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Background The reverse question mark (RQM) incision has been traditionally utilized to perform decompressive hemicraniectomies (DHC) to relieve refractory intracranial hypertension. Alternative incisions have been proposed in the literature but have not been compared directly. Objective To present the retroauricular (RA) incision as an alternative incision that we hypothesize will increase calvarium exposure to maximize the removal of the hemicranium and will decrease wound-related complications compared to the RQM incision. Methods This study is a retrospective review of all DHCs performed at our institution over a span of 34 mo, stratified based on the type of scalp incision. The surface areas of the cranial defects were calculated, normalizing to their respective skull diameters. For those patients surviving beyond 1 wk, complications were examined from both cohorts. Results A total of 63 patients in the RQM group and 43 patients in the RA group were included. The average surface area for the RA and RQM incisions was 117.0 and 107.8 cm2 (P = .0009), respectively. The ratio of average defect size to skull size for RA incision was 0.81 compared to 0.77 for the RQM group (P = .0163). Of those who survived beyond 1 wk, the absolute risk for surgical site complications was 14.0% and 8.3% for RQM and RA group (P = .5201), respectively. Conclusion The RA incision provides a safe and effective alternative incision to the traditional RQM incision used for DHC. This incision affords a potentially larger craniectomy while mitigating postoperative wound complications.

Objective The true incidence of perioperative coronavirus disease 2019 (COVID-19) has not been well elucidated in neurosurgical studies. We reviewed the effects of the pandemic on the neurosurgical case volume to study the incidence of COVID-19 in patients undergoing these procedures during the perioperative period and compared the characteristics and outcomes of this group to those of patients without COVID-19. Methods The neurosurgical and neurointerventional procedures at 2 tertiary care centers during the pandemic were reviewed. The case volume, type, and acuity were compared to those during the same period in 2019. The perioperative COVID-19 tests and results were evaluated to obtain the incidence. The baseline characteristics, including a modified Medically Necessary Time Sensitive (mMeNTS) score, and outcome measures were compared between those with and without COVID-19. Results A total of 405 cases were reviewed, and a significant decrease was found in total spine, cervical spine, lumbar spine, and functional/pain cases. No significant differences were found in the number of cranial or neurointerventional cases. Of the 334 patients tested, 18 (5.4%) had tested positive for COVID-19. Five of these patients were diagnosed postoperatively. The mMeNTS score, complications, and case acuity were significantly different between the patients with and without COVID-19. Conclusion A small, but real, risk exists of perioperative COVID-19 in neurosurgical patients, and those patients have tended to have a greater complication rate. Use of the mMeNTS score might play a role in decision making for scheduling elective cases. Further studies are warranted to develop risk stratification and validate the incidence.

Post-traumatic stress disorder (PTSD) manifests as emotional suffering and problem-solving impairments under extreme stress. This meta-analysis aimed to pool the findings from all the studies examining emotion and cognition in individuals with PTSD to develop a robust mechanistic understanding of the related brain dysfunction. We identified primary studies through a comprehensive literature search of the MEDLINE and PsychINFO databases. The GingerALE software (version 2.3.6) from the BrainMap Project was used to conduct activation likelihood estimation meta-analyses of the eligible studies for cognition, emotion and interface of both. Relative to the non-clinical (NC) group, the PTSD group showed greater activation during emotional tasks in the amygdala and parahippocampal gyrus. In contrast, the NC group showed significantly greater activation in the bilateral anterior cingulate cortex (ACC) than did the PTSD group in the emotional tasks. When both emotional and cognitive processing were evaluated, the PTSD group showed significantly greater activation in the striatum than did the NC group. No differences in activation between the PTSD and NC groups were noted when only the cognitive systems were examined. Individuals with PTSD exhibited overactivity in the subcortical regions, i.e., amygdala and striatum, when processing emotions. Underactivity in the emotional and cognitive processing intermediary cortex, i.e., the ACC, was especially prominent in individuals with PTSD relative to the NC population following exposure to emotional stimuli. These findings may explain the trauma-related fear, irritability, and negative effects as well as the concentration difficulties during cognitive distress associated with emotional arousal, that are commonly observed in individuals with PTSD.

Adolescence is a vulnerable period for major depressive disorder (MDD). The aim of our study was to investigate resting-state functional connectivity (RSFC) in first-episode, medication-naïve adolescent MDD patients. Twenty-three drug-naïve adolescents diagnosed with first-episode MDD and 27 healthy participants were enrolled. Seed-to-voxel RSFC analyses were performed. The frontolimbic circuit regions of interest included the amygdala, anterior cingulate cortex, insula, and hippocampus. A correlation analysis between the RSFC and Children's Depression Inventory, Hamilton depression rating scale, and duration of episodes was performed. The adolescents with MDD exhibited the following characteristics: a lower RSFC between the right amygdala and right superior frontal gyrus; a lower RSFC between the right hippocampus and clusters including the right insula and right middle frontal gyrus; a higher RSFC between the left insula and clusters including the bilateral middle frontal gyrus, right superior frontal gyrus, and right frontal pole; and a higher RSFC between the left dorsal anterior cingulate cortex and a cluster including the left insula. Medication-naïve adolescents with depression display lower connectivity of several brain regions implicated in processing, regulation, and memory of emotions. Higher connectivity was observed in brain regions that potentially explain rumination, impaired concentration, and physiological arousal.

Objectives Attention deficit has been shown to exist in adult and pediatric bipolar disorder across the life span. Given that emotion dysregulation is central to bipolar disorder, this study hypothesizes that emotional circuitry regions are altered along with anomalies in the attentional systems during cognitive deployment in bipolar disorder. Methods An activation likelihood estimation meta-analysis of attentional activities using GingerALE software was completed for adult and pediatric bipolar disorder populations in all published studies till December 2017. The meta-analysis of all fMRI studies included a total of ten pediatric studies (comprised of pediatric bipolar disorder (PBD) and typically developing (TD) groups) and nine adult patient studies (comprised of adult bipolar disorder (ABD) and healthy control (HC) groups). Results While engaged in attentional tasks, increased activation was seen in inferior frontal gyrus with decreased activation in limbic regions in subjects with PBD, relative to TD. Differential patterns of underactivity were also noted in the dorsal attentional system i.e., frontostriatal circuit (dorsolateral prefrontal cortex, anterior cingulate cortex, right lentiform nucleus and right globus pallidus) in PBD patients relative to the TD. However, we did not see any significant differences between the adult groups i.e., ABD vs. HC. Conclusions In PBD, deploying attentional system potentially improves the fronto-limbic affective circuitry function, despite impaired dorsal attentional system i.e., fronto-striatal circuitry. In contrast, these neural correlates underlying attentional engagement appeared to be not significant in adult BD. Limitations We examined the PBD vs. TD and the ABD vs. HC separately instead of four-way contrast (dual meta-analytic study). Also, attentional tasks were not unidimensional and tend to capture selective and sustained attention along with response inhibition, thereby recruiting multiple brain circuits.

Objective Coronavirus disease 2019 (COVID-19) continues to affect all aspects of health care delivery, and neurosurgical practices are not immune to its impact. We aimed to evaluate neurosurgical practice patterns as well as the perioperative incidence of COVID-19 in neurosurgical patients and their outcomes. Methods A retrospective review of neurosurgical and neurointerventional cases at 2 tertiary centers during the first 3 months of the first peak of COVID-19 pandemic (March 8 to June 8) as well as following 3 months (post-peak pandemic; June 9 to September 9) was performed. Baseline characteristics, perioperative COVID-19 test results, modified Medically Necessary, Time-Sensitive (mMeNTS) score, and outcome measures were compared between COVID-19–positive and–negative patients through bivariate and multivariate analysis. Results In total, 652 neurosurgical and 217 neurointerventional cases were performed during post-peak pandemic period. Cervical spine, lumbar spine, functional/pain, cranioplasty, and cerebral angiogram cases were significantly increased in the postpandemic period. There was a 2.9% (35/1197) positivity rate for COVID-19 testing overall and 3.6% (13/363) positivity rate postoperatively. Age, mMeNTS score, complications, length of stay, case acuity, American Society of Anesthesiologists status, and disposition were significantly different between COVID-19–positive and–negative patients. Conclusions A significant increase in elective case volume during the post-peak pandemic period is feasible with low and acceptable incidence of COVID-19 in neurosurgical patients. COVID-19–positive patients were younger, less likely to undergo elective procedures, had increased length of stay, had more complications, and were discharged to a location other than home. The mMeNTS score plays a role in decision-making for scheduling elective cases.

BACKGROUND Smartphone applications (apps) in the health care arena are being increasingly developed with the aim of benefiting both patients and their physicians. The delivery of adequate instructions both before and after a procedure or surgery is of paramount importance in ensuring the best possible outcome for patients. OBJECTIVE To demonstrate that app-based instructions with built-in reminders may improve patient understanding and compliance and contribute to reducing the number of surgery cancellations and postoperative complications and readmissions. METHODS We prospectively accrued 56 patients undergoing routine neurosurgery procedures who subsequently downloaded the app. The median age was 54 (range 27-79). Patients were followed for successful registration and use of the app, compliance with reading instructions before and after surgery, and sending pain scores and/or wound images. The number of surgeries cancelled, postoperative complications, 30-d readmissions, and phone calls for surgery-related questions were examined. RESULTS Fifty-four of the 56 patients successfully registered, downloaded, and used the app and read and complied with instructions both before and after surgery. There were no cancelled surgeries. There was 1 postoperative complication. There were no readmissions. Eight of the 54 patients (14.8%) called the office on a single occasion for a surgery related question. CONCLUSION We demonstrate the utility of a smartphone application in the perioperative neurosurgical care setting with regard to patient compliance and satisfaction as well as surgery cancellations and readmissions. Further study of a larger number of patients with a control group is warranted.

Nucleus accumbens (NAc) is a key region in the brain that is integral to both the reward and the emotional systems. The aim of the current paper is to synthesize the basic and the clinical neuroscience discoveries relevant to the NAc for the purpose of two-way translation. Selected literature on the structure and the functionality of the NAc is reviewed across animal and human studies. Dopamine, gamma-aminobutyric acid (GABA) and glutamate are the three key neurotransmitters that modulate the reward function and the motor activity. Dissociative roles of the core and the shell of the NAc include getting to the reward and staying on task with discretion, respectively. NAc shows decreased activation to reward in the individuals with major depressive disorder and the bipolar disorder, relative to that healthy controls (HC). The “difficult to please” or insatiability in response to reward in the emotional disorders may possibly be explained by such a neural pattern. Furthermore, it is likely that the increased amygdala activity reported in mood disorders could be accentuating the “wanting” of the reward by the virtue of its connections with the NAc, explaining the potential “hot mess”. In contrast, the NAc shows increased reward response in substance use disorders, relative to HC, in response to reward and emotional tasks. Accurate characterization of the NAc and its functionality in the human imaging studies of mood and substance use has important treatment implications.

Background Ventriculoperitoneal shunts (VPS) are placed for a variety of etiologies. It is common for general surgery to assist with insertion of the distal portion in the peritoneum. Objective To determine if there is a difference in revision rates in patients undergoing VPS placement with general surgery as well as those undergoing laparoscopic insertion. Methods A retrospective review of all consecutive patients undergoing VPS placements was performed in a three-year period (2017−2019). Those that underwent placement with general surgery were compared to those without general surgery. Additionally, patients undergoing distal placement via mini-laparotomy versus laparoscopy were compared. Multivariable logistic regression was used to examine risk factors for distal VPS failure. Results 331 patients were included. 202 (61.0 %) underwent VPS placement with general surgery. 121 (36.6 %) patients underwent insertion via laparoscopic technique. General surgery involvement reduced operative times, decreased length of stay, and lowered overall revision rates with distal revision rates being most significant (1.5 % vs 8.5 %; p = 0.0034). Patients undergoing VPS placement via laparoscopic technique had decreased operative time, length of stay, in-hospital complications and revision rates, with significant decrease in shunt infection (1.7 % vs 7.1 %; p = 0.0366). A history of prior shunt or abdominal surgery (OR 3.826; p = 0.0282) and lack of general surgery involvement (OR 20.98; p = 0.0314) are independent risk factors for distal shunt revision in our cohort. Conclusion The use of general surgeons in VPS insertion can be of benefit by decreasing operative time, length of stay, total revisions, and distal revision rates. Further prospective studies are warranted to determine true benefit.

Treating pediatric bipolar disorder (BD) requires new knowledge based on emerging and consistent neuroscience findings. It entails recognition and addressing the deficits in eight domains such as emotion processing, executive function, attention, impulse control, working memory, reward and risk response, perspective taking, and, finally, the interface of emotion and cognition. Skillful integration of four components: (A) assessment (disorder and domain functions), (B) educating the families that it is early-onset brain dysfunction based on what we now know through research, (C) chemotherapy with the hope of reversing the brain dysfunction, and (D) addressing the individual dynamics specific to the family and through neuroscience informed psychological treatment such as RAINBOW therapy. Imaging findings in pediatric BD offered four major contributions: (1) prefrontal cortex regions improve in function with some pharmacological agents, while amygdala in the subcortical region does not reach normality till after longer-term treatment; (2) various medications differentially engage different brain circuitry regions, supporting why combined therapy is required in severely ill BD; (3) there is invariable interlink between affective and cognitive domain dysfunctions in pediatric BD, by the virtue of early-onset illness diathesis; and (4) consistent and strong evidence that negative stimuli impact both affect regulation and cognitive function argues towards not using negative “punishment” in psychological treatment, thereby leading to the construction and completion of the randomized controlled trial of RAINBOW therapy or child- and family-focused cognitive behavior therapy. Ultimately, translating the new research findings to clinically ill population and educating researchers on clinical challenges are both critical steps towards a determined advancement with a singular focus to help children and their families.

Objective This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). Method Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. Results A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. Conclusion This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. Clinical trial registration information: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/ ; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/ ; NCT01166425 (CoLT 2).

Background: The insula is instrumental in integrating the emotional, cognitive, and sensory-motor systems. This manuscript lays a foundational framework for understanding the insula’s mechanistic role in moderating brain networks in illness and wellness. Methods: Reviewed here is the select literature on the brain anatomy and function relevant to the insula’s role in psychiatrically ill and normative populations. Results: The insula is a hub for moderating social cognition, empathy, reward-driven decision-making, arousal, reactivity to emotional stimuli, and somatic pain processing. Findings indicate a spectrum of increasing complexity in insular function – from receiving and interpreting sensorimotor sensations in the posterior insula to subjective perception of emotions in the anterior insula. The insula plays a key role at the interface of cognitive and emotional domains, functioning in concert with other brain regions that share common cytoarchitecture, such as the ventrolateral prefrontal cortex and the anterior cingulate cortex. Pharmacotherapy and mindfulness-based interventions can alter insular activation. Conclusion: The insula serves as a receiver and interpreter of emotions in the context of cognitive and sensory-motor information. Therefore, insular function and connectivity may potentially be utilized as a biomarker for treatment selection and outcome.

Postoperative central nervous system infections (PCNSIs) are serious complications following neurosurgical intervention. We previously investigated the incidence and causative pathogens of PCNSIs at a resource-limited, neurosurgical center in south Asia. This follow-up study was conducted to analyze differences in PCNSIs at the same institution following only one apparent change: the operating room air filtration system.This was a retrospective study of all neurosurgical cases performed between December 1, 2013, and March 31, 2016 at our center. Providers, patient demographic data, case types, perioperative care, rate of PCNSI, and rates of other complications were reviewed. These results were then compared with the findings of our previous study of neurosurgical cases between June 1, 2012, and June 30, 2013.All 623 neurosurgical operative cases over the study period were reviewed. Four patients (0.6%) had a PCNSI, and no patients had a positive cerebrospinal fluid (CSF) culture. In the previous study, among 363 cases, 71 patients (19.6%) had a PCNSI and 7 (1.9%) had a positive CSF culture (all Gram-negative organisms). The differences in both parameters are statistically significant (P0.001). Between the 2 studies, there was no change in treatment providers, case types, case durations, antibiotic administration practices, and patient demographics.The rates of PCNSI and positive CSF culture were significantly lower in our present cohort compared with the cohort in our previous study. The sole apparent change involves the air filtration system inside the neurosurgical operating rooms; this environmental change occurred during the 5 months between the 2 studies. This study demonstrates the impact of environmental factors in reducing infections.

Injury to the thoracic duct during anterior cervical spine surgery is a rare occurrence. A delayed chyle leak following an elective anterior cervical spinal surgery has not been reported in the literature. We present a report of a 59-year-old female with multiple prior neck surgeries who underwent an anterior cervical corpectomy and fusion (ACCF). The patient developed a delayed thoracic duct injury on postoperative day (POD) one, as no injury was noted intraoperatively. She was managed with conservative care involving a low-fat diet along with octreotide which led to the resolution of her symptoms. We present this case report because of its unique presentation and to assist spine surgeons with initial management. Surgeons should have increased awareness when performing anterior cervical approaches to the lower cervical and upper thoracic levels from the left side.

“In reality, it is the interpretation of symptomatology that leads to accurate diagnosis, rather than the short-term training and inter-rater reliability attained by conducting semi-structured research diagnostic interviews.”

This article offers a pragmatic model of conceptualizing attention deficit hyperactivity disorder and pediatric bipolar disorder when they present alone, together, or as overlapping subsyndromes. Evidence-based findings from the US Food and Drug Administration-approved medications and randomized controlled trials of psychotherapy are quilted together to design a personalized treatment model. The treatment paradigm consists of an “ABCD” model of components: (A) Assessment of psychopathology toward individual diagnosis or comorbidity, (B) Brain circuitry function offering explanatory power for the phenomenology that includes affective and cognitive domain difficulties common in both the disorders, (C) Chemical imbalance addressed through pharmacotherapy for mania, mixed mania, depression, and attention deficit hyperactivity disorder, and (D) Delivery of proven psychosocial treatment coupled with addressing the key dynamics of interpersonal relationships. This intervention, based on empirical findings, is applicable to clinical practice. Identifying the neurocircuitry of cognitive and emotional impairment in pediatric bipolar disorder and attention-deficit/hyperactivity disorder guides the application of targeted treatments: a paradigm of translating science to clinical service. [ Psychiatr Ann . 2014; 44(10):471–480.]

Objective Activation changes at the interface of affective and cognitive systems are examined over a 3 year period in pediatric bipolar disorder (PBD). Methods Thirteen participants with PBD and 10 healthy controls (HC) matched on demographics and IQ were scanned at baseline, at 16 weeks, and after 3 years. All patients received pharmacotherapy based on a medication algorithm. A pediatric affective color matching paradigm was used to probe cognitive processing under emotional challenge. Results At baseline, in response to emotional vs. neutral words, patients with PBD showed greater activation than HC in the right dorsal lateral prefrontal cortex (DLPFC) and amygdala, ventral lateral prefrontal cortex (VLPFC), bilateral anterior cingulate cortex (ACC), and ventral striatum. Increased activation in DLPFC in the PBD group normalized by 16 weeks. By 3 years, normalization was observed in VLPFC, ACC, amygdala, and striatum. Limitations Small sample size renders the present findings preliminary. Conclusions Greater activation in fronto-striatal and fronto-limbic circuits were observed in unmedicated patients with PBD. Present findings suggest the possibility that DLPFC is most malleable to pharmacological intervention with systematic pharmacotherapy leading to immediate response, which extended to amygdalostriatal and ventral cortical regions at 3 years. The seminal observation from this study is the prolonged length of recovery time in the normalization of subcortical activity along with their interfacing cortical regions. Findings from this proof of concept study need to be replicated in a larger sample.

This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions.Outpatients, ages 7-17 years, meeting American Psychiatric Association, diagnostic and statistical manual of mental disorders, 4th ed. (DSM-IV) diagnostic criteria for bipolar disorder I (BP-I) (manic or mixed) who demonstrated at least a partial response to 8 weeks of open-label treatment with lithium (phase I) were eligible to receive open-label lithium for an additional 16 weeks (phase II). Up to two adjunctive medications could be prescribed to patients experiencing residual symptoms of mania or comorbid psychiatric conditions, following a standardized algorithm.Forty-one patients received continued open-label long-term treatment with lithium for a mean of 14.9 (3.0) weeks during phase II. The mean weight-adjusted total daily dose at end of phase II was 27.8 (6.7) mg/kg/day, with an average lithium concentration of 1.0 (0.3) mEq/L. Twenty-five of the 41 patients (60.9%) were prescribed adjunctive psychotropic medications for residual symptoms. The most frequent indications for adjunctive medications were refractory mania (n=13; 31.7%) and attention-deficit/hyperactivity disorder (ADHD) (n=15; 36.6%). At the end of this phase 28 (68.3%) patients met a priori criteria for response (≥50% reduction from phase I baseline in young mania rating scale [YMRS] summary score and a clinical global impressions-improvement [CGI-I] score of 1 or 2), with 22 (53.7%) considered to be in remission (YMRS summary score≤12 and CGI-severity score of 1 or 2). These data suggest that patients who initially responded to lithium maintained mood stabilization during continuation treatment, but partial responders did not experience further improvement during Phase II, despite the opportunity to receive adjunctive medications. The most commonly reported (≥20%) adverse events associated with lithium treatment were vomiting, headache, abdominal pain, and tremor.Lithium may be a safe and effective longer-term treatment for patients with pediatric bipolar disorder who respond to acute treatment with lithium. Partial responders to acute lithium did not appear to experience substantial symptom improvement during the continuation phase, despite the possibility that adjunctive medications could be prescribed.

Background Brain metastases of gastrointestinal origin are a rare occurrence. Radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) is an effective established treatment modality in either the definitive or adjuvant setting. The aim of this study is to assess the long-term clinical outcomes of patients with gastrointestinal (GI) brain metastases treated with SRS or WBRT. Methods In this single institutional retrospective review, we detail the outcomes of patients diagnosed with metastatic brain tumors from an adenocarcinoma gastrointestinal primary. Patients were treated using stereotactic radiosurgery or whole brain radiation therapy. Initial site control (defined as lesions visualized on imaging at time of treatment), new site control (defined as new intracranial lesions visualized on follow-up imaging), and overall survival were calculated using the Kaplan-Meier method. Results Thirty-three patients were treated from August 2008 to December 2015. Primary malignancy locations were as follows: 18 colon, 6 esophagus, 4 rectum, 5 other. Median total dose delivered was 25 Gy (18–35 Gy) in a median of 4 fractions for SRS and 30 Gy (10.8–40 Gy) in 10 fractions for WBRT. Crude initial site control at last radiographic follow-up was 64.3% after SRS and 41.7% after WBRT. Eleven of the 28 brain lesions (39.3%) treated with SRS had resection of the SRS-treated lesion prior to radiation therapy. Five of the twelve patients (41.7%) undergoing WBRT underwent cranial resection prior to radiation therapy. Crude new site control at last radiographic follow-up was 46.4% after SRS and 83.3% after WBRT. Kaplan-Meier analysis of overall survival did not show any statistically significant difference between WBRT and SRS (p = 0.424). Median overall survival for SRS patients was 5.2 months (0.5–57.5) and for WBRT patients 4.4 months (0–15). Kaplan-Meier analysis of new site control was significantly improved with WBRT versus SRS (p = 0.017). Total dose, treatment with WBRT, and active extracranial disease were statistically significant on multivariate analysis for new site control (p

Objective To describe child- and family-focused cognitive-behavioral therapy (CFF-CBT), a new developmentally sensitive psychosocial intervention for pediatric bipolar disorder (PBD) that is intended for use along with medication. CFF-CBT integrates principles of family-focused therapy with those of CBT. The theoretical framework is based on (1) the specific problems of children and families coping with bipolar disorder, (2) a biological theory of excessive reactivity, and (3) the role of environmental stressors in outcome. CFF-CBT actively engages parents and children over 12 hour-long sessions. Method An exploratory investigation was conducted to determine the feasibility of CFF-CBT. Participants included 34 patients with PBD (mean age 11.33 years, SD=3.06) who were treated with CFF-CBT plus medication in a specialty clinic. Treatment integrity, adherence, and parent satisfaction were assessed. Symptom severity and functioning were evaluated before and after treatment using the severity scales of the Clinical Global Impression Scales for Bipolar Disorder (CGI-BP) and the Children's Global Assessment Scale (CGAS) respectively. Results On completion of therapy, patients with PBD showed significant reductions in severity scores on all CGI-BP scales and significantly higher CGAS scores compared to pretreatment results. High levels of treatment integrity, adherence, and satisfaction were achieved. Conclusions CFF-CBT has a strong theoretical and conceptual foundation and represents a promising approach to the treatment of PBD. Preliminary results support the potential feasibility of the intervention.

Mobile schwannomas of the spine have been sparsely documented in the literature. In cases referred to in existing literature, the migratory schwannoma was documented to occur in the lumbar spine. We added another case to the small available literature. In our case report, the patient had a previously known lumbar schwannoma that was being managed conservatively. Due to an acute change in clinical symptoms, repeat imaging was performed. A magnetic resonance imaging (MRI) of his spine revealed migration of the schwannoma two levels rostral to his recent imaging from six weeks earlier. The patient underwent surgical resection of his lesion. During the operation, the ultrasound was utilized to confirm the lesion prior to dural opening. In this report, we attempt to provide further evidence of the utility of an intraoperative ultrasound for intradural lesions and intend to add to the published literature of mobile schwannomas of the spine

Evidence for white matter abnormalities in bipolar disorder (BD) was first observed in deep white matter hyperintensities in T2-weighted anatomical magnetic resonance images (1, 2). Abnormal expression of genes involved in regulation of oligodendrocytes provides further evidence supporting the possibility of white matter abnormalities in bipolar disorder (3). Diffusion tensor imaging (DTI) is specifically suited to interrogate the integrity of white matter by capitalizing on structural components restricting the diffusion of water (4, 5). Neuronal membrane and myelin sheaths are cellular structures that restrict the diffusion of water. In white matter where neuronal membrane of axons form tubular shapes, water can diffuse down the longitudinal axis of axons more easily than in radial directions of axonal axis, in which direction diffusion is restricted by neuronal membrane and myelin sheaths. Because DTI measures are derived from Brownian motion of water, this technique takes advantage of axonal membrane shape to tap into integrity of structures within white matter. Fractional anisotropy (FA) reflects the proportion of diffusivity along the axial axis of fiber tracts relative to radial directions (4, 5). Alterations in FA may be due to change in diffusivity in either the axial or radial directions, and thus it can be fruitful to examine diffusion in these directions separately. Prior DTI studies of BD have had mixed findings. Studies that took a region-of-interest (ROI) approach have focused on prefrontal-limbic circuits theorized to underlie affective dysregulation in BD. In pediatric BD, these studies have found lower FA in the anterior corona radiata (6) and superior frontal white matter (7). In adult BD, findings are more mixed in both direction of findings and location of abnormality, with some reporting lower FA in the anterior cingulum (8) and frontal white matter (9), and others reporting higher FA in the genu of the corpus callosum (10) and frontal white matter (11) or no abnormality in these regions (12). Examinations of specific tracts within the prefrontal-limbic circuit in adults have also yielded mixed findings, with some reporting lower FA in the anterior thalamic radiation (13), which makes up a part of the anterior limb of the internal capsule (14), and others reporting no difference between adult BD and healthy controls in subgenual cingulate or the amygdalo-hippocampal complex (15). Studies that examined the entire brain using either voxel-based morphometry (VBM) or tract based spatial statistics (TBSS) have found white matter abnormalities in regions beyond the frontal-limbic circuit. In pediatric BD, these included lower FA in superior longitudinal fasciculus (16), posterior corona radiata (17), posterior cingulum (16, 17), corpus callosum (16, 17), fornix (17), and occipital white matter (18). Findings in adults are again more mixed, with some studies reporting lower FA in the corpus callosum (19, 20), posterior thalamic radiation (21), and arcuate fasciculus (21), while others reported higher FA in inferior parietal (22) and occipital white matter (22, 23). In sum, studies of pediatric BD have tended to find more consistently lower FA than studies of adult BD. The literature from healthy white matter development is a helpful context in which to consider this pattern of findings. Cross sectional studies of typically developing individuals have found higher FA with age in the corpus callosum, internal capsule, thalamic radiations, corona radiata, arcuate fasciculus, and frontal and temporal white matter (24–26). Lebel and colleagues (26) examined maturation rate across commissural, association, and projection fibers, and reported that callosal fibers and association fibers reach maturity by late childhood and adolescence respectively, while projection fibers continue to mature into early adulthood. To date, no one has examined how white matter microstructure deviates from a typical maturational trajectory in BD, and whether the inconsistencies in the BD literature may be partially explained by deviations from a normal neurodevelopmental trajectory. Based on the above, we sought to determine whether early onset BD is associated with greater or more consistent white matter alterations than BD with adult onset. We measured FA in medication free pediatric and adult onset BD during the first episode of illness and investigated FA differences in BD relative to healthy controls. Because each tract follows a different normal developmental trajectory, we first obtained the center of tracts (skeleton) for each participant, then applied tract masks and extracted mean FA within each tract skeleton to evaluate group, age, and interaction effects at the level of the tract. We specifically hypothesized that white matter tracts that connect prefrontal and limbic regions such as the anterior limb of internal capsule (ALIC), anterior corona radiata (ACR), and cingulum would have lower FA in the BD group (6, 27), and that these differences would be more evident in the pediatric onset BD patients.

Objective Prolactin elevation has been proposed as a risk factor for low bone density and potentially osteoporosis in patients on long-term treatment with prolactin-elevating antipsychotics. Our objective was to study the acute effects of prolactin elevation on serum markers of bone formation and resorption in patients treated with risperidone. Methods Thirty participants meeting Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria for schizophrenia, major depressive disorder with psychotic features, or bipolar disorder with psychosis were enrolled. At baseline, subjects were antipsychotic free. Subjects were evaluated before and after 4 weeks of risperidone treatment. Assessments included symptom ratings along with testosterone, estradiol, prolactin, osteocalcin (marker of bone formation), and n-telopeptide crosslinks (NTx marker of bone resorption). Primary analysis examined the impact of risperidone treatment on change in the bone markers and hormone levels from pre to post treatment. Results Prolactin levels significantly increased from 12.1 ± 1.9 ng/ml to 65.7 ± 12.2 ng/ml after treatment ( p < 0.001). NTx markers of bone resorption significantly decreased from 18.31 ± 1.49 nM bone collagen equivalent (BCE) before treatment to 15.50 ± 1.22 nM BCE after treatment in the study sample as a whole ( p < 0.05). A trend was observed indicating that NTx may increase in individuals who have the greatest increases in prolactin after treatment r = 0.33, p = 0.07). Conclusions These findings suggest that prolactin elevation is associated with changes in bone physiology very early in the course of treatment with risperidone. Bone resorption decreased in many subjects but higher levels of bone resorption occurred in patients with the greatest increases in prolactin. This may have important implications for prolactin monitoring or the periodic assessment of osteoporosis-related outcomes in patients requiring extended treatment.

Recently, there has been increased interest in identifying possible endophenotypes of pediatric bipolar disorder (BD; Leibenluft & Rich, 2008). In particular, greater attention is being given to the identification of disease associated traits that are more directly linked to the underlying molecular genetics of BD and its associated subtypes than the phenotypic disease state itself (Balanza–Martiez et al., 2008). Indeed, the identification of neurocognitive profiles across differing subtypes of pediatric BD is one way to elucidate the underlying pathophysiological domains that may be loosely linked to specific genes (Deo, Costa, DeLisi, DeSalle, & Haghighi, 2010; Glahn et al., 2004, 2010; Schulze, 2010). Understanding cognitive profiles across separate subtypes of BD can also aid in the development of more tailored cognitive interventions (Cahill et al., 2009; Henin et al., 2009a; Joseph et al., 2008). Deficits in attention, executive function, working memory, verbal learning and memory, visual memory, response inhibition, and processing speed have been documented in both child and adult BD patients (Arts et al., 2007; Cahill et al., 2009; Joseph et al., 2008; Henin et al., 2009a; Kurtz & Gerraty, 2009). Cognitive deficits are observed in first-degree relatives (Bora, Yucel, & Pantelis, 2009; Doyle et al., 2009), as well as symptomatic and euthymic patients, and appear to be a “trait-like” feature of the disorder (Martinez-Aran et al., 2004; Pavuluri et al., 2006). Deficits in verbal memory and executive functioning are the most prominent and consistent finding in BD patients across the life span (Joseph et al., 2008; Kurtz & Gerraty, 2009; Robinson et al., 2006). These deficits persist even after remission in adults (Martinez-Aran et al., 2004; van Gorp et al, 1998), and become more severe over the course of development in early onset pediatric BD patients (Pavuluri et al., 2009a). While there are a limited number of adult studies that have attempted to differentiate cognitive profiles among BD I versus II patients, none exist in pediatric BD. The majority of investigations of cognitive dysfunction among pediatric BD youth have focused exclusively on BD I patients (Bearden et al., 2007; McClure et al., 2005; Pavuluri et al., 2006) or have used heterogeneous samples of varying BD subtypes (Dickstein et al., 2004; Doyle et al., 2005; Glahn et al., 2005; McClure et al., 2005; Rucklidge et al., 2006). Differentiating cognitive profiles among pediatric BD subtypes may therefore help us to understand potential differences between BD I and II patients and may also help to clarify past findings on neurocognitive deficits. The majority of findings in BD adults lean towards a more impaired pattern of cognitive dysfunction among BD I patients, most notably on tasks of verbal learning and memory and executive functioning (Hsiao et al., 2009, Simonsen et al., 2008; Torrent et al., 2006). However, results have been inconsistent, with some studies reporting more impaired cognitive dysfunction among BD II patients (Harkavy-Friedman et al., 2006; Summers et al., 2006). Methodological issues such as the inclusion of patients in heterogeneous clinical states and medication effects may have contributed to some of the discrepancies. The potential impact of pharmacotherapy on cognitive functioning in BD patients has been gaining increased attention (Donaldson et al., 2003; Holmes et al., 2008; Pavuluri et al., 2010). Recent evidence indicates that higher doses of mood stabilizers (Henin et al., 2009b; Holmes et al., 2008) and antipsychotic medications (Donaldson et al., 2003), can lead to greater cognitive impairment in adult as well as pediatric patients. Because BD I and II patients often vary in the type and number of medications they receive, we sought to study unmedicated acutely ill patients as an important first-step in identifying possible cognitive endophenotypes of the disorder, prior to investigating this in medicated euthymic patients. Therefore, the aim of this study was to investigate neurocognitive functioning in unmedicated BD I and II youth and matched healthy controls (HC). Given the findings from adult studies of BD, we hypothesized that BD I patients would show more severe and widespread cognitive dysfunction, displaying greater deficits on tasks of attention, executive function, working memory, visual memory, and verbal learning and memory compared to BD II patients and HC. Given that there have been no prior studies of this issue in pediatric BD populations, we expected that this study would further inform us on the commonalities and differences in cognitive dysfunction across subtypes of BD, beyond the level of symptom severity.

Objective The aim of the current study was to determine the influence of implicated affective circuitry disturbance in pediatric bipolar disorder (PBD) on behavioral inhibition. The differential influence of an antipsychotic and an anti-epileptic medication on the functional connectivity across affective and cognitive neural operations in PBD was examined. Methods This was a six-week double blind randomized fMRI trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania ( n = 22; 13.6 ± 2.5 years). Healthy controls (HC; n = 14, 14.5 ± 2.8 years) were also scanned for normative comparison. Participants performed a response inhibition fMRI task where a motor response, already ‘on the way’ to execution, had to be voluntarily inhibited on trials where a stop signal was presented. Independent component analysis was used to map functional connectivity across the whole brain. Results While there were no behavioral differences between the groups at pre- or post-drug trial, there was significant improvement on manic symptoms in the patient groups. All participants engaged an evaluative affective circuit (EAC: bilateral inferior frontal gyrus, middle frontal gyrus, anterior cingulate cortex (ACC), middle temporal gyrus, insulae, caudate and putamen) and a reactive affective circuit (RAC: bilateral occipital cortex, amygdala, medial frontal gyrus and insula) during task performance. Within the EAC, post-treatment and relative to HC, greater engagement was seen in left insula in risperidone group and left subgenual ACC in divalproex group. Within the RAC, greater baseline amygdala connectivity in patients did not alter with treatment. Conclusion EAC and RAC are two key circuits that moderate emotional influence on response inhibition in PBD. Risperidone and divalproex differentially engage the EAC. Limited change in amygdala activity with treatment in all patients indicates a likely trait deficit in PBD.

The aim of this study was to determine functional connectivity among patients with pediatric bipolar disorder (PBD) who are responders to pharmacotherapy and those who are nonresponders, and learn how they differ from healthy controls (HC) while performing a task that engages affective and cognitive neural systems. PBD participants (n = 34; 13.4 ± 2.3 years) were defined as responders if there was ≥ 50% improvement in Young Mania Rating Scale (YMRS) scores (n = 22) versus nonresponders with < 50% improvement (n = 12) with one of three mood stabilizing medications (divalproex, risperidone, or lamotrigine). HC (n = 14; 14.2 ± 3.1 years) participants also were scanned at baseline and follow-up. During functional magnetic resonance imaging, participants performed a color-matching task in which they had to match the color of positive, negative, or neutral words with colored dots. Independent component analysis was used to identify functionally connected networks across the whole brain, which were subsequently interrogated using region-of-interest analyses to test for group differences. A frontolimbic network was identified that showed impaired functional integration in PBD relative to HC when participants viewed negatively valenced words. PBD medication responders showed greater connectivity of the amygdala into the network before and after treatment compared with nonresponders, with responders showing a pattern more similar to HC than to nonresponders. Regardless of medication type, the degree of amygdala functional connectivity predicted medication response as well as the improvement in YMRS scores across responders and nonresponders. These findings suggest that increased functional integration of the amygdala within the frontolimbic network might be a biomarker of general mood stabilizer medication responsivity in bipolar disorder.

The aim of this research was to determine the relative effects of risperidone and divalproex on brain function in pediatric mania. This is a double-blind 6-week functional magnetic resonance imaging trial with 24 unmedicated manic patients randomized to risperidone or divalproex, and 14 healthy controls (HCs) matched for IQ and demographic factors (mean age: 13.1±3.3years). A pediatric affective color matching task, in which subjects matched the color of a positive, negative or neutral word with one of two colored circles, was administered. The primary clinical measure was the Young Mania Rating Scale (YMRS). The risperidone group, relative to HC, showed an increase in activation from pre- to post-treatment in right pregenual and subgenual anterior cingulate cortex and decreased activation in bilateral middle frontal gyrus during the negative condition; and decreased activation in left inferior and medial, and right middle frontal gyri, left inferior parietal lobe, and right striatum with positive condition. In the divalproex group, relative to HC, there was an increased activation in right superior temporal gyrus in the negative condition; and in left medial frontal gyrus and right precuneus with the positive condition. Greater pre-treatment right amygdala activity with negative and positive condition in the risperidone group, and left amygdala activity with positive condition in divalproex group, predicted poor response on YMRS. Risperidone and divalproex yield differential patterns of prefrontal activity during an emotion processing task in pediatric mania. Increased amygdala activity at baseline is a potential biomarker predicting poor treatment response to both the risperidone and divalproex.

Viewing emotional as compared with neutral images results in an increase in force production. An emotion-driven increase in force production has been associated with increased brain activity in ventrolateral prefrontal cortex and primary motor cortex (M1). In many instances, however, force production must be held constant despite changes in emotional state and the neural circuits underlying this form of control are not well understood. To address this issue, we designed a task in which subjects viewed pleasant, unpleasant, and neutral images during a force production task. We measured brain activity using functional magnetic resonance imaging and examined functional connectivity between emotion and motor circuits. Despite similar force performance across conditions, increased brain activity was evidenced in dorsomedial prefrontal cortex (dmPFC) and left ventral premotor cortex (PMv) when force was produced during emotional as compared with neutral conditions. Connectivity analyses extended these findings by demonstrating a task-dependent functional circuit between dmPFC and ventral and dorsal portions of premotor cortex. Our findings show that when force production has to be consistent despite changes in emotional context, a functional circuit between dmPFC and PMv and dorsal premotor cortex is engaged.

The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder.Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing30 kg were automatically assigned to Arm I, whereas youths weighing ≥30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of ≤ 2 and a 50% decrease from baseline on the Young Mania Rating Scale.Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a ≥ 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium.On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial.

A deeper understanding of how the relationships between impulsivity, reward systems and executive function deficits may be similar or different in attention-deficit/hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD) is fundamental for better defining phenotypy in these two developmental illnesses, and moving towards improved treatment and intervention. We focus our article on recent neurocognitive and neuroimaging data examining the behavioral and neural aspects of poor behavior regulation, response inhibition and reward systems in ADHD and PBD. In light of recent research evidence, we propose that the common behavioral manifestations of impulsivity in ADHD and PBD may indeed originate from different neural mechanisms mediated by altered reward systems. In order to define and differentiate these mechanisms, unlike previous approaches, our theoretical model examines the interface of the dorsal frontostriatal circuit, involved in behavior regulation, and the ventral frontostriatal circuit, which is involved in reward-related and affect processes. Preliminary evidence suggests that the neural systems involved in impulsivity, reward systems and executive function engage differently in the two illnesses. In PBD, `emotional impulsivity' is predominantly `bottom-up' and emotionally/motivationally driven, and stems from ventral frontostriatal circuitry dysfunction. By contrast, in ADHD `cognitive impulsivity' is predominantly `top-down' and more `cognitively driven', and stems from dorsal frontostriatal dysfunction. We discuss this evidence in view of clinically relevant questions and implications for illness-based intervention. We conclude that the reward-related mechanisms underlying the interactions between executive function, behavior regulation and impulsivity in PBD and ADHD may be differentially compromised, and in accordance differently shape the clinical symptoms of impulsivity and goal-directed behavior.

Neural deficits at the interface of affect and cognition may improve with pharmacotherapy in pediatric bipolar disorder (PBD).We examined lamotrigine treatment impact on the neural interface of working memory and affect in PBD.Un-medicated, acutely ill, patients with mania and hypomania (n = 17), and healthy controls (HC; n = 13; mean age = 13.36 ± 2.55) performed an affective two-back functional magnetic resonance imaging task with blocks of angry vs neutral faces (i.e., angry face condition) or happy vs neutral faces (i.e., happy face condition) before treatment and at follow-up, after 8-week treatment with second-generation antipsychotics followed by 6 weeks of lamotrigine monotherapy.At baseline, for the angry face condition, PBD, relative to HC, showed reduced activation in the left ventrolateral prefrontal cortex (VLPFC) and right caudate; for the happy face condition, PBD showed increased activation in bilateral PFC and right amygdala and middle temporal gyrus. Post-treatment, PBD showed greater activation in right amygdala relative to HC for both conditions. Patients, relative to HC, exhibited greater changes over time in the right VLPFC and amygdala, left subgenual anterior cingulate cortex and left caudate for the angry face condition, and in right middle temporal gyrus for the happy face condition.Pharmacotherapy resulted in symptom improvement and normalization of higher cortical emotional and cognitive regions in patients relative to HC, suggesting that the VLPFC dysfunction may be state-specific in PBD. Amygdala was overactive in PBD, relative to HC, regardless of reduction in manic symptoms, and may be a trait marker of PBD.

Background The development of valid parent-report measures of symptom change in pediatric bipolar disorder (PBD) is imperative to evaluate the effectiveness of different treatment approaches; yet, few studies have tested the sensitivity of symptom measures. The current study evaluated the sensitivity of the Child Mania Rating Scale (CMRS-P) to detect symptom change over time in a treatment study for PBD. Methods Data on symptom change were drawn from a prospective six-week, double-blind, placebo-controlled, randomized outpatient medication treatment trial of risperidone versus divalproex. The sample included 66 children with Bipolar type I disorder. Measures were administered every week for six weeks of treatment. Results The CMRS-P demonstrated statistically (p ≤ .05) and clinically significant change in symptom report from pre to post-test. Growth curve modeling indicated that the CMRS-P demonstrated overall similarity to the YMRS in the magnitude and trajectory of change over time. Finally, results indicate that the CMRS-P is able to detect response rates with moderate levels of agreement with other measures. Limitations Limitations of this study include a relatively small sample size and uncertain generalizability beyond treatment trials. Conclusions The CMRS-P is short, easy to administer, and represents parent's report of symptoms, all strengths which make it a compelling treatment outcome tool. This preliminary evidence of its validity as a treatment outcome measure makes it applicable in other research settings and suggests its potential use in clinical settings.

It is well established that pediatric bipolar disorder (PBD) not only presents with affected dysregulation but also cognitive difficulties in working memory, attention, verbal memory, and executive functional domains (Pavuluri et al, 2009). Neural circuitry abnormalities that explain this multi-domain dysfunction (Pavuluri, in press) have led to the pursuit of how such abnormal pathophysiology can be reversed with pharmacotherapy (Mayanil et al, 2011). We conducted the first series of fMRI studies in pediatric mania by examining the effects of lamotrigine, risperidone, and divalproex sodium (DVPX) individually as well as through a pharmacotherapy algorithm. The pharmacological fMRI studies used tasks to probe the domains of emotion processing, response inhibition, and the interface of emotion and cognition. Biomarkers of pharmacotherapy response, especially the increase in ventrolateral prefrontal cortex (VLPFC) activity in PBD relative to the healthy controls (HC), have been tied to the reduction in manic symptoms regardless of any task (Mayanil et al, 2011). Most studies summarized here were conducted on adolescents suffering from hypomanic state at baseline and are illustrated in Figure 1.

Objective To determine the relative effects of risperidone and divalproex in pediatric mania.

In adolescent bipolar disorder (ABD), inattention, impulsivity and behavioral dis-inhibition are prominent and persist even after achieving mood stability.4 The frontostriatal circuitry that supports motor response inhibition has been shown to be affected in ABD.5 Appropriate goals of treatment, therefore, are to aim for mood stabilization, reducing motor response inhibition problems, and reversing the related frontostriatal deficits in ABD. Lamotrigine is one such medication that is used to stabilize mood in ABD6 and adult bipolar disorder (BD)7;8 due to its glutamatergic attenuating function that is believed to have the potential to improve cognitive function related to motor response inhibition problems.9–11 There is preliminary evidence from two fMRI studies indicating that lamotrigine may enhance brain circuitry function in bipolar disorder.6;12 In a study of patients with ABD performing an affective task requiring the rating of emotions in pictures, reduction in depressive symptoms was correlated with decreased right amygdala activation over an 8-week period.6 In an adult study of euthymic bipolar patients performing an “N back” working memory task, greater activation in the left medial prefrontal cortex (MPFC) and bilateral pregenual anterior cingulate cortex (ACC) was observed after 6 weeks of treatment with lamotrigine.12 Methodological limitations in these studies include a short treatment period and lack of demonstration of greater improvement in brain function after treatment in patients relative to matched healthy controls (HC) retested over a similar time period. This control group is essential for interpreting change over time as representing a drug treatment effect rather than a benefit from practice effects with the task or the scanning experience. Further, meta-analysis of studies of response inhibition in HC has demonstrated increased activity in the right prefrontal cortex.13 The task of response inhibition is complex and multifactorial with attention, perceptual discrimination, and motor executive control. Response suppression involves a situation that is highly stereotyped, requiring repetitive responses with little deliberation, except when an unusual event occurs in the midst of this routine task with clear stimulus-response requirements. This effort is shown to deploy dorsal, ventral, and medial PFC regions in HC.13–15 It was also shown that in ABD poor performance on voluntary motor response inhibition tasks is related to the high degree of impulsivity and inattention5 with underlying frontostriatal disturbances.5;16;17 Patients with adult BD, relative to HC, have also shown decreased activation in the orbitofrontal cortex during response suppression.18 Therefore, the primary aim of the current study is to evaluate the differences between ABD and HC in the domain of neurobehavioral deficits in frontostriatal circuitry that support the ability to voluntarily suppress behavioral responses. Our aim is to see if pharmacotherapy can reverse the frontostriatal circuitry dysfunction in ABD. Our pharmacotherapy consists of second generation antipsychotics (SGAs) for acute mania followed by lamotrigine for continued mood stabilization. We did not use SGAs for maintenance treatment due to high risk for metabolic side effects if prescribed for long-term treatment,19 in addition to our interest in determining the beneficiary effects of lamotrigine for optimal symptomatic recovery and cognitive function. We designed a Response Inhibition Task to probe the neural circuitry supporting “stopping process and motor inhibition.” We administered this task at baseline and after 14 weeks to HC and to ABD patients, who were acutely ill and unmedicated at baseline and at 14 weeks after mood stabilization with pharmacotherapy. The concept underlying this task is to compare the process of motor response inhibition to motor execution in ABD patients compared to HC, rather than examining response inhibition in the context of a pre-potent tendency to respond.20 This is an important first step in clarifying the basic neural circuits for motor inhibition versus execution in these patients. To this end, we contrasted blocks of trials that mainly required motor inhibition (Stop trials) to blocks of trials that mainly required motor action (Go trials). We predicted that there would be differences in prefrontal activation between the ABD subjects and HC at baseline. We hypothesized that lamotrigine, by virtue of pharmacological effects on prefrontal and striatal systems, would reverse the dysfunction in these regions that are believed to contribute to behavioral control deficits in ABD.

Bipolar I disorder (BP-I) in children and adolescents is associated with substantive psychosocial dysfunction and human suffering [1, 2]. Safe and effective treatments are needed to reduce symptomatology and improve quality of life for the vulnerable youngsters and families impacted by this illness. Lithium is a benchmark treatment for adults suffering from bipolar illness [3], with evidence of benefit dating back almost 60 years [4]. However, there has been relatively little research regarding the use of lithium in the treatment of youths suffering from mania [5]. Given this paucity of information, a Written Request (WR) was issued by the Food and Drug Administration (FDA) under the auspices of the Best Pharmaceuticals for Children Act (BPCA) (FDA 2002) for the study of this agent in youths. In response, a contract was awarded to rigorously study lithium in children and adolescents with mania. A key step in developing evidence-based dosing paradigms for any compound is the characterization of the drug s pharmacokinetics (PK) [6]. Therefore, two of the goals of this contract were to characterize the pharmacokinetics of lithium and to develop evidence-based dosing for lithium in children and adolescents [7]. Although many studies have examined the PK of lithium in adults [8a??10], relatively little is known about the PK of lithium in pediatric patients. Vitiello et al. [11] described lithium PK in nine children (aged 9a??12 years) with a DSM-III-R primary diagnosis of conduct disorder or adjustment disorder. Subjects received one single 300 mg dose of lithium carbonate. The disposition of lithium in these children appeared to generally be similar to that seen in adults. However, their elimination half-life and greater total lithium clearance were shorter than reported in adult studies. The present study was performed in order to describe the first dose PK of lithium in children and adolescents. In addition to characterizing the disposition of lithium in children and adolescents with BP-I, we also explored whether patient-specific characteristics (e.g. age, gender and weight) influence the PK of lithium in this patient population.

Background Brain-derived neurotrophic factor (BDNF) is a member of a neurotrophin family and is involved in many physiological functions, including cell proliferation, migration, and differentiation, and neuron survival in the human nervous system. Abnormalities of BDNF have been implicated in the pathophysiology of depression based on observations that antidepressant drugs cause increases in the levels of BDNF in rat brains and its abnormalities have appeared in the serum of depressed patients and in postmortem brains of suicide victims. Methods We examined the gene expression of BDNF in the lymphocytes and protein expression in the platelets of adult and pediatric depressed patients during a drug-free period. We determined BDNF gene expression using a quantitative RT-PCR method and protein expression using the ELISA method. Results We observed that the gene expression of BDNF was significantly decreased in the lymphocytes of adult and pediatric depressed patients compared with normal control subjects. Similarly, the protein expression of BDNF was significantly decreased in the platelets of adult and pediatric depressed patients compared with normal control subjects. Conclusions To our knowledge, this is the first study that reports a decrease in BDNF gene expression in the peripheral cells of depressed patients. Because of the bidirectional movement of BDNF between the periphery and the CNS, the reduced gene expression in the lymphocytes and the protein expression in the platelets may be an index of similar abnormalities in the brain and could be a target for antidepressant drugs.

Impulsivity, inattention and poor behavioral inhibition are common deficits in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). This study aimed to identify similarities and differences in the neural substrate of response inhibition deficits that are associated with these disorders. A functional magnetic resonance imaging (fMRI) study was conducted on 15 unmedicated PBD patients (Type I, manic/mixed), 11 unmedicated ADHD patients, and 15 healthy controls (HC) (mean age = 13.5 years; S.D. = 3.5). A response inhibition task examined the ability to inhibit a motor response to a target when a stop cue appeared shortly after. The PBD and ADHD groups did not differ on behavioral performance, although both groups were less accurate than the HC group. fMRI findings showed that for trials requiring response inhibition, the ADHD group, relative to the PBD and HC groups, demonstrated reduced activation in both ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, and increased bilateral caudate activation compared with HC. The PBD group, relative to HC, showed decreased activation in the left VLPFC, at the junction of the inferior and middle frontal gyri, and in the right anterior cingulate cortex (ACC). Prefrontal dysfunction was observed in both the ADHD and PBD groups relative to HC, although it was more extensive and accompanied by subcortical overactivity in ADHD.

Our knowledge on the development of the affective and cognitive circuitries that underlie affect regulation is still limited. This functional magnetic resonance imaging (fMRI) study examined whether there is more efficient prefrontal modulation of affective circuits with development. Ten adolescents (mean age 14 +/- 2 years) and 10 adults (mean age 30 +/- 6 years) underwent two scanning conditions that required different levels of cognitive control over face emotion processing. A 'directed' emotion processing condition required judgment of facial expressions. An 'incidental' emotion processing condition required an age judgment. For the incidental emotion processing condition, adolescents, compared with adults, showed less activation in right ventrolateral prefrontal cortex (VLPFC) and greater activation in paralimbic regions, suggesting greater emotional reactivity and immature prefrontal circuitries for affect regulation. For the directed emotion processing condition, adolescents, compared with adults, showed decreased recruitment of both the dorsal and pregenual right anterior cingulate cortex (ACC), suggesting immature modulatory functions of the ACC during directed face emotion processing. These results indicate that the neural circuitries for affect regulation are still developing in adolescence and have not yet reached the adult level.

This fMRI study investigates the neural bases of cognitive control of emotion processing in pediatric bipolar disorder (PBD) and attention deficit hyperactivity disorder (ADHD). Seventeen un-medicated PBD patients, 15 un-medicated ADHD patients, and 14 healthy controls (HC) (mean age = 13.78 ± 2.47) performed an emotional valence Stroop Task, requiring them to match the color of an emotionally valenced word to the color of either of two adjacent circles. Both patient groups responded significantly slower than HC, but there were no group differences in accuracy. A voxel-wise analysis of variance on brain activation revealed a significant interaction of group by word valence [F(2,41) = 4.44; p = .02]. Similar group differences were found for negative and positive words. For negative versus neutral words, both patient groups exhibited greater activation in dorsolateral prefrontal cortex (DLPFC) and parietal cortex relative to HC. The PBD group exhibited greater activation in ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) relative to HC. The ADHD group exhibited decreased VLPFC activation relative to HC and the PBD group. During cognitive control of emotion processing, PBD patients deployed the VLPFC to a greater extent than HC. The ADHD patients showed decreased VLPFC engagement relative to both HC and PBD patients. (JINS, 2010, 16, 106–117.)

Adjunctive psychosocial interventions are increasingly recognized as an important aspect of comprehensive treatment for bipolar disorder (BPD) in childhood and adolescence. Research in this area is relatively new, but psychosocial interventions being developed and tested include: multi-family psychoeducation groups for school-aged children with either BPD or depressive disorders; family-focused treatment, dialectical behavior therapy, and interpersonal and social rhythm therapy for adolescents with BPD; and child and family-focused cognitive-behavioral therapy for school-aged children with BPD. Preliminary evidence, where available, indicates that these interventions are feasible, well-received by families, and associated with positive outcomes. The continued study of adjunctive psychosocial interventions will help identify critical treatment ingredients that target specific areas of functioning and enhance overall treatment effectiveness for children and adolescents with BPD and their families.

Background To investigate microstructure of white matter fiber tracts in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD). Methods A diffusion tensor imaging (DTI) study was conducted at 3 Tesla on age- and IQ-matched children and adolescents with PBD ( n = 13), ADHD ( n = 13), and healthy control subjects (HC) ( n = 15). Three DTI parameters, fractional anisotropy (FA), apparent diffusion coefficient (ADC), and regional fiber coherence index (r-FCI), were examined in eight fiber tracts: anterior corona radiata (ACR), anterior limb of the internal capsule (ALIC), superior region of the internal capsule (SRI), posterior limb of the internal capsule (PLIC), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), cingulum (CG), and splenium (SP). Results Significantly lower FA was observed in ACR in both PBD and ADHD relative to HC. In addition, FA and r-FCI values were significantly lower in ADHD relative to PBD and HC in both the ALIC and the SRI. Further, ADC was significantly greater in ADHD relative to both the PBD and HC in ACR, ALIC, PLIC, SRI, CG, ILF, and SLF. Conclusions Decreased FA in ACR implies an impaired fiber density or reduced myelination in both PBD and ADHD in this prefrontal tract. These abnormalities, together with the reduced fiber coherence, extended to corticobulbar tracts in ADHD. Increased ADC across multiple white matter tracts in ADHD indicates extensive cellular abnormalities with less diffusion restriction in ADHD relative to PBD.