The influence of methylphenidate on auditory brainstem response patients with attention deficit hyperactivity disorder; an exploratory study.

Background: Attention-deficit hyperactivity disorder (ADHD), characterized by periods of inattention, overactivity, and impulsiveness, is the most prevalent neurodevelopmental disorder among children. Auditory Brainstem Response (ABR) is a technique in which clickshaped sounds elicit potentials that are recorded from electrodes placed on a patient's skull. Extant research indicates that ABR is frequently affected in neurodevelopmental disorders such as ADHD. Methylphenidate (MPH), a psychostimulant, is often prescribed to children with ADHD as a first-line pharmacological treatment. The aim of this study was to explore the effects of Methylphenidate treatment on previously observed amplitude alterations in the ABR of patients with ADHD. Methods: We recruited 32 drug-naïve children and adolescents (19 males and 13 females; mean age 11 years) diagnosed with ADHD and 35 health controls (15 males and 20 females; mean age 12 years). The ADHD group was treated with Methylphenidate, and ABR was recorded before treatment and at a steady state of medical treatment. Results: Medicated ADHD patients exhibited increased activity in the right side ABR in Wave VI. Conclusions: A significant increase in activity was found in a part of the ABR thought to correspond to the thalamic area in medicated ADHD patients compared to the same area of non-medicated ADHD patients. The results add to the growing body of research suggesting that specific ABR peaks correlate to certain psychiatric symptoms.

Reduced thalamic activity in ADHD under ABR forward masking conditions.

Attention-deficit hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder characterized by symptoms of inattention, overactivity, and/or impulsiveness. The prevalence of ADHD varies in different settings and there have been voices raised to call for more objective measures in order to avoid over- and underdiagnosing of ADHD. Auditory Brainstem Response (ABR) is a method where click shaped sounds evoke potentials that are recorder from electrodes on the skull of a patient. The aim of this study was to explore possible alterations in the ABR of 29 patients with ADHD compared to 39 healthy controls. We used a forward masked sound. We found differences in ABR that correspond to the thalamic area. The thalamus seems to play an active role in regulation of activity level in ADHD. More research is needed to draw any further conclusions on using ABR as an objective measurement to detect ADHD.

Involvement of fear, incompleteness, and disgust during symptoms of pediatric obsessive-compulsive disorder.

Fear has been assigned a central role in models of obsessive-compulsive disorder (OCD), but empirical investigations into the emotions that underpin OCD symptoms are few, especially in pediatric samples. Using validated, clinician-led structured interviews, 124 youth with OCD reported on the presence and severity of symptoms across the main symptom dimensions of OCD (aggressive, symmetry, contamination) and the degree to which fear, incompleteness, and disgust accompanied these symptoms. For comparison purposes, the degree of fear, incompleteness, and disgust during symptoms was obtained also from youth with social anxiety disorder (SAD; n = 27) and generalized anxiety disorder (GAD; n = 28). Participants with OCD reported that all three emotions were involved in their symptoms; however, fear was most strongly linked to aggressive symptoms, incompleteness to symmetry symptoms, and disgust to contamination symptoms. Incompleteness differentiated youth with OCD from those with SAD and GAD. No differences for these emotions were found for youth with OCD with versus without the tic-disorder subtype or comorbid autism. A positive association between incompleteness and self-reported hoarding emerged among youth with OCD. Further studies of the emotional architecture of pediatric OCD, and its relationship to etiology and treatment, are warranted.

Incompleteness, harm avoidance, and disgust: A comparison of youth with OCD, anxiety disorders, and no psychiatric disorder.

Psychological models of pediatric obsessive-compulsive disorder (OCD) place a heavy emphasis on harm avoidance as a maintaining factor and target for treatment. Incompleteness and disgust may also play a role in pediatric OCD but remain understudied. Youth with OCD (n = 100), anxiety disorders (n = 96), and no impairing psychiatric symptoms (n = 25) completed self-report measures of trait-level incompleteness, harm avoidance, and disgust and current symptoms of OCD, anxiety, and depression. Group differences and associations between emotions, symptoms, and pre- to post-treatment change in overall OCD severity were examined. Youth with OCD and anxiety disorders scored higher on harm avoidance and disgust than youth with no psychiatric disorder. Youth with OCD scored higher on incompleteness than youth with anxiety disorders and youth with no psychiatric disorder. Harm avoidance showed unique associations to self-reported symptoms of OCD, anxiety, and depression while incompleteness was uniquely related to OCD and disgust to anxiety. Within the OCD sample, incompleteness and harm avoidance were differentially related to the major OCD symptom dimensions, and change in incompleteness was uniquely related to pre- to post-treatment change in OCD severity. Trait-level incompleteness appears to play a central role in pediatric OCD and studies investigating its direct involvement in symptoms and associations with treatment outcome are needed. The role of disgust in relation to pediatric OCD remains unclear.

Validation of an interview-only version of the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) in treatment-seeking youth with obsessive-compulsive disorder.

There is a growing body of evidence suggesting that individuals with obsessive-compulsive disorder (OCD) may be sub-typed along different symptom dimensions. These dimensions may help explain responsiveness to current treatments. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a validated instrument involving a self-report screening tool followed by a structured interview in which the presence/absence and severity of OCD symptom dimensions are assessed and rated. The present study investigated the validity of a briefer, interview-only version of the DY-BOCS modified for use in routine care. Clinically-referred children and adolescents (N = 119) with OCD were administered the DY-BOCS along with other measures of OCD, anxiety, depression, and overall functioning and a subset (N = 100) were reassessed on average 14 months after initial assessment. This briefer, interview-only version of the DY-BOCS demonstrated high levels of internal consistency and correlated in the moderate to strong range with alternative measures of OCD severity and OCD symptom dimensions. Change scores on the DY-BOCS from baseline to follow-up were significantly correlated with change scores on the alternative measures of OCD and clinician-rated improvement, suggesting that this brief version of the DY-BOCS is valid and sensitive to the effects of treatment for OCD delivered in routine clinical care.

The effects of ADHD on cognitive performance.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common and impairing neurodevelopmental disorder. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computerized test battery with standardized procedures and solid psychometric properties targeting multiple neuropsychological functions. AIMS: The aim of this study was to look at the effects of ADHD on cognitive performance using CANTAB expressed as a statistical interaction term in regression modeling. METHODS: We assessed 112 drug-naïve subjects (age: 7-18 years) with ADHD based on DSM IV criteria and compared them to 95 control subjects (age: 7-18 years). All participants were administered five CANTAB tasks designed to capture different aspects of executive functioning: Stockings of Cambridge (SOC), Intra/Extra dimensional shift (IED), Spatial Working Memory (SWM), Simple Reaction Time (SRT) and Stop Signal Task (SST). RESULTS: T-tests showed a difference between ADHD and control subjects in all cognitive measures except SOC. The majority of measures showed a non-linear effect of age. SWM strategy and SST direction errors showed a linear effect of age. ADHD diagnosis had a statistically significant effect on performance. For all tests except SOC, ADHD produced the main effect without interaction with age. DISCUSSION: For all CANTAB measures, ADHD diagnosis had a significant effect on performance and produced this effect without interaction with age in all tests except SOC, indicating that the developmental trajectories were parallel in both groups. The results indicate that cognitive performance is impaired in youth with ADHD and that CANTAB can be a valuable tool in the diagnostic assessment of ADHD.

Abnormal brainstem auditory response in young females with ADHD.

Studies have shown that the auditory brainstem response (ABR) is often affected in neurodevelopmental disorders. The aim of this study is to investigate possible differences in ABR between young females with ADHD compared to control subjects. This study focuses on young females, age 7-17 with ADHD, comparing the ABR of 43 young females with ADHD to 21 age- and gender-matched control subjects. Young females with ADHD have a significantly different ABR in a region between cochlear nucleus and superior olivary complex as well as in the thalamic region compared to control subjects. These data indicate specific differences in ABR between girls with ADHD compared to female controls.

Lithium in drinking water and thyroid function.

BACKGROUND: High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function. OBJECTIVES: We assessed associations between exposure to lithium from drinking water and other environmental sources and thyroid function. METHODS: Women (n=202) were recruited in four Andean villages in northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T4) and pituitary gland thyroid-stimulating hormone (TSH), analyzed by routine immunometric methods. RESULTS: The median urinary lithium concentration was 3,910 µg/L (5th, 95th percentiles, 270 µg/L, 10,400 µg/L). Median plasma concentrations (5th, 95th percentiles) of T4 and TSH were 17 pmol/L (13 pmol/L, 21 pmol/L) and 1.9 mIU/L, (0.68 mIU/L, 4.9 mIU/L), respectively. Urine lithium was inversely associated with T4 [ß for a 1,000-µg/L increase=-0.19; 95% confidence interval (CI), -0.31 to -0.068; p=0.002] and positively associated with TSH (ß=0.096; 95% CI, 0.033 to 0.16; p=0.003). Both associations persisted after adjustment (for T4, ß=-0.17; 95% CI, -0.32 to -0.015; p=0.032; for TSH: ß=0.089; 95% CI, 0.024 to 0.15; p=0.007). Urine selenium was positively associated with T4 (adjusted T4 for a 1 µg/L increase: ß=0.041; 95% CI, 0.012 to 0.071; p=0.006). CONCLUSIONS: Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources.

Instructive cross-talk between neural progenitor cells and gliomas.

Gliomas are the most common primary brain tumors and offer a poor prognosis in patients because of their infiltrative and treatment-resistant nature. The median survival time after diagnosis is approximately 11-12 months. There is a strong need for novel treatment modalities in targeting gliomas, and recent advances use neural progenitor cells as delivery systems for different therapeutic strategies. In this study, we show that rat embryonic neural progenitor cell (NPC) lines, transplanted at a distant site from a 3-day-preestablished glioma in the striatum, were able to migrate toward and colocalize with tumor isles without general spread into the brain parenchyma. Upon encounter with tumor, neural progenitor cells changed phenotype and became vimentin positive. These results demonstrate that transplanted neural progenitor cells respond to queues from a tumor and home to and exert an antitumor effect on the preestablished glioma, significantly decreasing the tumor volume with approximately 67% compared with control tumors after 1-2 weeks. Moreover, these early effects could be translated into increased survival times of animals treated with neural progenitor cell grafts 3 days after intrastriatal tumor inoculation. In contrast, there was no activation or migration of endogenous subventricular zone (SVZ) neuroblasts in response to an intrastriatal syngeneic tumor. In conclusion, NPC possess the ability to influence tumor growth as well as respond to queues from the tumor or tumor microenvironment, demonstrating a cross-talk between the cells.

Noninvasive acoustic cell trapping in a microfluidic perfusion system for online bioassays.

Techniques for manipulating, separating, and trapping particles and cells are highly desired in today's bioanalytical and biomedical field. The microfluidic chip-based acoustic noncontact trapping method earlier developed within the group now provides a flexible platform for performing cell- and particle-based assays in continuous flow microsystems. An acoustic standing wave is generated in etched glass channels (600x61 microm2) by miniature ultrasonic transducers (550x550x200 microm3). Particles or cells passing the transducer will be retained and levitated in the center of the channel without any contact with the channel walls. The maximum trapping force was calculated to be 430+/-135 pN by measuring the drag force exerted on a single particle levitated in the standing wave. The temperature increase in the channel was characterized by fluorescence measurements using rhodamine B, and levels of moderate temperature increase were noted. Neural stem cells were acoustically trapped and shown to be viable after 15 min. Further evidence of the mild cell handling conditions was demonstrated as yeast cells were successfully cultured for 6 h in the acoustic trap while being perfused by the cell medium at a flowrate of 1 microL/min. The acoustic microchip method facilitates trapping of single cells as well as larger cell clusters. The noncontact mode of cell handling is especially important when studies on nonadherent cells are performed, e.g., stem cells, yeast cells, or blood cells, as mechanical stress and surface interaction are minimized. The demonstrated acoustic trapping of cells and particles enables cell- or particle-based bioassays to be performed in a continuous flow format.

Chemokine-directed migration of tumor-inhibitory neural progenitor cells towards an intracranially growing glioma.

We have earlier shown that the rat neural progenitor cell line HiB5 is capable of suppressing intracranial growth of glioma cells in Fisher rats. Unlike some neural progenitor cells, HiB5 cells have not shown homing capacity towards glioma cells growing intracranially. In this study, we have genetically modified HiB5 progenitor cells to over-express the chemokine receptor CXCR3. We show that the introduced receptor is functionally responding to ligand stimulation with increased phosphorylation levels of ERK and SAPK/JNK and a transcriptional response of an AP-1 reporter system introduced into HIB5 cells. These transfected progenitor cells migrate in vitro in response to IP-10 and I-TAC. Further, we show an enhanced in vivo migration of the CXCR3 transfected HiB5 cells over the corpus callosum towards an IP-10 and I-TAC expressing glioma, as compared to wild type HiB5 cells. Our data indicate that it is possible to take advantage of chemokines natural capacity to initiate migratory responses, and to use this ability to enhance tumor-inhibitory neural progenitor cells to target an intracranially growing glioma.

Neural progenitor cell lines inhibit rat tumor growth in vivo.

Current therapies for gliomas often fail to address their infiltrative nature. Conventional treatments leave behind small clusters of neoplastic cells, resulting in eventual tumor recurrence. In the present study, we have evaluated the antitumor activity of neural progenitor cells against gliomas when stereotactically injected into nucleus Caudatus of Fisher rats. We show that the rat neural progenitor cell lines HiB5 and ST14A, from embryonic hippocampus and striatum primordium, respectively, are able to prolong animal survival and, in 25% of the cases, completely inhibit the outgrowth of N29 glioma compared with control animals. Delayed tumor outgrowth was also seen when HiB5 cells were inoculated at the site of tumor growth 1 week after tumor inoculation or when a mixture of tumor cells and HiB5 cells were injected s.c. into Fisher rats. HiB5 cells were additionally coinoculated together with two alternative rat gliomas, N32 and N25. N32 was growth inhibited, but rats inoculated with N25 cells did not show a prolonged survival. To evaluate the possibility of the involvement of the immune system in the tumor outgrowth inhibition, we show that HiB5 cells do not evoke an immune response when injected into Fisher rats. Furthermore, the rat neural progenitor cells produce all transforming growth factor beta isotypes, which could explain the observed immunosuppressive nature of these cells. Hence, some neural progenitor cells have the ability to inhibit tumor outgrowth when implanted into rats. These results indicate the usefulness of neural stem cells as therapeutically effective cells for the treatment of intracranial tumors.

Identification and characterization of a human smad3 splicing variant lacking part of the linker region.

Smad3 is one of the signal transducers that are activated in response to transforming growth factor-beta (TGF-beta). We have identified and characterized a splicing variant of smad3. The splicing variant (smad3-Delta3) lacks exon 3 resulting in a truncated linker region. We could detect mRNA expression of smad3-Delta3 in all investigated human tissues. Real-time PCR analyses demonstrated that the fraction of smad3-Delta3 mRNA compared to normal smad3 varies between tissues. The amount of spliced mRNA was estimated to represent 0.5-5% of the normal smad3 mRNA. When smad3-Delta3 is overexpressed in a fibrosarcoma cell line, the Smad3-Delta3 is translocated to the nucleus upon TGF-beta stimulation and binds the Smad responsive element. Using a CAGA luciferase reporter system, we demonstrate that Smad3-Delta3 has transcriptional activity and we conclude that Smad3-Delta3 possesses functional transactivating properties.

Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix.

A preformed gelatin matrix containing adherent rat colon carcinoma cells was transplanted subcutaneously into rats to analyze the outgrowth of the tumor and the inflammatory response. The gelatin matrix simplifies the precise localization of the tumor cells early after implantation and allows the gelatin piece with a growing tumor to be dissected for analysis in vitro, after various times in vivo. The immortalized mesenchymal progenitor cell line MPC1cE was cocultured with rat colon carcinoma cells in vivo in gelatin matrix. The mesenchymal progenitor cells inhibited the outgrowth of the rat colon carcinoma and a complete inhibition was seen if the number of mesenchymal progenitor cells were at least equal to the number of tumor cells. The mixture of tumor cells and mesenchymal progenitor cells induced more infiltration of monocytes and granulocytes than tumor cells or mesenchymal progenitor cells alone. Infiltration of T cells and CD31+ endothelial cells correlated to the presence of tumor cells and not to mesenchymal progenitor cells. These findings suggest that tumor cell culture in vivo in a gelatin matrix is effective for early localization of tumor cells in vivo and that mesenchymal progenitor cells effectively inhibit the growth of the tumor cells in vivo.