MicroRNA regulation of prefrontal cortex development and psychiatric risk in adolescence.

In this review, we examine the role of microRNAs in the development of the prefrontal cortex (PFC) in adolescence and in individual differences in vulnerability to mental illness. We describe results from clinical and preclinical research indicating that adolescence coincides with drastic changes in local microRNA expression, including microRNAs that control gene networks involved in PFC and cognitive refinement. We highlight that altered levels of microRNAs in the PFC are associated with psychopathologies of adolescent onset, notably depression and schizophrenia. We show that microRNAs can be measured non-invasively in peripheral samples and could serve as longitudinal physiological readouts of brain expression and psychiatric risk in youth.

Fine Spike Timing in Hippocampal-Prefrontal Ensembles Predicts Poor Encoding and Underlies Behavioral Performance in Healthy and Malformed Brains.

Spatial working memory (SWM) is a central cognitive process during which the hippocampus and prefrontal cortex (PFC) encode and maintain spatial information for subsequent decision-making. This occurs in the context of ongoing computations relating to spatial position, recall of long-term memory, attention, among many others. To establish how intermittently presented information is integrated with ongoing computations we recorded single units, simultaneously in hippocampus and PFC, in control rats and those with a brain malformation during performance of an SWM task. Neurons that encode intermittent task parameters are also well modulated in time and incorporated into a functional network across regions. Neurons from animals with cortical malformation are poorly modulated in time, less likely to encode task parameters, and less likely to be integrated into a functional network. Our results implicate a model in which ongoing oscillatory coordination among neurons in the hippocampal-PFC network describes a functional network that is poised to receive sensory inputs that are then integrated and multiplexed as working memory. The background temporal modulation is systematically altered in disease, but the relationship between these dynamics and behaviorally relevant firing is maintained, thereby providing potential targets for stimulation-based therapies.

Neural network modelling reveals changes in directional connectivity between cortical and hypothalamic regions with increased BMI.

BACKGROUND/OBJECTIVES: Obesity has been ascribed to corticostriatal regions taking control over homeostatic areas. To test this assumption, we applied an effective connectivity approach to reveal the direction of information flow between brain regions and the valence of connections (excitatory versus inhibitory) as a function of increased BMI and homeostatic state. SUBJECTS/METHODS: Forty-one participants (21 overweight/obese) underwent two resting-state fMRI scans: after overnight fasting (hunger) and following a standardised meal (satiety). We used spectral dynamic causal modelling to unravel hunger and increased BMI-related changes in directed connectivity between cortical, insular, striatal and hypothalamic regions. RESULTS: During hunger, as compared to satiety, we found increased excitation of the ventromedial prefrontal cortex over the ventral striatum and hypothalamus, suggesting enhanced top-down modulation compensating energy depletion. Increased BMI was associated with increased excitation of the anterior insula over the hypothalamus across the hunger and satiety conditions. The interaction of hunger and increased BMI yielded decreased intra-cortical excitation from the dorso-lateral to the ventromedial prefrontal cortex. CONCLUSIONS: Our findings suggest that excess weight and obesity is associated with persistent top-down excitation of the hypothalamus, regardless of homeostatic state, and hunger-related reductions of dorso-lateral to ventromedial prefrontal inputs. These findings are compatible with eating without hunger and reduced self-regulation views of obesity.

Microstructural abnormalities found in uncinate fasciculus and superior cerebellar tracts in children with global developmental delay: a feasibility study.

AIM: To evaluate the microstructural abnormalities of the white matter tracts (WMT) using diffusion tensor imaging (DTI) in children with global developmental delay (GDD). MATERIALS AND METHODS: Sixteen children with GDD underwent magnetic resonance imaging (MRI) and cross-sectional DTI. Formal developmental assessment of all GDD patients was performed using the Mullen Scales of Early Learning. An automated processing pipeline for the WMT assessment was implemented. The DTI-derived metrics of the children with GDD were compared to healthy children with normal development (ND). RESULTS: Only two out of the 17 WMT demonstrated significant differences (p<0.05) in DTI parameters between the GDD and ND group. In the uncinate fasciculus (UF), the GDD group had lower mean values for fractional anisotropy (FA; 0.40 versus 0.44), higher values for mean diffusivity (0.96 versus 0.91×10-3 mm2/s) and radial diffusivity (0.75 versus 0.68×10-3 mm2/s) compared to the ND group. In the superior cerebellar peduncle (SCP), mean FA values were lower for the GDD group (0.38 versus 0.40). Normal myelination pattern of DTI parameters was deviated against age for GDD group for UF and SCP. CONCLUSION: The UF and SCP WMT showed microstructural changes suggestive of compromised white matter maturation in children with GDD. The DTI metrics have potential as imaging markers for inadequate white matter maturation in GDD children.

Eye movements in idiopathic rapid eye movement sleep behaviour disorder: High antisaccade error rate reflects prefrontal cortex dysfunction.

Abnormalities of eye movements have been reported in patients with Parkinson's disease (PD). However, it is unclear if they occur in the prodromal stage of synucleinopathy represented by idiopathic rapid eye movement sleep behaviour disorder (iRBD). We thus aimed to study eye movements in subjects with iRBD and in de novo PD, to assess if their abnormalities may serve as a clinical biomarker of neurodegeneration. Fifty subjects with polysomnography-confirmed iRBD (46 male, age 40-79 years), 18 newly diagnosed, untreated PD patients (13 male, age 43-75 years) and 25 healthy controls (20 male, age 42-79 years) were prospectively enrolled. Horizontal and vertical ocular prosaccades and antisaccades were investigated with video-oculography. All patients completed the MDS-UPDRS and the Montreal Cognitive Assessment. In addition, a neuropsychological battery was performed on iRBD subjects. When compared with healthy controls, both de novo PD patients and iRBD subjects showed increased error rates in the horizontal antisaccade task (p < 0.01, p < 0.05 respectively). In the iRBD group, the error rates in horizontal and vertical antisaccades correlated with performances in the Prague Stroop Test and the Grooved Pegboard Test, as well as with motor scores of the MDS-UPDRS. De novo PD patients showed a lower gain (p < 0.01) compared with controls. In conclusion, the increased error rate in the antisaccade task of iRBD and PD patients reflects a dysfunction of the dorsolateral prefrontal cortex and is related to the impairment of executive functions and attention.

Functional Reorganization of Right Prefrontal Cortex Underlies Sustained Naming Improvements in Chronic Aphasia via Repetitive Transcranial Magnetic Stimulation.

BACKGROUND AND OBJECTIVE: While noninvasive brain stimulation techniques show promise for language recovery after stroke, the underlying mechanisms remain unclear. We applied inhibitory repetitive transcranial magnetic stimulation (rTMS) to regions of interest in the right inferior frontal gyrus of patients with chronic poststroke aphasia and examined changes in picture naming performance and cortical activation. METHODS: Nine patients received 10 days of 1-Hz rTMS (Monday through Friday for 2 weeks). We assessed naming performance before and immediately after stimulation on the first and last days of rTMS therapy, and then again at 2 and 6 months post-rTMS. A subset of six of these patients underwent functional magnetic resonance imaging pre-rTMS (baseline) and at 2 and 6 months post-rTMS. RESULTS: Naming accuracy increased from pre- to post-rTMS on both the first and last days of treatment. We also found naming improvements long after rTMS, with the greatest improvements at 6 months post-rTMS. Long-lasting effects were associated with a posterior shift in the recruitment of the right inferior frontal gyrus: from the more anterior Brodmann area 45 to the more posterior Brodmann areas 6, 44, and 46. The number of left hemispheric regions recruited for naming also increased. CONCLUSIONS: This study found that rTMS to the right hemisphere Broca area homologue confers long-lasting improvements in picture naming performance. The mechanism involves dynamic bilateral neural network changes in language processing, which take place within the right prefrontal cortex and the left hemisphere more generally. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT00608582).

Neuronal Heterotopias Affect the Activities of Distant Brain Areas and Lead to Behavioral Deficits.

Neuronal heterotopia refers to brain malformations resulting from deficits of neuronal migration. Individuals with heterotopias show a high incidence of neurological deficits, such as epilepsy. More recently, it has come to be recognized that focal heterotopias may also show a range of psychiatric problems, including cognitive and behavioral impairments. However, because focal heterotopias are not always located in the brain areas responsible for the symptoms, the causal relationship between the symptoms and heterotopias remains elusive. In this study, we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited spatial working memory deficit and low competitive dominance behavior, which have been shown to be closely associated with the activity of the medial prefrontal cortex (mPFC) in rodents. Analysis of the mPFC activity revealed that the immediate-early gene expression was decreased and the local field potentials of the mPFC were altered in the mice with heterotopias compared with the control mice. Moreover, activation of these ectopic and overlying sister neurons using the DREADD (designer receptor exclusively activated by designer drug) system improved the working memory deficits. These findings suggest that cortical regions containing focal heterotopias can affect distant brain regions and give rise to behavioral abnormalities. Significance statement: Recent studies reported that patients with heterotopias have a variety of clinical symptoms, such as cognitive disturbance, psychiatric symptoms, and autistic behavior. However, the causal relationship between the symptoms and heterotopias remains elusive. Here we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited behavioral deficits that have been shown to be associated with the mPFC activity in rodents. The existence of heterotopias indeed altered the neural activities of the mPFC, and direct manipulation of the neural activity of the ectopic neurons and their sister neurons in the overlying cortex improved the behavioral deficit. Thus, our results indicate that focal heterotopias could affect the activities of distant brain areas and cause behavioral abnormalities.

Abnormalities in orbitofrontal cortex gyrification and mental health outcomes in adolescents born extremely preterm and/or at an extremely low birth weight.

Extremely preterm (EP, <28 weeks) and/or extremely low birth weight (ELBW, <1000 g) infants are at high risk of aberrant neurodevelopment. Sulcogyral folding patterns of the orbitofrontal cortex (OFC) are determined during the third trimester, however little is known about OFC patterning in EP/ELBW cohorts, for whom this gestational period is disturbed. This study investigated whether the distribution of OFC pattern types and frequency of intermediate and/or posterior orbital sulci (IOS/POS) differed between EP/ELBW and control adolescents. This study also investigated whether OFC pattern type was associated with mental illness or executive function outcome in adolescence. Magnetic resonance images of 194 EP/ELBW and 147 full term (>37 completed weeks) and/or normal birth weight (> 2500 g) adolescents were acquired, from which the OFC pattern of each hemisphere was classified as Type I, II, or III. Compared with controls, more EP/ELBW adolescents possessed a Type II in the left hemisphere (P = 0.019). The EP/ELBW group had fewer IOS (P = 0.024) and more POS (P = 0.021) in the left hemisphere compared with controls. OFC pattern type was not associated with mental illness, however in terms of executive functioning, Type III in the left hemisphere was associated with better parent-reported metacognition scores overall (P = 0.008) and better self-reported behavioral regulation scores in the control group (P = 0.001) compared with Type I. We show, for the first time that EP/ELBW birth is associated with changes in orbitofrontal development, and that specific patterns of OFC folding are associated with executive function at age 18 years in both EP/ELBW and control subjects.

Changes in prefrontal axons may disrupt the network in autism.

Neural communication is disrupted in autism by unknown mechanisms. Here, we examined whether in autism there are changes in axons, which are the conduit for neural communication. We investigated single axons and their ultrastructure in the white matter of postmortem human brain tissue below the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and lateral prefrontal cortex (LPFC), which are associated with attention, social interactions, and emotions, and have been consistently implicated in the pathology of autism. Area-specific changes below ACC (area 32) included a decrease in the largest axons that communicate over long distances. In addition, below ACC there was overexpression of the growth-associated protein 43 kDa accompanied by excessive number of thin axons that link neighboring areas. In OFC (area 11), axons had decreased myelin thickness. Axon features below LPFC (area 46) appeared to be unaffected, but the altered white matter composition below ACC and OFC changed the relationships among all prefrontal areas examined, and could indirectly affect LPFC function. These findings provide a mechanism for disconnection of long-distance pathways, excessive connections between neighboring areas, and inefficiency in pathways for emotions, and may help explain why individuals with autism do not adequately shift attention, engage in repetitive behavior, and avoid social interactions. These changes below specific prefrontal areas appear to be linked through a cascade of developmental events affecting axon growth and guidance, and suggest targeting the associated signaling pathways for therapeutic interventions in autism.

Astrocyte-mediated hepatocyte growth factor/scatter factor supplementation restores GABAergic interneurons and corrects reversal learning deficits in mice.

Many psychiatric and neurological disorders present persistent neuroanatomical abnormalities in multiple brain regions that may reflect a common origin for a developmental disturbance. In mammals, many of the local GABAergic inhibitory interneurons arise from a single subcortical source. Perturbations in the ontogeny of the GABAergic interneurons may be reflected in the adult by interneuron deficits in both frontal cerebral cortical and striatal regions. Disrupted GABAergic circuitry has been reported in patients with schizophrenia and frontal lobe epilepsy and may contribute to their associated impairments in behavioral flexibility. The present study demonstrates that one type of behavioral flexibility, reversal learning, is dependent upon proper numbers of GABAergic interneurons. Mice with abnormal interneuron ontogeny have reduced numbers of parvalbumin-expressing GABAergic local interneurons in the orbitofrontal cortical and striatal regions and impaired reversal leaning. Using a genetic approach, both the anatomical and functional deficiencies are restored with exogenous postnatal growth factor supplementation. These results show that GABAergic local circuitry is critical for modulating behavioral flexibility and that birth defects can be corrected by replenishing crucial growth factors.

Executive functioning-related brain abnormalities associated with the genetic liability for schizophrenia: an activation likelihood estimation meta-analysis.

BACKGROUND: Relatives of schizophrenia patients demonstrate abnormalities in prefrontal cortical activation during executive processing as measured by functional neuroimaging, albeit not consistently. A meta-analysis was conducted to determine whether reliable patterns of brain hypo- and hyperactivity, especially in the middle frontal region, were present in the relatives of patients. METHOD: Seventeen studies, containing 18 samples of relatives and controls, were included in this meta-analysis. Studies were included if relatives of schizophrenia patients were compared to controls, an executive processing task was used, and standard space coordinates were reported for the functional activations. Activation likelihood estimation (ALE) was implemented to find convergence across functional neuroimaging experiment coordinates. A separate analysis was conducted to assess the potential impact of a priori hypothesis testing used in region-of-interest (ROI) approaches on the meta-analysis results. RESULTS: Relatives demonstrated hypo- and hyperactivity in statistically overlapping right middle frontal regions [Brodmann area (BA) 9/10]. Use of an ROI analysis that a priori focused on prefrontal regions resulted in more findings of reduced activity in the middle frontal region. CONCLUSIONS: The cortical regions identified by this meta-analysis could potentially serve as intermediate biological markers in the search for candidate genes for schizophrenia. As neurocognitive deficits are related to functional impairments in patients, a better understanding of neural and genetic vulnerabilities would be beneficial in our efforts to remediate these important deficits.

Behavioral effects of congenital ventromedial prefrontal cortex malformation.

BACKGROUND: A detailed behavioral profile associated with focal congenital malformation of the ventromedial prefrontal cortex (vmPFC) has not been reported previously. Here we describe a 14 year-old boy, B.W., with neurological and psychiatric sequelae stemming from focal cortical malformation of the left vmPFC. CASE PRESENTATION: B.W.'s behavior has been characterized through extensive review Patience of clinical and personal records along with behavioral and neuropsychological testing. A central feature of the behavioral profile is severe antisocial behavior. He is aggressive, manipulative, and callous; features consistent with psychopathy. Other problems include: egocentricity, impulsivity, hyperactivity, lack of empathy, lack of respect for authority, impaired moral judgment, an inability to plan ahead, and poor frustration tolerance. CONCLUSIONS: The vmPFC has a profound contribution to the development of human prosocial behavior. B.W. demonstrates how a congenital lesion to this cortical region severely disrupts this process.

Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: signature of altered neural development?

The development of the human neocortex gives rise to a complex cytoarchitecture, grouping together cells with similar structure, connectivity and function. As a result, the six neocortical laminae show distinct molecular content. In schizophrenia, many anatomical and neurochemical changes appear to be restricted to a subset of lamina and/or cell types. In this study, we hypothesized that supragranular (SG; laminae II-III) and infragranular layers (IG; laminae V-VI) of area 46 in the human prefrontal cortex will show distinct and specific transcriptome alterations between subjects with schizophrenia and matched controls. To enhance sample homogeneity, we compared the gene expression patterns of the SG and IG layers of 8 matched middle-aged male subjects with schizophrenia to 8 pairwise matched controls using two replicate DNA microarrays for each sample. The study revealed strong disease-related laminar expression differences between the SG and IG layers. Expression changes were dominated by an overall underexpression of the IG-enriched genes in the schizophrenia subjects compared to normal control subjects. Furthermore, using a diagnosis-blind, unsupervised clustering of the control-derived SG or IG-enriched transcripts, the IG-enriched markers segregated the subjects with schizophrenia from the matched controls with a high degree of confidence. Importantly, multiple members of the semaphorin gene family reported altered gene expression, suggesting that the IG gene expression disturbances in subjects with schizophrenia may be a result of altered cortical development and disrupted brain connectivity.

Hippocampal malrotation in pediatric patients with epilepsy associated with complex prefrontal dysfunction.

PURPOSE: The cognitive consequences of hippocampal malrotation (HIMAL) were investigated in a matched control study of children with epilepsy. METHODS: Seven children with HIMAL were compared on a range of memory and attention tasks with 21 control children with epilepsy without temporal role pathology and 7 children with epilepsy and magnetic resonance imaging (MRI)-documented hippocampal sclerosis. In addition, in a statistical morphometric analysis, MRI studies from four children with HIMAL were compared to similar images of 20 age-matched typically developing control children. RESULTS: Although the task battery was sensitive to the memory deficit of the children with hippocampal sclerosis, it did not reveal memory impairment in the patients with HIMAL. In contrast, the patients with HIMAL were impaired on the attentionally more demanding dual tasks, compared to both the control and the hippocampal sclerosis group. The structural MRI analysis revealed morphometric abnormalities in the tail of the affected hippocampus, the adjacent neocortex, and the ipsilateral medial thalamus. The basal forebrain was bilaterally affected. Abnormalities in remote cortex were found in the ipsilateral temporal lobe, the contralateral anterior cingulate gyrus, and bilateral in the dorsolateral and lateral-orbitofrontal prefrontal cortex. DISCUSSION: Because the prefrontal cortical regions have been shown to be active during dual-task performance, the MRI results converge with the neuropsychological findings of impairment on these tasks. We conclude that HIMAL had no direct memory repercussions, but was secondary to subtle but widespread neurologic abnormalities that also affected morphology and functioning of the prefrontal cortex.

Fractional amplitude of low frequency fluctuation in drug-naïve first-episode patients with anorexia nervosa: A resting-state fMRI study.

To characterize the fractional amplitude of low-frequency fluctuation (fALFF) in drug-naïve first-episode female patients with anorexia nervosa (AN) using resting-state functional magnetic resonance imaging (rs-fMRI).Whole brain rs-fMRI data were collected from 7 drug-naïve first-episode female patients with DSM-5 AN and 14 age-matched healthy female controls. fALFF values were calculated and compared between the two groups using a two-sample t test. Correlation analysis between the fALFF values in the entire brain and body mass index (BMI) was performed.Compared with the healthy controls, increased fALFF values were observed in the AN patients in their right hippocampus and left superior frontal gyrus, while decreased fALFF values were observed in their left rectus and left middle occipital gyrus. Moreover, low BMI was significantly associated with decreased fALFF in the left inferior frontal gyrus but increased fALFF in the left calcarine. In particular, the z-standardized fALFF (zfALFF) value of the left rectus was positive associated with BMI.Our findings suggest that spontaneous brain activity in the frontal region, hippocampus and rectus, characterized by fALFF values, was altered in drug-naïve, first-episode female patients with AN.

Impaired fear extinction learning and cortico-amygdala circuit abnormalities in a common genetic mouse strain.

Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as d-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor d-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.

Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components.

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.

Shared and disorder-specific prefrontal abnormalities in boys with pure attention-deficit/hyperactivity disorder compared to boys with pure CD during interference inhibition and attention allocation.

BACKGROUND: Inhibitory and attention deficits have been suggested to be shared problems of disruptive behaviour disorders. Patients with attention deficit hyperactivity disorder (ADHD) and patients with conduct disorder (CD) show deficits in tasks of attention allocation and interference inhibition. However, functional magnetic resonance imaging (fMRI) of inhibitory and attention control has only been investigated in patients with ADHD, including comorbidity with CD, finding fronto-striatal and temporo-parietal dysfunction. This study investigates differences and commonalities in functional neural networks mediating interference inhibition and attention allocation between medication-naïve children and adolescents with pure CD and those with pure ADHD. METHODS: Event-related fMRI was used to compare brain activation of 13 boys with non-comorbid CD, 20 boys with non-comorbid ADHD and 20 healthy comparison boys during a Simon task that measures interference inhibition and controls for attention allocation, thus tapping into interference inhibition and selective attention networks. RESULTS: During interference inhibition, both patient groups shared reduced activation compared to controls in right superior temporal lobe and in predominantly right precuneus. During the oddball condition, both patient groups showed reduced activation compared to healthy control children in right medial prefrontal lobe. However, only ADHD patients showed a disorder-specific under-activation compared to the other two groups in an extensive activation cluster in left inferior prefrontal cortex. CONCLUSIONS: This study shows shared dysfunction in both patients groups in right hemispheric temporal and parietal brain regions during interference inhibition and in right dorsolateral prefrontal cortex during attention allocation. Ventrolateral prefrontal dysfunction, however, was specific to ADHD and not observed in patients with CD in the context of attention allocation. The findings suggest that the typically reduced functional activation in patients with ADHD in ventrolateral prefrontal cortex may be specific to the disorder, at least when compared to patients with CD.

Preliminary evidence for progressive prefrontal abnormalities in adolescents and young adults with bipolar disorder.

Previous cross-sectional study of ventral prefrontal cortex (VPFC) implicated progressive volume abnormalities during adolescence in bipolar disorder (BD). In the present study, a within-subject, longitudinal design was implemented to examine brain volume changes during adolescence/young adulthood. We hypothesized that VPFC volume decreases over time would be greater in adolescents/young adults with BD than in healthy comparison adolescents/young adults. Eighteen adolescents/young adults (10 with BD I and 8 healthy comparison participants) underwent two high-resolution magnetic resonance imaging scans over approximately 2 years. Regional volume changes over time were measured. Adolescents/young adults with BD displayed significantly greater volume loss over time, compared to healthy comparison participants, in a region encompassing VPFC and rostral PFC and extending to rostral anterior cingulate cortex (p < .05). Additional areas where volume change differed between groups were observed. While data should be interpreted cautiously due to modest sample size, this study provides preliminary evidence to support the presence of accelerated loss in VPFC and rostral PFC volume in adolescents/young adults with BD.