulthood. Tourette syndrome (TS), defined as the chronic presence of motor and vocal tics, has been increasingly conceptualized as a disorder of impaired self‐regulatory control. This disordered control is thought to give rise to semicompulsory urges to perform the movements that constitute simple tics, complex tics, or compulsions. Neuroimaging studies suggest that the expression of the genetic diathesis to TS is influenced by genetic and nongenetic factors affecting activity‐dependent reorganization of neuroregulatory systems, thereby influencing the phenotype, illness severity, and adult outcome of tic disorders. Similar developmental processes during adolescence likely determine the phenotype and natural history of a broad range of other complex neuropsychiatric disorders of childhood onset, and they likely contribute to the acquisition of improved self‐regulatory capacities that characterize normal adolescent development.

Is Behavioral Regulation in Children with ADHD Aggravated by Comorbid Anxiety Disorder

Background: The present study investigated the impact of coexisting anxiety disorder in children with ADHD on their ability to regulate behavior. Method: Parent reports on the Behavior Rating Inventory of Executive Function (BRIEF) in a comorbid group of children with ADHD and anxiety (n = 11) were compared to BRIEF reports in a group of children with a “pure” ADHD (n = 23), a “pure” anxiety (n = 24) and a group without any diagnosis (n = 104) in a 2 (ADHD vs. no ADHD) × 2 (anxiety vs. no anxiety) design. Results: The children with ADHD and anxiety disorder scored significantly higher on the Inhibit scale than children within the other three groups. Main effects of diagnosis appeared in ADHD children on the Inhibit, Emotional Control, and Working Memory scales, and on the Shift and Emotional Control scales in anxious children. Conclusion: The results indicate that a behavioral dysregulation in ADHD children is aggravated by comorbid anxiety.

Adults with attention-deficit/hyperactivity disorder — A diffusion-tensor imaging study of the corpus callosum

The objective of the present study was to investigate the microstructure and the macrostructure of the corpus callosum (CC) in adults with Attention-Deficit/Hyperactivity Disorder (ADHD) by means of magnetic resonance imaging (MRI). Twenty-nine participants with ADHD and 37 controls were included from the Norwegian ADHD project in Bergen. We measured the fractional anisotropy (FA) values, as well as the size of different subdivisions of the CC, using diffusion tensor imaging (DTI) and anatomical MRI. The isthmus/splenium part of the CC in the ADHD group showed reduced FA values compared to the control group, whereas the size of the CC did not differ across groups. Our findings thus demonstrate a divergence between microstructural and macrostructural measures in the CC of adults with ADHD. This contrasts with findings in children demonstrating callosal abnormalities in both microstructure and macrostructure. Our results may indicate that adults with ADHD in part have succeeded in passing by an earlier developmental delay of the CC, resulting in a normalization of callosal macrostructure into adulthood. However, microstructural differences are still present in adults, which may point to an abnormal lateralization in adults with ADHD, or could be a sign of a persisting impairment.

Neuroimaging of tic disorders with co-existing attention-deficit/hyperactivity disorder

BackgroundTourette syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) are common and debilitating neuropsychiatric illnesses that typically onset in the preschool years. Recently, both conditions have been subject to neuroimaging studies, with the aim of understanding their underlying neurobiological correlates.ObjectiveThe relation of TS and ADHD is discussed against the background of findings from previous Magnetic Resonance Imaging (MRI) studies.MethodsWe review the designs and major findings of previous studies that have examined TS with comorbid ADHD, and we briefly contrast these findings with those in ADHD without comorbid tic disorders.ResultsThe frequent comorbidity of TS and ADHD may reflect a common underlying neurobiological substrate, and studies confirm the hypothesized involvement of fronto-striatal circuits in both TS and ADHD. However, poor inhibitory control and volumetric reductions in fronto-striatal circuits appear to be core features of ADHD, whereas reduced volumes of the caudate nucleus, together with activation and hypertrophy of prefrontal regions that likely help to suppress tics, seem to be core features of TS.ConclusionThe etiological relationship between TS and ADHD must be clarified further with cross-sectional and, if possible, longitudinal imaging studies that examine samples of substantial size, including subgroups with pure TS and ADHD, as well as with comorbid conditions.

Case-Control Study of Six Genes Asymmetrically Expressed in the Two Cerebral Hemispheres: Association of BAIAP2 with Attention-Deficit/Hyperactivity Disorder

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disease that persists into adulthood in at least 30% of patients. There is evidence suggesting that abnormal left-right brain asymmetries in ADHD patients may be involved in a variety of ADHD-related cognitive processes, including sustained attention, working memory, response inhibition and planning. Although mechanisms underlying cerebral lateralization are unknown, left-right cortical asymmetry has been associated with transcriptional asymmetry at embryonic stages and several genes differentially expressed between hemispheres have been identified. METHODS We selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, and ID2) and performed a case-control association study in an initial Spanish sample of 587 ADHD patients (270 adults and 317 children) and 587 control subjects. RESULTS The single- and multiple-marker analysis provided evidence for a contribution of BAIAP2 to adulthood ADHD (p = .0026 and p = .0016, respectively). We thus tested BAIAP2 for replication in two independent adult samples from Germany (639 ADHD patients and 612 control subjects) and Norway (417 ADHD cases and 469 control subjects). While no significant results were observed in the Norwegian sample, we replicated the initial association between BAIAP2 and adulthood ADHD in the German population (p = .0062). CONCLUSIONS Our results support the participation of BAIAP2 in the continuity of ADHD across life span, at least in some of the populations analyzed, and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in this disorder.