Increases in functional connectivity between the default mode network and sensorimotor network correlate with symptomatic improvement after transcranial direct current stimulation for obsessive-compulsive disorder.

BACKGROUND: Non-invasive neuromodulation is a promising intervention for obsessive-compulsive disorder (OCD), although its neurobiological mechanisms of action are still poorly understood. Recent evidence suggests that abnormalities in the connectivity of the default mode network (DMN) and the supplementary motor area (SMA) with other brain regions and networks are involved in OCD pathophysiology. We examined if transcranial direct current stimulation (tDCS) alters these connectivity patterns and if they correlate with symptom improvement in treatment-resistant OCD. METHODS: In 23 patients from a larger clinical trial (comparing active tDCS to sham) who underwent pre- and post-treatment MRI scans, we assessed resting-state functional MRI (rs-fMRI) data. The treatment involved 30-minute daily tDCS sessions for four weeks (weekdays only), with the cathode over the SMA and the anode over the left deltoid. We conducted whole-brain connectivity analysis comparing active tDCS-treated to sham-treated patients. RESULTS: We found that active tDCS, but not sham, led to connectivity increasing between the DMN and the bilateral pre/postcentral gyri (p = 0.004, FDR corrected) and temporal-auditory areas plus the SMA (p = 0.028, FDR corrected). Also, symptom improvement was directly associated with connectivity increasing between the left lateral sensorimotor network and the left precuneus (r = 0.589, p = 0.034). LIMITATIONS: Limited sample size (23 participants with resting-state neuroimaging), inability to analyze specific OCD symptom dimensions (e.g., harm, sexual/religious, symmetry/checking, cleaning/contamination). CONCLUSIONS: These data offer novel information concerning functional connectivity changes associated with non-invasive neuromodulation interventions in OCD and can guide new brain stimulation interventions in the framework of personalized interventions.

Eye tracking - The overlooked method to measure cognition in neurodegeneration?

Eye tracking (ET) studies are becoming increasingly popular due to rapid methodological and technological advances as well as the development of cost efficient and portable eye trackers. Although historically ET has been mostly employed in psychophysics or developmental cognition studies, there is also promising scope to use ET for movement disorders and measuring cognitive processes in neurodegeneration. Particularly, ET can be a powerful tool for cognitive and neuropsychological assessments of patients with pathologies affecting motor and verbal abilities, as tasks can be adapted without requiring motor (except eye movements) or verbal responses. In this review, we will examine the existing evidence of ET methods in neurodegenerative conditions and its potential clinical impact for cognitive assessment. We highlight that current evidence for ET is mostly focused on diagnostics of cognitive impairments in neurodegenerative disorders, where it is debatable whether it has any more sensitivity or specificity than existing cognitive assessments. By contrast, there is currently a lack of ET studies in more advanced disease stages, when patients' motor and verbal functions can be significantly affected, and standard cognitive assessments are challenging or often not possible. We conclude that ET is a promising method not only for cognitive diagnostics but more importantly, for potential cognitive disease tracking in progressive neurodegenerative conditions.

Thermoregulatory profile of neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular streptozotocin in rats.

AIM: Here, we have extensively investigated the relationship between thermoregulation and neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular injections of streptozotocin (icv-STZ). METHODS: Male Wistar rats were treated with bilateral injections of icv-STZ, and their thermoregulatory profiles (core body temperature, tail-skin temperature, cold and heat defence responses and thermal place preference) were evaluated. Spatial memory, locomotor activity, social interaction, brain ventricular volume, and Aß1-42 and tau protein levels in the brain were analysed to characterize the effects of STZ on the brain and behaviour. RESULTS: In addition to deficits in spatial memory, reduced social interaction and an increased brain ventricular volume, icv-STZ rats presented a pattern of hyperthermia, as demonstrated by an increased core body temperature. Hyperthermia was due to the activation of both autonomic heat conservation and behavioural cold avoidance, as STZ-treated rats presented tail-cutaneous vasoconstriction and an altered thermal preference. They also showed a distinct cold defence response when exposed to cold. CONCLUSION: Our data bring evidence that icv-STZ in rats causes hyperthermia, with activation of both autonomic and behavioural thermoregulatory defence responses when challenged at colder temperatures, leading us to hypothesize that they are more efficient in preventing hypothermia. These data are relevant for a better understanding of neurodegenerative disease mechanisms.

Feature selection before EEG classification supports the diagnosis of Alzheimer's disease.

OBJECTIVE: In many decision support systems, some input features can be marginal or irrelevant to the diagnosis, while others can be redundant among each other. Thus, feature selection (FS) algorithms are often considered to find relevant/non-redundant features. This study aimed to evaluate the relevance of FS approaches applied to Alzheimer's Disease (AD) EEG-based diagnosis and compare the selected features with previous clinical findings. METHODS: Eight different FS algorithms were applied to EEG spectral measures from 22 AD patients and 12 healthy age-matched controls. The FS contribution was evaluated by considering the leave-one-subject-out accuracy of Support Vector Machine classifiers built in the datasets described by the selected features. RESULTS: The Filtered Subset Evaluator technique achieved the best performance improvement both on a per-patient basis (91.18% of accuracy) and on a per-epoch basis (85.29±21.62%), after removing 88.76±1.12% of the original features. All algorithms found out that alpha and beta bands are relevant features, which is in agreement with previous findings from the literature. CONCLUSION: Biologically plausible EEG datasets could achieve improved accuracies with pre-processing FS steps. SIGNIFICANCE: The results suggest that the FS and classification techniques are an attractive complementary tool in order to reveal potential biomarkers aiding the AD clinical diagnosis.

Coordinated brain development: exploring the synchrony between changes in grey and white matter during childhood maturation.

Brain development during childhood and early adolescence is characterized by global changes in brain architecture. Neuroimaging studies have revealed overall decreases in cortical thickness (CT) and increases in fractional anisotropy (FA). Furthermore, previous studies have shown that certain cortical regions display coordinated growth during development. However, there is significant heterogeneity in the timing and speed of these developmental transformations, and it is still unclear whether white and grey matter changes are co-localized. In this multimodal neuroimaging study, we investigated the relationship between grey and white matter developmental changes and asynchronous maturation within brain regions in 249 normally developing children between the ages 7-14. We used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to analyze CT and FA, respectively, as well as their covariance across development. Consistent with previous studies, we observed overall cortical thinning with age, which was accompanied by increased FA. We then compared the coordinated development of grey and white matter as indexed by covariance measures. Covariance between grey matter regions and the microstructure of white matter tracts connecting those regions were highly similar, suggesting that coordinated changes in the cortex were mirrored by coordinated changes in their respective tracts. Examining within-brain divergent trajectories, we found significant structural decoupling (decreased covariance) between several brain regions and tracts in the 9- to 11-year-old group, particularly involving the forceps minor and the regions that it connects to. We argue that this decoupling could reflect a developmental pattern within the prefrontal region in 9- and 11-year-old children, possibly related to the significant changes in cognitive control observed at this age.

Gene expression alterations related to mania and psychosis in peripheral blood of patients with a first episode of psychosis.

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Healthy individuals treated with clomipramine: an fMRI study of brain activity during autobiographical recall of emotions.

Various functional magnetic resonance imaging studies addressed the effects of antidepressant drugs on brain functioning in healthy subjects; however, none specifically investigated positive mood changes to antidepressant drug. Sixteen subjects with no personal or family history of psychiatric disorders were selected from an ongoing 4-week open trial of small doses of clomipramine. Follow-up interviews documented clear positive treatment effects in six subjects, with reduced irritability and tension in social interactions, improved decision making, higher self-confidence and brighter mood. These subjects were then included in a placebo-controlled confirmatory trial and were scanned immediately after 4 weeks of clomipramine use and again 4 weeks after the last dose of clomipramine. The functional magnetic resonance imaging (fMRI) scans were run during emotion-eliciting stimuli. Repeated-measures analysis of variance of brain activity patterns showed significant interactions between group and treatment status during induced irritability (P<0.005 cluster-based) but not during happiness. Individuals displaying a positive subjective response do clomipramine had higher frontoparietal cortex activity during irritability than during happiness and neutral emotion, and higher temporo-parieto-occipital cortex activity during irritability than during happiness. We conclude that antidepressants not only induce positive mood responses but also act upon autobiographical recall of negative emotions.

Cortical thinning of the right anterior cingulate cortex in spider phobia: a magnetic resonance imaging and spectroscopy study.

There a lack of consistent neuroimaging data on specific phobia (SP) and a need to assess volumetric and metabolic differences in structures implicated in this condition. The aim of this study is investigate possible metabolic (via (1)H MRS) and cortical thickness abnormalities in spider-phobic patients compared to healthy volunteers. Participants were recruited via public advertisement and underwent clinical evaluations and MRI scans. The study started in 2010 and the investigators involved were not blind in respect to patient groupings. The study was conducted at the Ribeirão Preto Medical School University Hospital of the University of São Paulo, Brazil. Patients with spider phobia (n=19) were matched to 17 healthy volunteers with respect to age, education and socio-economic status. The spider SP group fulfilled the diagnostic criteria for spider phobia according to the Structured Clinical Interview for DSM-IV. None of the participants had a history of neurological, psychiatric or other relevant organic diseases, use of prescribed psychotropic medication or substance abuse. All imaging and spectroscopy data were collected with a 3 T MRI scanner equipped with 25 mT gradient coils in 30-minute scans. The Freesurfer image analysis package and LC Model software were used to analyze data. The hypothesis being tested was formulated before the data collection (neural correlates of SP would include the amygdala, insula, anterior cingulate gyrus and others). The results indicated the absence of metabolic alterations, but thinning of the right anterior cingulate cortex (ACC) in the SP group when compared to the healthy control group (mean cortical thickness±SD: SP=2.11±0.45 mm; HC=2.16±0.42 mm; t (34)=3.19, p=0.001 [-35.45, 71.00, -23.82]). In spectroscopy, the ratios between N-acetylaspartate and creatine and choline levels were measured. No significant effect or correlation was found between MRS metabolites and scores in the Spider Phobia Questionnaire and Beck Anxiety Inventory (p>0.05). The ACC is known to be related to the cognitive processing of fear and anxiety and to be linked with the conditioning circuit. The MRS findings are preliminary and need more studies. The finding of reduced ACC thickness in SP is in agreement with evidence from previous functional neuroimaging studies and highlights the importance of this brain area in the pathophysiology of SP.

Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry.

Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O-methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders.

Engagement of multifocal neural circuits during recall of autobiographical happy events

Happy emotional states have not been extensively explored in functional magnetic resonance imaging studies using autobiographic recall paradigms. We investigated the brain circuitry engaged during induction of happiness by standardized script-driven autobiographical recall in 11 healthy subjects (6 males), aged 32.4 ± 7.2 years, without physical or psychiatric disorders, selected according to their ability to vividly recall personal experiences. Blood oxygen level-dependent (BOLD) changes were recorded during auditory presentation of personal scripts of happiness, neutral content and negative emotional content (irritability). The same uniform structure was used for the cueing narratives of both emotionally salient and neutral conditions, in order to decrease the variability of findings. In the happiness relative to the neutral condition, there was an increased BOLD signal in the left dorsal prefrontal cortex and anterior insula, thalamus bilaterally, left hypothalamus, left anterior cingulate gyrus, and midportions of the left middle temporal gyrus (P < 0.05, corrected for multiple comparisons). Relative to the irritability condition, the happiness condition showed increased activity in the left insula, thalamus and hypothalamus, and in anterior and midportions of the inferior and middle temporal gyri bilaterally (P < 0.05, corrected), varying in size between 13 and 64 voxels. Findings of happiness-related increased activity in prefrontal and subcortical regions extend the results of previous functional imaging studies of autobiographical recall. The BOLD signal changes identified reflect general aspects of emotional processing, emotional control, and the processing of sensory and bodily signals associated with internally generated feelings of happiness. These results reinforce the notion that happiness induction engages a wide network of brain regions.

Identification of COL6A1 as a differentially expressed gene in human astrocytomas.

Diffuse infiltrating gliomas are the most common tumors of the central nervous system. Gliomas are classified by the WHO according to their histopathological and clinical characteristics into four classes: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma multiforme). Several genes have already been correlated with astrocytomas, but many others are yet to be uncovered. By analyzing the public SAGE data from 21 patients, comprising low malignant grade astrocytomas and glioblastomas, we found COL6A1 to be differentially expressed, confirming this finding by real time RT-PCR in 66 surgical samples. To the best of our knowledge, COL6A1 has never been described in gliomas. The expression of this gene has significantly different means when normal glia is compared with low-grade astrocytomas (grades I and II) and high-grade astrocytomas (grades III and IV), with a tendency to be greater in higher grade samples, thus rendering it a powerful tumor marker.

Engagement of multifocal neural circuits during recall of autobiographical happy events.

Happy emotional states have not been extensively explored in functional magnetic resonance imaging studies using autobiographic recall paradigms. We investigated the brain circuitry engaged during induction of happiness by standardized script-driven autobiographical recall in 11 healthy subjects (6 males), aged 32.4 +/- 7.2 years, without physical or psychiatric disorders, selected according to their ability to vividly recall personal experiences. Blood oxygen level-dependent (BOLD) changes were recorded during auditory presentation of personal scripts of happiness, neutral content and negative emotional content (irritability). The same uniform structure was used for the cueing narratives of both emotionally salient and neutral conditions, in order to decrease the variability of findings. In the happiness relative to the neutral condition, there was an increased BOLD signal in the left dorsal prefrontal cortex and anterior insula, thalamus bilaterally, left hypothalamus, left anterior cingulate gyrus, and midportions of the left middle temporal gyrus (P < 0.05, corrected for multiple comparisons). Relative to the irritability condition, the happiness condition showed increased activity in the left insula, thalamus and hypothalamus, and in anterior and midportions of the inferior and middle temporal gyri bilaterally (P < 0.05, corrected), varying in size between 13 and 64 voxels. Findings of happiness-related increased activity in prefrontal and subcortical regions extend the results of previous functional imaging studies of autobiographical recall. The BOLD signal changes identified reflect general aspects of emotional processing, emotional control, and the processing of sensory and bodily signals associated with internally generated feelings of happiness. These results reinforce the notion that happiness induction engages a wide network of brain regions.

Identification of COL6A1 as a differentially expressed gene in human astrocytomas

Diffuse infiltrating gliomas are the most common tumors of the central nervous system. Gliomas are classified by the WHO according to their histopathological and clinical characteristics into four classes: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma multiforme). Several genes have already been correlated with astrocytomas, but many others are yet to be uncovered. By analyzing the public SAGE data from 21 patients, comprising low malignant grade astrocytomas and glioblastomas, we found COL6A1 to be differentially expressed, confirming this finding by real time RT-PCR in 66 surgical samples. To the best of our knowledge, COL6A1 has never been described in gliomas. The expression of this gene has significantly different means when normal glia is compared with low-grade astrocytomas (grades I and II) and high-grade astrocytomas (grades III and IV), with a tendency to be greater in higher grade samples, thus rendering it a powerful tumor marker.

The role of conventional MR imaging sequences in the evaluation of neurocysticercosis: impact on characterization of the scolex and lesion burden.

BACKGROUND AND PURPOSE: There are few studies comparing the capacity of lesion detection of conventional MR imaging in neurocysticercosis (NCC). This study was designed to clarify its role in the evaluation of this disease, focusing on the total number of lesions identified and the characterization of the scolex. MATERIALS AND METHODS: MR images from 115 patients were prospectively collected during a 3-year interval, including axial spin-echo (SE) T1-weighted; axial fast SE T2-weighted; axial fluid-attenuated inversion recovery (FLAIR); and gadolinium-enhanced axial, coronal, and sagittal SE T1-weighted sequences. They were compared regarding the potential for detection of NCC lesions and specifically of the scolex. RESULTS: Comparing all sequences, we found that FLAIR images were more sensitive to the detection of the scolex (P < .003), whereas the last gadolinium-enhanced T1-weighted series (coronal or sagittal) identified the highest number of lesions (P < .001). CONCLUSION: When dealing with NCC, optimal MR imaging protocols should include FLAIR images to obtain maximal rates of scolex detection. Special attention should be paid to the last gadolinium-enhanced sequence, which maximizes the quantification of lesion load.

Multivoxel proton MR spectroscopy in malformations of cortical development.

BACKGROUND AND PURPOSE: Malformations of cortical development (MCD) are traditionally considered as a cause of epilepsy. Our aim was to study patients with focal MCD, by using multivoxel proton MR spectroscopy; we focused not only on the lesion but also on the normal-appearing contralateral side (NACS). Our hypothesis was that the metabolic abnormality extends to the NACS; therefore, it would be inadequate to consider NACS as an internal control. MATERIALS AND METHODS: We studied 16 patients with focal MCD. MR spectroscopy was performed by using a point-resolved spectroscopy sequence technique, including the MCD area and the NACS. In each volume of interest, a smaller volume of interest of 2.25 cm(3) centered on the MCD was selected to study the N-acetylaspartate/creatine (NAA/Cr) ratio. In NACS, this ratio was studied by placing a symmetric voxel in comparison with the smaller MCD volume of interest. A control group (n=30) was also studied to evaluate both white and gray matter by using the same MR spectroscopy protocol. RESULTS: From 16 analyzed volumes of interest with MCD, 9 were composed of gray matter heterotopia and 7 of cortical dysplasia. MR spectroscopy of both MCD lesions and NACS (n=10) showed decreased NAA/Cr compared with that of the control group. NACS in these patients did not present significant differences regarding NAA/Cr in comparison with the affected side. CONCLUSIONS: MR spectroscopy demonstrated abnormal NAA/Cr in both MCD lesions and NACS in patients harboring focal MCD, giving support to the hypothesis that in MCD metabolic abnormalities extend far away from the limits of the lesion, reaching the contralateral side.

Time-varying modeling of gene expression regulatory networks using the wavelet dynamic vector autoregressive method.

MOTIVATION: A variety of biological cellular processes are achieved through a variety of extracellular regulators, signal transduction, protein-protein interactions and differential gene expression. Understanding of the mechanisms underlying these processes requires detailed molecular description of the protein and gene networks involved. To better understand these molecular networks, we propose a statistical method to estimate time-varying gene regulatory networks from time series microarray data. One well known problem when inferring connectivity in gene regulatory networks is the fact that the relationships found constitute correlations that do not allow inferring causation, for which, a priori biological knowledge is required. Moreover, it is also necessary to know the time period at which this causation occurs. Here, we present the Dynamic Vector Autoregressive model as a solution to these problems. RESULTS: We have applied the Dynamic Vector Autoregressive model to estimate time-varying gene regulatory networks based on gene expression profiles obtained from microarray experiments. The network is determined entirely based on gene expression profiles data, without any prior biological knowledge. Through construction of three gene regulatory networks (of p53, NF-kappaB and c-myc) for HeLa cells, we were able to predict the connectivity, Granger-causality and dynamics of the information flow in these networks. SUPPLEMENTARY INFORMATION: Additional figures may be found at http://mariwork.iq.usp.br/dvar/.