NeuroImage: Clinical

Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [(11)C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38-68 years) and ten age- and [(11)C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33-65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (p FWE < 0.05). Region of interest analysis revealed increased [(11)C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = -0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [(11)C]-PBR28 as a marker of treatments that target neuroinflammation.

We evaluated in vivo the integrity of brain cholinergic pathways in Multiple System Atrophy (MSA) and the relationship between cholinergic dysfunction and motor disturbances, by measuring the vesicular acetylcholine transporter (VAChT) expression using Single Photon Emission Computed Tomography (SPECT) and [(123)I]-iodobenzovesamicol ([(123)I]-IBVM). Nine patients with probable MSA and 12 healthy volunteers underwent a dynamic [(123)I]-IBVM SPECT-CT scan and a magnetic resonance imaging (MRI) scan. All patients were examined with the Unified MSA Rating Scale (UMSARS; subscale I = activities of daily living (ADL), II = motor and IV = disability). CT and MRI images were used to register the dynamic SPECT image to the Montreal Neurological Institute brain template, which includes the regions of interest (ROI) of striatum and Ch1 (medial septum nucleus-hippocampus), Ch4 (nucleus basalis of Meynert-cortex) and Ch5-Ch6 (pedunculopontine and laterodorsal tegmental nuclei-thalamus) cholinergic pathways. For each ROI, pharmacokinetic modeling of regional time activity curves led to the calculation of [(123)I]-IBVM to VAChT binding potential (BPND) value, proportional to VAChT expression. When compared to controls, BPND values for MSA in Ch5-Ch6 were significantly decreased in both the pedunculopontine-laterodorsal nuclei and the thalamus (p = 0.004 and p = 0.006, respectively). Additionally, thalamus BPND values were correlated with UMSARS ADL (p = 0.006), motor (p = 0.002) and disability (p = 0.02) sub-scores. UMSARS motor subscale items 13 (postural instability) and 14 (gait) were also correlated with thalamus BPND values (p = 0.04). Ch5-Ch6 are the most affected cholinergic pathways in MSA at both cell bodies and thalamic cholinergic terminals. These results underscore the relevant role of [(123)I]-IBVM SPECT for improving our understanding of the pathophysiology in MSA.

[This corrects the article DOI: 10.1016/j.nicl.2012.10.003.].

Catecholamine depletion with alpha-methylparatyrosine (AMPT) has previously been shown to induce depressive symptoms in currently remitted patients with major depressive disorder (MDD) but not healthy controls. Thus sensitivity to catecholamine depletion has been hypothesized to be an endophenotype of MDD. Here we tested this hypothesis in the context of a randomized, double-blinded, placebo-controlled design by measuring changes in mood in a group of psychiatrically-healthy individuals at risk of mood disorders by virtue of family history (high-risk subjects, HRs). In addition, we tested whether HRs differed from healthy controls with no family-history of mood disorders (low-risk controls, LRs) in their cerebral metabolic response when undergoing catecholamine depletion. Eight healthy LRs (6 males, mean age = 34.1 ± 7.1) and 6 healthy HRs (3 males, mean age = 29.3 ± 4.6) participated in two, 3-day-long identical sessions during which they completed standardized measures of depression, anxiety and fatigue and an [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scan. On one occasion participants received 4 weight-adjusted doses of AMPT and on the other occasion participants received 4 doses of placebo. The LR and HR groups did not differ from each other in their mood during sham depletion. However, during the period of peak catecholamine depletion, the HR group reported significantly more depression, anxiety and fatigue than the LR group. A region-of-interest analysis showed that during catecholamine depletion versus placebo the combined LR and HR groups displayed a significant increase in cerebral metabolic rate in the left and right ventral striata, left and right amygdalae, and left and right hippocampi (FWE-corrected p < 0.05). Whole brain voxel-wise analyses indicated significantly increased glucose metabolism in the left and right putamina (FWE-corrected p < 0.05) in the combined LR and HR groups in the AMPT versus the placebo session. In the LR group, alone, no significant elevation in glucose metabolism was observed in the regions-of-interest in the catecholamine depletion versus placebo condition. In the HR group, alone, the region-of-interest analysis showed a significant increase in cerebral metabolic rate in the left and right ventral striata (FWE-corrected p < 0.05). No regions-of-interest showed significantly different metabolism in the HR group versus the LR group in the placebo condition, however compared with the LR group, the HR group displayed nominally increased glucose metabolism in the left amygdala during catecholamine depletion (SVC-corrected p = 0.05). A region-of-interest analysis for the interaction contrast confirmed that catecholamine depletion had differential effects on HR and LR participants. Compared with the LR group, the HR group displayed significantly increased glucose metabolism in the left ventral striatum, left amygdala, and left lateral orbitofrontal cortex (OFC) (FWE-corrected p < 0.05). Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic-cortical-striatal-pallidal-thalamic circuitry.

To date, there has been little work describing the neurochemical profile of young, heavy marijuana users. In this study, we examined 27 young-adult marijuana users and 26 healthy controls using single-voxel magnetic resonance spectroscopy on a 3 T scanner. The voxel was placed in the dorsal striatum, and estimated concentrations of glutamate + glutamine, myo-inositol, taurine + glucose, total choline and total N-acetylaspartate were examined between groups. Therewere no overall group effects, but two metabolites showed group by sex interactions. Lower levels of glutamate + glutamine (scaled to total creatine) were observed in female, but not male, marijuana users compared to controls. Higher levels of myo-inositol were observed in female users compared to female non-users and to males in both groups. Findings are discussed in relation to patterns of corticostriatal connectivity and function, in the context of marijuana abuse.

Cardio-metabolic risk factors have been associated with poor physical and mental health. Epidemiological studies have shown peripheral risk markers to be associated with poor cognitive functioning in normal healthy population and in disease. The aim of the study was to explore the relationship between cardio-metabolic risk factors and cortical thickness in a neurologically healthy middle aged population-based sample. T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness in 40 adult males (average age = 50.96 years), selected from the pSoBid study. The relationship between cardio-vascular risk markers and cortical thickness across the whole brain, was examined using the general linear model. The relationship with various covariates of interest was explored. Lipid fractions with greater triglyceride content (TAG, VLDL and LDL) were associated with greater cortical thickness pertaining to a number of regions in the brain. Greater C reactive protein (CRP) and intercellular adhesion molecule (ICAM-1) levels were associated with cortical thinning pertaining to perisylvian regions in the left hemisphere. Smoking status and education status were significant covariates in the model. This exploratory study adds to a small body of existing literature increasingly showing a relationship between cardio-metabolic risk markers and regional cortical thickness involving a number of regions in the brain in a neurologically normal middle aged sample. A focused investigation of factors determining the inter-individual variations in regional cortical thickness in the adult brain could provide further clarity in our understanding of the relationship between cardio-metabolic factors and cortical structures.

22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins. High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10-25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed. Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS. Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.

As a group, people with the sex chromosome aneuploidy 49,XXXXY have characteristic physical and cognitive/behavioral tendencies, although there is high individual variation. In this study we use magnetic resonance imaging (MRI) to examine brain morphometry in 14 youth with 49,XXXXY compared to 42 age-matched healthy controls. Total brain size was significantly smaller (t=9.0, p<.001), and rates of brain abnormalities such as colpocephaly, plagiocephaly, periventricular cysts, and minor craniofacial abnormalities were significantly increased. White matter lesions were identified in 50% of subjects, supporting the inclusion of 49,XXXXY in the differential diagnosis of small multifocal white matter lesions. Further evidence of abnormal development of white matter was provided by the smaller cross sectional area of the corpus callosum. These results suggest that increased dosage of genes on the X chromosome has adverse effects on white matter development.

Hippocampal focal T2 hyperintensities (HT2Hs), also referred to as hippocampal sulcal cavities, are a common finding on Magnetic Resonance (MR) images. There is uncertainty about their etiology and clinical significance. In this study we aimed to describe these HT2Hs in more detail using high resolution 7 Tesla MR imaging, addressing 1) the MR signal characteristics of HT2Hs, 2) their occurrence frequency, 3) their location within the hippocampus, and 4) their relation with age. We also performed an explorative post-mortem study to examine the histology of HT2Hs. Fifty-eight persons without a history of invalidating neurological or psychiatric disease (mean age 64 ± 8 years; range 43–78 years), recruited through their general practitioners, were included in this study. They all underwent 7 Tesla MRI, including a T1, T2, and FLAIR image. MR signal characteristics of the HT2Hs were assessed on these images by two raters. Also, the location and number of the HT2Hs were assessed. In addition, four formalin-fixed brain slices from two subjects were scanned overnight. HT2Hs identified in these slices were subjected to histopathological analysis. HT2Hs were present in 97% of the subjects (median number per person 10; range 0–20). All HT2Hs detected on the T2 sequence were hypointense on T1 weighted images. Of all HT2Hs, 94% was hypointense and 6% hyperintense on FLAIR. FLAIR hypointense HT2Hs were all located in the vestigial sulcus of the hippocampus, FLAIR hyperintense HT2Hs in the hippocampal sulcus or the gray matter. Post-mortem MRI and histopathological analysis suggested that the hypointense HT2Hs on FLAIR were cavities filled with cerebrospinal fluid. A hyperintense HT2H on FLAIR proved to be a microinfarct upon microscopy. In conclusion, hippocampal T2Hs are extremely common and unrelated to age. They can be divided into two types (hypo- and hyperintense on FLAIR), probably with different etiology.

Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy ((1)H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI-(1)H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia.

Compulsive behaviors in obsessive-compulsive disorder (OCD) may be related to deficits in reward processing mediated by corticostriatal circuitry, a brain network implicated in the pathophysiology of OCD. Performing compulsive actions can be perceived as a reward to OCD patients because it temporarily reduces the anxiety provoked by obsessions. Although most OCD literature provides evidence of altered regional activity in these corticostriatal circuits, very little is known about the connectivity between individual regions of the corticostriatal-limbic circuits, including the cognitive and affective neural circuitry associated with OCD. Thus, this study investigated the differences in functional connectivity (FC) patterns in this network during resting-state and incentive processing. Nineteen patients with OCD and 18 well-matched healthy controls were scanned during resting-state and a monetary incentive delay task (task state). FC was assessed using both voxel-wise and region-of-interest (ROI)-wise analyses. Voxel-wise FC analysis with the nucleus accumbens seed revealed that patients with OCD exhibited increased FC between the nucleus accumbens and the lateral orbitofrontal cortex during resting-state. Additionally, these patients showed decreased FC between the nucleus accumbens and limbic areas such as the amygdala during incentive processing. Exploratory ROI-wise FC analysis revealed that OCD patients demonstrated enhanced FC between the nucleus accumbens and the lateral orbitofrontal cortex and increased total connectivity of the lateral orbitofrontal cortex during resting-state. Additionally, patients showed alterations in FC between resting and task state. This study provides evidence that patients with OCD have altered FC in the corticostriatal-limbic network, particularly in striatal-amygdala and striatal-orbitofrontal circuitry, during incentive processing and resting-state. These findings also emphasize that functional connections in the network are modulated by affective/motivational states and further suggest that OCD patients may have abnormalities of such modulation in this network.

To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics. Dynamic contrast-enhanced MRI was used to measure BBB permeability in 27 patients with MS and compared to 24 matched healthy controls. Permeability measured as K(trans) was significantly higher in periventricular normal appearing white matter (NAWM) and thalamic gray matter in MS patients when compared to healthy controls, with periventricular NAWM showing the most pronounced difference. Recent relapse coincided with significantly higher permeability in periventricular NAWM, thalamic gray matter, and MS lesions. Immunomodulatory treatment and recent relapse were significant predictors of permeability in MS lesions and periventricular NAWM. Our results suggest that after an MS relapse permeability gradually decreases, possibly an effect of immunomodulatory treatment. Our results emphasize the importance of BBB pathology in MS, which we find to be most prominent in the periventricular NAWM, an area prone to development of MS lesions. Both the facts that recent relapse appears to cause widespread BBB disruption and that immunomodulatory treatment seems to attenuate this effect indicate that BBB permeability is intricately linked to the presence of MS relapse activity. This may reveal further insights into the pathophysiology of MS.

Down Syndrome is the most common genetic cause for intellectual disability, yet the pathophysiology of cognitive impairment in Down Syndrome is unknown. We compared fMRI scans of 15 individuals with Down Syndrome to 14 typically developing control subjects while they viewed 50 min of cartoon video clips. There was widespread increased synchrony between brain regions, with only a small subset of strong, distant connections showing underconnectivity in Down Syndrome. Brain regions showing negative correlations were less anticorrelated and were among the most strongly affected connections in the brain. Increased correlation was observed between all of the distributed brain networks studied, with the strongest internetwork correlation in subjects with the lowest performance IQ. A functional parcellation of the brain showed simplified network structure in Down Syndrome organized by local connectivity. Despite increased interregional synchrony, intersubject correlation to the cartoon stimuli was lower in Down Syndrome, indicating that increased synchrony had a temporal pattern that was not in response to environmental stimuli, but idiosyncratic to each Down Syndrome subject. Short-range, increased synchrony was not observed in a comparison sample of 447 autism vs. 517 control subjects from the Autism Brain Imaging Exchange (ABIDE) collection of resting state fMRI data, and increased internetwork synchrony was only observed between the default mode and attentional networks in autism. These findings suggest immature development of connectivity in Down Syndrome with impaired ability to integrate information from distant brain regions into coherent distributed networks.

Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n = 25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject's connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic-cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.

Ataxia with Oculomotor Apraxia type 2 (AOA2) is one of the most frequent types of autosomal degenerative cerebellar ataxia. The first objective of this work was to identify specific cerebellar atrophy using MRI in patients with AOA2. Since increased iron deposits have been reported in degenerative diseases, our second objective was to report iron deposits signals in the dentate nuclei in AOA2. Five patients with AOA2 and 5 age-matched controls were subjects in a 3T MRI experiment that included a 3D turbo field echo T1-weighted sequence. The normalized volumes of twenty-eight cerebellar lobules and the percentage of atrophy (relative to controls) of the 4 main cerebellar regions (flocculo-nodular, vermis, anterior and posterior) were measured. The dentate nucleus signals using 3D fast field echo sequence for susceptibility-weighted images (SWI) were reported, as a measure of iron content. We found that all patients had a significant atrophy of all cerebellar lobules as compared to controls. The percentage of atrophy was the highest for the vermis, consistent with patients' oculomotor presentation, and for the anterior lobe, consistent with kinetic limb ataxia. We also describe an absence of hypointensity of the iron signal on SWI in the dentate nucleus of all patients compared to control subjects. This study suggests that patients with Ataxia with Oculomotor Apraxia type 2 present MRI patterns consistent with their clinical presentation. The absence of SWI hypointensity in dentate nucleus is a new radiological sign which was identified in all patients. The specificity of this absence of signal must be further determined in AOA2.

Sensory processing disorders (SPD) affect 5-16% of school-aged children and can cause long-term deficits in intellectual and social development. Current theories of SPD implicate primary sensory cortical areas and higher-order multisensory integration (MSI) cortical regions. We investigate the role of white matter microstructural abnormalities in SPD using diffusion tensor imaging (DTI). DTI was acquired in 16 boys, 8-11 years old, with SPD and 24 age-, gender-, handedness- and IQ-matched neurotypical controls. Behavior was characterized using a parent report sensory behavior measure, the Sensory Profile. Fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) were calculated. Tract-based spatial statistics were used to detect significant group differences in white matter integrity and to determine if microstructural parameters were significantly correlated with behavioral measures. Significant decreases in FA and increases in MD and RD were found in the SPD cohort compared to controls, primarily involving posterior white matter including the posterior corpus callosum, posterior corona radiata and posterior thalamic radiations. Strong positive correlations were observed between FA of these posterior tracts and auditory, multisensory, and inattention scores (r = 0.51-0.78; p < 0.001) with strong negative correlations between RD and multisensory and inattention scores (r = - 0.61-0.71; p < 0.001). To our knowledge, this is the first study to demonstrate reduced white matter microstructural integrity in children with SPD. We find that the disrupted white matter microstructure predominantly involves posterior cerebral tracts and correlates strongly with atypical unimodal and multisensory integration behavior. These findings suggest abnormal white matter as a biological basis for SPD and may also distinguish SPD from overlapping clinical conditions such as autism and attention deficit hyperactivity disorder.

Although magnetoencephalography (MEG) studies show superior temporal gyrus (STG) auditory processing abnormalities in schizophrenia at 50 and 100 ms, EEG and corticography studies suggest involvement of additional brain areas (e.g., frontal areas) during this interval. Study goals were to identify 30 to 130 ms auditory encoding processes in schizophrenia (SZ) and healthy controls (HC) and group differences throughout the cortex. The standard paired-click task was administered to 19 SZ and 21 HC subjects during MEG recording. Vector-based Spatial-temporal Analysis using L1-minimum-norm (VESTAL) provided 4D maps of activity from 30 to 130 ms. Within-group t-tests compared post-stimulus 50 ms and 100 ms activity to baseline. Between-group t-tests examined 50 and 100 ms group differences. Bilateral 50 and 100 ms STG activity was observed in both groups. HC had stronger bilateral 50 and 100 ms STG activity than SZ. In addition to the STG group difference, non-STG activity was also observed in both groups. For example, whereas HC had stronger left and right inferior frontal gyrus activity than SZ, SZ had stronger right superior frontal gyrus and left supramarginal gyrus activity than HC. Less STG activity was observed in SZ than HC, indicating encoding problems in SZ. Yet auditory encoding abnormalities are not specific to STG, as group differences were observed in frontal and SMG areas. Thus, present findings indicate that individuals with SZ show abnormalities in multiple nodes of a concurrently activated auditory network.

Various types of multiple sclerosis (MS) related pain have been discussed. One concept is that deafferentation secondary to lesions in the spino-thalamo-cortical network can cause central pain. However, this hypothesis is somehow limited by a lack of a robust association between pain episodes and sites of lesion location. We tested the hypothesis that temporary tissue alterations in the thalamus that are not detectable by conventional magnetic resonance imaging (T1w, FLAIR) can potentially explain a focal, paroxysmal central pain episode of a patient with MS. For microstructural tissue assessment we employed ten longitudinal diffusion tensor imaging (DTI) examinations. We could demonstrate an abnormal, unilateral temporary increase of the fractional anisotropy (FA) in the thalamus contralateral to the affected body side. Before the pain episode and after pain relief the FA reached completely normal values as seen in identically investigated age and gender matched 100 healthy control subjects. THESE FINDINGS SUGGEST THAT: i.) frequently applied and quantitatively evaluated DTI could be used as a sensitive imaging technique for detection of pathological processes associated with MS not detectable with conventional imaging strategies, ii.) temporary pathological processes in the "normal-appearing" thalamus may explain waxing and waning symptoms like episodes of central pain, and iii.) cross-sectional case examinations on (MS) patients with central pain should be performed to investigate how often thalamic alterations occur together with central pain.

Bipolar disorder (BD) is a chronic mental illness characterized by severe disruptions in mood and cognition. Diffusion tensor imaging (DTI) studies suggest that white matter (WM) tract abnormalities may contribute to the clinical hallmarks of the disorder. Using DTI and whole brain voxel-based analysis, we mapped the profile of WM anomalies in BD. All patients in our sample were euthymic and lithium free when scanned. Diffusion-weighted and T1-weighted structural brain images were acquired from 23 lithium-free euthymic subjects with bipolar I disorder and 19 age- and sex-matched healthy control subjects on a 1.5 T MRI scanner. Scans were processed to provide measures of fractional anisotropy (FA) and mean and radial diffusivity (MD and RD) at each WM voxel, and processed scans were nonlinearly aligned to a customized brain imaging template for statistical group comparisons. Relative to controls, the bipolar group showed widespread regions of lower FA, including the corpus callosum, cortical and thalamic association fibers. MD and RD were abnormally elevated in patients in many of these same regions. Our findings agree with prior reports of WM abnormalities in the corpus callosum and further link a bipolar diagnosis with structural abnormalities of the tapetum, fornix and stria terminalis. Future studies assessing the diagnostic specificity and prognostic implications of these abnormalities would be of interest.

Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD.

Diabetes mellitus affects the brain. Both type 1 and type 2 diabetic patients are associated with white matter (WM) damage observable to diffusion tensor imaging (DTI). The underlying histopathological mechanisms, however, are poorly understood. The objectives of this study are 1) to determine whether streptozotocin (STZ)-induced type 1 diabetes is associated with WM damage observable to DTI; and 2) to understand the pathophysiological aspects underlying STZ-induced brain injuries. Male Sprague-Dawley rats received a single intraperitoneal injection of STZ (62 mg/kg). DTI was used to assess brain abnormalities at 4 weeks after induction, combined with histological assessments and ultrastructural analysis. Compared to controls, the STZ-induced rats showed significantly reduced fractional anisotropy (FA) in the motor/somatosensory cortex and striatum. Histologically, the cortex and striatum of the diabetic animals are characterized by demyelination and axonal degradation. In conclusion, STZ-induced diabetes is associated with striatal/cortical injuries observable to DTI. The DTI abnormalities are likely manifestations of demyelination and axonal degradation in the affected brain regions, and can potentially be used as surrogates for evaluating diabetic brain injuries.

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI), exhibiting improved sensitivity and specificity in detecting developmental and pathological changes in neural tissues. However, little attention was paid to the performances of DKI and DTI in detecting white matter abnormality in schizophrenia. In this study, DKI and DTI were performed in 94 schizophrenia patients and 91 sex- and age-matched healthy controls. White matter integrity was assessed by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK) of DKI and FA, MD, AD and RD of DTI. Group differences in these parameters were compared using tract-based spatial statistics (TBSS) (P < 0.01, corrected). The sensitivities in detecting white matter abnormality in schizophrenia were MK (34%) > AK (20%) > RK (3%) and RD (37%) > FA (24%) > MD (21%) for DKI, and RD (43%) > FA (30%) > MD (21%) for DTI. DKI-derived diffusion parameters (RD, FA and MD) were sensitive to detect abnormality in white matter regions (the corpus callosum and anterior limb of internal capsule) with coherent fiber arrangement; however, the kurtosis parameters (MK and AK) were sensitive to reveal abnormality in white matter regions (the juxtacortical white matter and corona radiata) with complex fiber arrangement. In schizophrenia, the decreased AK suggests axonal damage; however, the increased RD indicates myelin impairment. These findings suggest that diffusion and kurtosis parameters could provide complementary information and they should be jointly used to reveal pathological changes in schizophrenia.

The current study investigates the whole brain myelin water content distribution applying a new approach that allows for the simultaneous mapping of total and relative myelin water content, T1 and T2* with full brain coverage and high resolution (1 × 1 × 2 mm3). The data was collected at two different sites in healthy controls to validate the independence of a specific setup. In addition, a group of patients with known white matter affections was investigated to compare two measures of myelin, i.e. relative and absolute myelin water content. Based on the first dataset, a quantitative myelin water content atlas was created which served as a control set for the other two datasets. Both control groups measured at different institutions yielded consistent results. However, distinct regions of reduced myelin water content were observed for the patient dataset, both on an individual basis and in a group-wise comparison. The comparison between the absolute and relative measurement of myelin water content in MS patients showed that the relative measurement, which is employed by many researchers, overestimates both disease volume and the corresponding reduction of myelin water content in white matter lesions. However, for normal appearing white matter, no difference between both approaches was detected. The results obtained in the current study demonstrate that absolute myelin water content can reliably be determined in a multicentre environment using standard MR sequences. The optimised protocol allows for a measurement of four quantitative parameters with full brain coverage in only 10 min. This might expedite a more widespread future use of quantitative MRI methods for clinical research and diagnosis.

Chronic alcohol abuse affects brain structure and function. We examined subcortical structure volumes in 77 short (6–15 week) and 90 long (multi-year) term abstinent alcoholics, along with 74 controls. We used a 3T Siemens MPRAGE sequence for image acquisition and FSL FIRST software for measuring subcortical volumes. When examining alcoholics without a comorbid stimulant disorder we found reduced hippocampal, pallidum and thalamus volumes in short term abstinence compared to a non-substance abusing control sample with numerically smaller yet still significant reductions compared to controls in long term abstinence. When examining alcoholics with a comorbid stimulant disorder, no difference from controls was found for any subcortical volume. Alcoholics with a stimulant disorder had significantly larger subcortical volumes than alcoholics without a stimulant disorder. This study replicates past research showing that chronic alcohol abuse is associated with lower subcortical volumes in short-term abstinent chronic alcoholics and extends this finding, although with smaller effects to long-term abstinent samples. The absence of this effect in the presence of a comorbid stimulant disorder suggests either a protective effect of stimulant abuse/dependence or that the measurements reflect the aggregate of alcohol dependence associated atrophy and stimulant abuse associated inflammation. Associations with function suggest the second of these two alternatives.

Alcoholism has been associated with a widespread pattern of gray matter atrophy. This study sought to investigate the spectrum of volume alterations in a population of alcoholics with only alcohol dependence, polysubstance abusing alcoholics, and a comparison population of healthy controls. Thirty-seven 'pure' alcoholics, 93 polysubstance abusing alcoholics, and 69 healthy controls underwent structural T1 MRI scans. Voxel-based morphometry was performed to investigate gray matter alterations. Alcoholic dependent inpatients (both with and without a history of DSM-IV substance abuse/dependence diagnosis) displayed significant gray matter differences in the mesial region of the frontal lobe and right temporal lobe. 'Pure' alcoholics exhibited a pattern of subcortical changes similar to that seen in Wernicke-Korsakoff Syndrome when compared to polysubstance abusing alcoholics. 'Pure' alcoholics and polysubstance abusing alcoholics did not differ significantly in measures of cortical gray matter, liver function, or nutrition. These findings reinforce the accepted literature in regards to frontal lobe gray matter atrophy in alcohol dependence. This study calls for additional research in order to investigate the spectrum from uncomplicated alcoholism to Wernicke-Korsakoff Syndrome. Further research is needed to elucidate the exact cause of this pattern of differences and to determine what factors are responsible for the patterns of gray matter reduction or difference in 'pure' and polysubstance abusing alcoholics.

In this research, we developed a robust two-layer classifier that can accurately classify normal hearing (NH) from hearing impaired (HI) infants with congenital sensori-neural hearing loss (SNHL) based on their Magnetic Resonance (MR) images. Unlike traditional methods that examine the intensity of each single voxel, we extracted high-level features to characterize the structural MR images (sMRI) and functional MR images (fMRI). The Scale Invariant Feature Transform (SIFT) algorithm was employed to detect and describe the local features in sMRI. For fMRI, we constructed contrast maps and detected the most activated/de-activated regions in each individual. Based on those salient regions occurring across individuals, the bag-of-words strategy was introduced to vectorize the contrast maps. We then used a two-layer model to integrate these two types of features together. With the leave-one-out cross-validation approach, this integrated model achieved an AUC score of 0.90. Additionally, our algorithm highlighted several important brain regions that differentiated between NH and HI children. Some of these regions, e.g. planum temporale and angular gyrus, were well known auditory and visual language association regions. Others, e.g. the anterior cingulate cortex (ACC), were not necessarily expected to play a role in differentiating HI from NH children and provided a new understanding of brain function and of the disorder itself. These important brain regions provided clues about neuroimaging markers that may be relevant to the future use of functional neuroimaging to guide predictions about speech and language outcomes in HI infants who receive a cochlear implant. This type of prognostic information could be extremely useful and is currently not available to clinicians by any other means.

Introduction: The segmentation and volumetric quantification of white matter (WM) lesions play an important role in monitoring and studying neurological diseases such as multiple sclerosis (MS) or cerebrovascular disease. This is often interactively done using 2D magnetic resonance images. Recent developments in acquisition techniques allow for 3D imaging with much thinner sections, but the large number of images per subject makes manual lesion outlining infeasible. This warrants the need for a reliable automated approach. Here we aimed to improve k nearest neighbor (kNN) classification of WM lesions by optimizing intensity normalization and using spatial tissue type priors (TTPs). Methods: The kNN-TTP method used kNN classification with 3.0 T 3DFLAIR and 3DT1 intensities as well as MNI-normalized spatial coordinates as features. Additionally, TTPs were computed by nonlinear registration of data from healthy controls. Intensity features were normalized using variance scaling, robust range normalization or histogram matching. The algorithm was then trained and evaluated using a leave-one-out experiment among 20 patients with MS against a reference segmentation that was created completely manually. The performance of each normalization method was evaluated both with and without TTPs in the feature set. Volumetric agreement was evaluated using intra-class coefficient (ICC), and voxelwise spatial agreement was evaluated using Dice similarity index (SI). Finally, the robustness of the method across different scanners and patient populations was evaluated using an independent sample of elderly subjects with hypertension. Results: The intensity normalization method had a large influence on the segmentation performance, with average SI values ranging from 0.66 to 0.72 when no TTPs were used. Independent of the normalization method, the inclusion of TTPs as features increased performance particularly by reducing the lesion detection error. Best performance was achieved using variance scaled intensity features and including TTPs in the feature set: this yielded ICC = 0.93 and average SI = 0.75 ± 0.08. Validation of the method in an independent sample of elderly subjects with hypertension, yielded even higher ICC = 0.96 and SI = 0.84 ± 0.14. Conclusion: Adding TTPs increases the performance of kNN based MS lesion segmentation methods. Best performance was achieved using variance scaling for intensity normalization and including TTPs in the feature set, showing excellent agreement with the reference segmentations across a wide range of lesion severity, irrespective of the scanner used or the pathological substrate of the lesions.

We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis - a form of neuroplasticity - and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging ((1)H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.

Frontotemporal dementia (FTD) is classically considered to be a neurodegenerative disease with cortical changes. Recent structural imaging findings, however, highlight that subcortical and in particular striatal regions are also affected in the FTD syndrome. The influence of striatal pathology on cognitive and behavioural changes in FTD is virtually unexplored. In the current study we employ the Weather Prediction Task (WPT), a probabilistic learning task which taps into striatal dysfunction, in a group of FTD patients. We also regressed the patients' behavioural performance with their grey matter atrophy via voxel-based morphometry (VBM) to identify the grey matter contributions to WPT performance in FTD. Based on previous studies we expected to see striatal and frontal atrophy to be involved in impaired probabilistic learning. Our behavioural results show that patients performed on a similar level to controls overall, however, there was a large variability of patient performance in the first 30 trials of the task, which are critical in the acquisition of the probabilistic learning rules. A VBM analysis covarying the performance for the first 30 trials across participants showed that atrophy in striatal but also frontal brain regions correlated with WPT performance in these trials. Closer inspection of performance across the first 30 trials revealed a subgroup of FTD patients that performed significantly poorly than the remaining patients and controls on the WPT, despite achieving the same level of probabilistic learning as the other groups in later trials. Additional VBM analyses revealed that the subgroup of FTD patients with poor early probabilistic learning in the first 30 trials showed greater striatal atrophy compared to the remaining FTD patients and controls. These findings suggest that the integrity of fronto-striatal regions is important for probabilistic learning in FTD, with striatal integrity in particular, determining the acquisition learning rate. These findings will therefore have implications for developing an easily administered version of the probabilistic learning task which can be used by clinicians to assess striatal functioning in neurodegenerative syndromes.

Likelihood thought-action fusion (TAF-L) refers to a cognitive bias in which individuals believe that the mere thought of a negative event increases its likelihood of occurring in reality. TAF-L is most commonly associated with obsessive-compulsive disorder (OCD) but is also present in depression, generalized anxiety disorder and psychosis. We induced TAF-L in individuals with high (High-OC, N = 23) and low (Low-OC, N = 24) levels of OC traits, and used low resolution electromagnetic tomography (LORETA) to localise the accompanying electrical brain activity patterns. The results showed greater TAF-L in the High-OC than in the Low-OC group (p < .005), which was accompanied by significantly greater upper beta frequency (19-30 Hz) activity in the precuneus (p < .05). Further, the precuneus activity was positively correlated with self-reported magnitude of TAF-L (p < .01), suggesting a specific role of this region in this cognitive bias. Results are discussed with reference to self-referential processing and the default-mode network.

An objective biomarker is a compelling need for the early diagnosis of attention deficit hyperactivity disorder (ADHD), as well as for the monitoring of pharmacological treatment effectiveness. The advent of fNIRS, which is relatively robust to the body movements of ADHD children, raised the possibility of introducing functional neuroimaging diagnosis in younger ADHD children. Using fNIRS, we monitored the oxy-hemoglobin signal changes of 16 ADHD children (6 to 13 years old) performing a go/no-go task before and 1.5 h after MPH or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design. 16 age- and gender-matched normal controls without MPH administration were also monitored. Relative to control subjects, unmedicated ADHD children exhibited reduced activation in the right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) during go/no-go tasks. The reduced right IFG/MFG activation was acutely normalized after MPH administration, but not after placebo administration. The MPH-induced right IFG/MFG activation was significantly larger than the placebo-induced activation. Post-scan exclusion rate was 0% among 16 right-handed ADHD children with IQ > 70. We revealed that the right IFG/MFG activation could serve as a neuro-functional biomarker for monitoring the acute effects of methylphenidate in ADHD children. fNIRS-based examinations were applicable to ADHD children as young as 6 years old, and thus would contribute to early clinical diagnosis and treatment of ADHD children.

Hemispheric lateralization is a frequently encountered phenomenon of cortical function. It describes the functional specialization of a region on one side of the brain for a given task. It is well characterized in motor and sensory, as well as language systems and becomes more and more known for various cognitive domains. While in the adult healthy brain hemispheric lateralization is mostly set, pathological processes may lead to cortical reorganization. In these cases neuroplasticity of the corresponding region in the non-dominant hemisphere seems to play an important role. In a previous study we investigated language associated regions in right-handed patients with frontal and temporal tumors of the left hemisphere. We observed a marked change of language lateralization in these patients towards the non-dominant hemisphere as measured by functional MRI (Partovi et al., 2012).

The differential diagnosis of autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) based solely on symptomatic and behavioral assessments can be difficult, even for experts. Thus, the development of a neuroimaging marker that differentiates ASDs from ADHD would be an important contribution to this field. We assessed the differences in prefrontal activation between adults with ASDs and ADHD using an entirely non-invasive and portable neuroimaging tool, near-infrared spectroscopy. This study included 21 drug-naïve adults with ASDs, 19 drug-naïve adults with ADHD, and 21 healthy subjects matched for age, sex, and IQ. Oxygenated hemoglobin concentration changes in the prefrontal cortex were assessed during a stop signal task and a verbal fluency task. During the stop signal task, compared to the control group, the ASDs group exhibited lower activation in a broad prefrontal area, whereas the ADHD group showed underactivation of the right premotor area, right presupplementary motor area, and bilateral dorsolateral prefrontal cortices. Significant differences were observed in the left ventrolateral prefrontal cortex between the ASDs and ADHD groups during the stop signal task. The leave-one-out cross-validation method using mean oxygenated hemoglobin changes yielded a classification accuracy of 81.4% during inhibitory control. These results were task specific, as the brain activation pattern observed during the verbal fluency task did not differentiate the ASDs and ADHD groups significantly. This study therefore provides evidence of a difference in left ventrolateral prefrontal activation during inhibitory control between adults with ASDs and ADHD. Thus, near-infrared spectroscopy may be useful as an auxiliary tool for the differential diagnosis of such developmental disorders.

Obsessive-compulsive disorder (OCD) is associated with dysfunctional brain activity in several regions which are also involved in the processing of motivational stimuli. Processing of reward and punishment appears to be of special importance to understand clinical symptoms. There is evidence for higher sensitivity to punishment in patients with OCD which raises the question how avoidance of punishment relates to activity within the brain's reward circuitry. We employed the monetary incentive delay task paradigm optimized for modeling the anticipation phase of immediate reward and punishment, in the context of a cross-sectional event-related FMRI study comparing OCD patients and healthy control participants (n = 19 in each group). While overall behavioral performance was similar in both groups, patients showed increased activation upon anticipated losses in a medial and superior frontal cortex region extending into the cingulate cortex, and decreased activation upon anticipated rewards. No evidence was found for altered activation of dorsal or ventral striatal regions. Patients also showed more delayed responses for anticipated rewards than for anticipated losses whereas the reverse was true in healthy participants. The medial prefrontal cortex has been shown to implement a domain-general process comprising negative affect, pain and cognitive control. This process uses information about punishment to control aversively motivated actions by integrating signals arriving from subcortical regions. Our results support the notion that OCD is associated with altered sensitivity to anticipated rewards and losses in a medial prefrontal region whereas there is no significant aberrant activation in ventral or dorsal striatal brain regions during processing of reinforcement anticipation.

In healthy humans, passage reading depends upon a critical organizing role played by the magnocellular/dorsal visual pathway. In a recent study, we found a significant correlation between orthographic reading deficits in schizophrenia and deficits in contrast sensitivity to low spatial frequency stimuli, suggesting an underlying magnocellular processing abnormality. The interrelationship between magnocellular dysfunction and passage reading impairments in schizophrenia was investigated in 21 patients with schizophrenia and 17 healthy control volunteers using behavioral and functional MRI (fMRI) based measures. fMRI activation patterns during passage- and single-word reading were evaluated in relation to cortical areas with differential sensitivity to low versus high spatial frequency cortical regions indentified using a phase-encoded fMRI paradigm. On average, patients with schizophrenia read at the 6th grade level, despite completion of more than 12 years of education and estimated normal pre-morbid IQ. Schizophrenia patients also showed significantly impaired contrast sensitivity to low spatial frequencies and abnormal neural activity in response to stimulation with low spatial frequencies, consistent with dysfunction of magnocellular processing. Further, these magnocellular deficits were predictive of poor performance on a standardized psychoeducational test of passage reading. These findings suggest that reading is an important index of cognitive dysfunction in schizophrenia and highlight the contribution of magnocellular dysfunction to overall cognitive impairments in schizophrenia.

Increased blood-brain barrier permeability is believed to be associated with complications following acute ischemic stroke and with infarct expansion. Measurement of blood-brain barrier permeability requires a delayed image acquisition methodology, which prolongs examination time, increasing the likelihood of movement artefacts and radiation dose. Existing quantitative methods overestimate blood-brain barrier permeability when early phase CT perfusion data are used. The purpose of this study is to develop a method that yields the correct blood-brain barrier permeability value using first-pass perfusion CT data. We acquired 43 CT perfusion datasets, comprising experimental (n = 30) and validation subject groups (n = 13). The Gjedde-Patlak method was used to estimate blood-brain barrier permeability using first-pass (30-60 s after contrast administration) and delayed phase (30-200 s) data. In the experimental group, linear regression was used to obtain a function predicting first-pass blood-brain barrier permeability estimates from delayed phase estimates in each stroke compartment. The reliability of prediction with this function was then tested using data from the validation group. The predicted delayed phase blood-brain barrier permeability was strongly correlated with the measured delayed phase value (r = 0.67 and 0.6 for experimental and validation group respectively; p < 0.01). Predicted and measured delayed phase blood-brain barrier permeability in each stroke compartment were not significantly different in both experimental and validation groups. We have developed a method of estimating blood-brain barrier permeability using first-pass perfusion CT data. This predictive method allows reliable blood-brain barrier permeability estimation within standard acquisition time, minimizing the likelihood of motion artefacts thereby improving image quality and reducing radiation dose.

Extinction is diagnosed when patients respond to a single contralesional item but fail to detect this item when an ipsilesional item is present concurrently. Extinction has been studied mainly in the visual modality but it occurs also in other sensory modalities (touch, audition) and hence can be considered a multisensory phenomenon. The functional and neuroanatomical relations between extinction in different modalities are poorly understood. Here, we used voxel-based mophometry (VBM) to examine the neuronal substrates of visual versus tactile extinction in a large group of sub-acute patients (n = 454) with strokes affecting different vascular territories. We found that extinction deficits in tactile and visual modalities were significantly correlated (r = 0.341; p < 0.01). Several lesions within the right hemisphere were linked to extinction including the inferior parietal lobule, the superior parietal lobule, the middle frontal and occipital gyri, while lesions involving the superior temporal gyrus, inferior temporal gyrus and putamen were associated with tactile extinction. Damage within the middle temporal gyrus and superior temporal sulcus was linked to both deficits. We conclude that extinction in different modalities emerges after damage to both common (supra-modal) and distinct (modality specific) brain regions, and that contrasting sites emerge after damage to different vascular territories. We discuss the implications for understanding extinction as a multisensory disorder.

Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a 'toxicity free' addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.

ADHD is characterized by increased intra-individual variability in response times during the performance of cognitive tasks. However, little is known about developmental changes in intra-individual variability, and how these changes relate to cognitive performance. Twenty subjects with ADHD aged 7-24 years and 20 age-matched, typically developing controls participated in an fMRI-scan while they performed a go-no-go task. We fit an ex-Gaussian distribution on the response distribution to objectively separate extremely slow responses, related to lapses of attention, from variability on fast responses. We assessed developmental changes in these intra-individual variability measures, and investigated their relation to no-go performance. Results show that the ex-Gaussian measures were better predictors of no-go performance than traditional measures of reaction time. Furthermore, we found between-group differences in the change in ex-Gaussian parameters with age, and their relation to task performance: subjects with ADHD showed age-related decreases in their variability on fast responses (sigma), but not in lapses of attention (tau), whereas control subjects showed a decrease in both measures of variability. For control subjects, but not subjects with ADHD, this age-related reduction in variability was predictive of task performance. This group difference was reflected in neural activation: for typically developing subjects, the age-related decrease in intra-individual variability on fast responses (sigma) predicted activity in the dorsal anterior cingulate gyrus (dACG), whereas for subjects with ADHD, activity in this region was related to improved no-go performance with age, but not to intra-individual variability. These data show that using more sophisticated measures of intra-individual variability allows the capturing of the dynamics of task performance and associated neural changes not permitted by more traditional measures.

This study investigated whether frontal lobe cortical morphology differs for boys and girls with ADHD (ages 8-12 years) in comparison to typically developing (TD) peers. Participants included 226 children between the ages of 8-12 including 93 children with ADHD (29 girls) and 133 TD children (42 girls) for which 3T MPRAGE MRI scans were obtained. A fully automated frontal lobe atlas was used to generate functionally distinct frontal subdivisions, with surface area (SA) and cortical thickness (CT) assessed in each region. Analyses focused on overall diagnostic differences as well as examinations of the effect of diagnosis within boys and girls. Girls, but not boys, with ADHD showed overall reductions in total prefrontal cortex (PFC) SA. Localization revealed that girls showed widely distributed reductions in the bilateral dorsolateral PFC, left inferior lateral PFC, right medial PFC, right orbitofrontal cortex, and left anterior cingulate; and boys showed reduced SA only in the right anterior cingulate and left medial PFC. In contrast, boys, but not girls, with ADHD showed overall reductions in total premotor cortex (PMC) SA. Further localization revealed that in boys, premotor reductions were observed in bilateral lateral PMC regions; and in girls reductions were observed in bilateral supplementary motor complex. In line with diagnostic group differences, PMC and PFC SAs were inversely correlated with symptom severity in both girls and boys with ADHD. These results elucidate sex-based differences in cortical morphology of functional subdivisions of the frontal lobe and provide additional evidence of associations among SA and symptom severity in children with ADHD.

Compared to healthy controls, individuals with autism spectrum disorders (ASD) have weaker posterior-anterior connectivity that strengthens less with age within the default network, a set of brain structures connected in the absence of a task and likely involved in social function. The serotonin transporter-linked polymorphic region (5-HTTLPR) genotypes that result in lowered serotonin transporter expression are associated with social impairment in ASD. Additionally, in healthy controls, low expressing 5-HTTLPR genotypes are associated with weaker default network connectivity. However, in ASD, the effect of 5-HTTLPR on the default network is unknown. We hypothesized that 5-HTTLPR's influence on posterior-anterior default network connectivity strength as well as on age-related changes in connectivity differs in the ASD group versus controls. Youth with ASD and healthy controls, ages 8-19, underwent a resting fMRI acquisition. Connectivity was calculated by correlating the posterior hub of the default network with all voxels. Triallelic genotype was assessed via PCR and Sanger sequencing. A genotype-by-diagnosis interaction significantly predicted posterior-anterior connectivity, such that low expressing genotypes (S/S, S/LG, LG/LG) were associated with stronger connectivity than high expressing genotypes (LA/LA, S/LA, LA/LG) in the ASD group, but the converse was true for controls. Also, youth with ASD and low expressing genotypes had greater age-related increases in connectivity values compared to those with high expressing genotypes and controls in either genotype group. Our findings suggest that the cascade of events from genetic variation to brain function differs in ASD. Also, low expressing genotypes may represent a subtype within ASD.

The objective of this study is to examine white matter microstructure using diffusion tensor imaging (DTI) in a sample of adolescents with alcohol use disorders (AUD) and no psychiatric or substance co-morbidity. Fifty adolescents with AUD and fifty non-alcohol abusing controls matched on gender and age were studied with DTI, neurocognitive testing, and a clinical assessment that included measures of alcohol use and childhood trauma. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were computed, registered to a common template, and voxel-wise statistical analysis used to assess group differences. Associations between regions of altered WM microstructure and clinical or neurocognitive measures were also assessed. Compared with controls, adolescent drinkers without co-morbid substance abuse or externalizing disorder, showed 1) no regions of significantly lower FA, 2) increased FA in WM tracts of the limbic system; 3) no MD differences; and 4) within the region of higher FA in AUD, there were no associations between FA and alcohol use, cognition, or trauma. The most important observation of this study is our failure to observe significantly smaller FA in this relatively large alcohol abuse/dependent adolescent sample. Greater FA in the limbic regions observed in this study may index a risk for adolescent AUD instead of a consequence of drinking. Drinking behavior may be reinforced in those with higher FA and perhaps greater myelination in these brain regions involved in reward and reinforcement.

Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.

Hippocampal volume (HV) decline is an important marker of psychosis and has been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation in various disorders. Given recent findings of sex differences in HPA axis function in psychosis, the current study investigated differences in HV in male and female first episode psychosis (FEP) patients and controls and the interaction of HV with the cortisol awakening response (CAR) and symptoms. Fifty-eight patients with a diagnosis of FEP (39 men, 19 women) and 27 healthy community controls (15 men, 12 women) underwent structural magnetic resonance imaging (MRI) on a 1.5 T scanner. Hippocampal volume was determined using previously established segmentation protocols. Saliva samples for cortisol assessment were collected at 0, 30 and 60 min after awakening. Psychotic symptoms were assessed with the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS) and the Global Assessment of Functioning (GAF) scale. Male patients had significantly smaller left and right HVs compared to male controls, which appeared to be secondary to global brain volume differences. However, even when controlling for overall brain size, male patients showed smaller HV compared to female patients. The CAR was significantly lower in male patients compared to male controls and female patients. Only in male patients, smaller left HV was significantly associated with a blunted CAR, and smaller HV bilaterally was related to positive psychotic symptoms and lower levels of functioning. We propose that reduced hippocampal volume and an attenuated cortisol awakening response are related markers of increased stress vulnerability in male psychosis patients and that both contribute to the unfavorable clinical picture in men.

We aimed to evaluate the clinical value of gamma oscillations in MEG for intractable neocortical epilepsy patients with cortical dysplasia by comparing gamma and interictal spike events. A retrospective analysis of MEG recordings of 30 adult neocortical epilepsy patients was performed. Gamma (30-70 Hz) and interictal spike events were independently identified, their independent or concurrent presence determined, and their source localization rates compared. Of 30 patients, gamma activities were detected in 28 patients and interictal spikes in 24 patients. Gamma events alone appeared in 5 patients, interictal spikes alone in 1 patient, and no events in 1 patient. Gamma co-occurred with interictal spikes in 20.1 ± 22.1% and interictal spikes co-occurred with gamma in 15.0 ± 19.2%. Rates of event localization within the resection cavity were significantly different (p = 0.042) between gamma (63.3 ± 32.6%) and interictal spike (47.0 ± 41.3%) events. In 4 of the 5 gamma-only patients the mean localization rate was 42.5%. Compared with the interictal spike localization rate, 4 of 9 seizure-free patients had higher gamma localization rates, 4 had the same rate, and 1 had a lower rate. Individual gamma events can be detected independently from interictal spike presence. Gamma can be localized to the resection cavity at least comparably to or more frequently than that from interictal spikes. Even when interictal spikes were undetected, gamma sources were localized to the resection cavity. Gamma oscillations may be a useful indicator of epileptogenic focus.

Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in tracts involved in emotion processing in autism spectrum disorder (ASD), but little is known regarding the nature and distribution of WM anomalies in relation to ASD trait severity in adults. Increasing evidence suggests that ASD occurs at the extreme of a distribution of social abilities. We aimed to examine WM microstructure as a potential marker for ASD symptom severity in a combined clinical-neurotypical population. SIENAX was used to estimate whole brain volume. Tract-based spatial statistics (TBSS) was used to provide a voxel-wise comparison of WM microstructure in 50 high-functioning young adults: 25 ASD and 25 neurotypical. The severity of ASD traits was measured by autism quotient (AQ); we examined regressions between DTI markers of WM microstructure and ASD trait severity. Cognitive abilities, measured by intelligence quotient, were well-matched between the groups and were controlled in all analyses. There were no significant group differences in whole brain volume. TBSS showed widespread regions of significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in ASD compared with controls. Linear regression analyses in the combined sample showed that average whole WM skeleton FA was negatively influenced by AQ (p = 0.004), whilst MD and RD were positively related to AQ (p = 0.002; p = 0.001). Regression slopes were similar within both groups and strongest for AQ social, communication and attention switching scores. In conclusion, similar regression characteristics were found between WM microstructure and ASD trait severity in a combined sample of ASD and neurotypical adults. WM anomalies were relatively more severe in the clinically diagnosed sample. Both findings suggest that there is a dimensional relationship between WM microstructure and severity of ASD traits from neurotypical subjects through to clinical ASD, with reduced coherence of WM associated with greater ASD symptoms. General cognitive abilities were independent of the relationship between WM indices and ASD traits.

People with autism spectrum disorders (ASD) may show unusual reactions to unexpected changes that appear in their environment. Although several studies have highlighted atypical auditory change processing in ASD, little is known in this disorder about the brain processes involved in visual automatic change detection. The present fMRI study was designed to localize brain activity elicited by unexpected visual changing stimuli in adults with ASD compared to controls. Twelve patients with ASD and 17 healthy adults participated in the experiment in which subjects were presented with a visual oddball sequence while performing a concurrent target detection task. Combined results across participants highlight the involvement of both occipital (BA 18/19) and frontal (BA 6/8) regions during visual change detection. However, adults with ASD display greater activity in the bilateral occipital cortex and in the anterior cingulate cortex (ACC) associated with smaller activation in the superior and middle frontal gyri than controls. A psychophysiological interaction (PPI) analysis was performed with ACC as the seed region and revealed greater functionally connectivity to sensory regions in ASD than in controls, but less connectivity to prefrontal and orbito-frontal cortices. Thus, compared to controls, larger sensory activation associated with reduced frontal activation was seen in ASD during automatic visual change detection. Atypical psychophysiological interactions between frontal and occipital regions were also found, congruent with the idea of atypical connectivity between these regions in ASD. The atypical involvement of the ACC in visual change detection can be related to abnormalities previously observed in the auditory modality, thus supporting the hypothesis of an altered general mechanism of change detection in patients with ASD that would underlie their unusual reaction to change.

Adults with attention-deficit/hyperactivity disorder (ADHD) often display executive function impairments, particularly in inhibitory control. The antisaccade task, which measures inhibitory control, requires one to suppress an automatic prosaccade toward a salient visual stimulus and voluntarily make an antisaccade in the opposite direction. ADHD patients not only have longer saccadic reaction times, but also make more direction errors (i.e., a prosaccade was executed toward the stimulus) during antisaccade trials. These deficits may stem from pathology in several brain areas that are important for executive control. Using functional MRI with a rapid event-related design, adults with combined subtype of ADHD (coexistence of attention and hyperactivity problems), who abstained from taking stimulant medication 20 h prior to experiment onset, and age-match controls performed pro- and antisaccade trials that were interleaved with pro- and anti-catch trials (i.e., instruction was presented but no target appeared, requiring no response). This method allowed us to examine brain activation patterns when participants either prepared (during instruction) or executed (after target appearance) correct pro or antisaccades. Behaviorally, ADHD adults displayed several antisaccade deficits, including longer and more variable reaction times and more direction errors, but saccade metrics (i.e., duration, velocity, and amplitude) were normal. When preparing to execute an antisaccade, ADHD adults showed less activation in frontal, supplementary, and parietal eye fields, compared to controls. However, activation in these areas was normal in the ADHD group during the execution of a correct antisaccade. Interestingly, unlike controls, adults with ADHD produced greater activation than controls in dorsolateral prefrontal cortex during antisaccade execution, perhaps as part of compensatory mechanisms to optimize antisaccade production. Overall, these data suggest that the saccade deficits observed in adults with ADHD do not result from an inability to execute a correct antisaccade but rather the failure to properly prepare (i.e., form the appropriate task set) for the antisaccade trial. The data support the view that the executive impairments, including inhibitory control, in ADHD adults are related to poor response preparation.

Advances in neonatal medicine have resulted in a larger proportion of preterm-born individuals reaching adulthood. Their increased liability to psychiatric illness and impairments of cognition and behaviour intimate lasting cerebral consequences; however, the central physiological disturbances remain unclear. Of fundamental importance to efficient brain function is the coordination and contextually-relevant recruitment of neural networks. Large-scale distributed networks emerge perinatally and increase in hierarchical complexity through development. Preterm-born individuals exhibit systematic reductions in correlation strength within these networks during infancy. Here, we investigate resting-state functional connectivity in functional magnetic resonance imaging data from 29 very-preterm (VPT)-born adults and 23 term-born controls. Neurocognitive networks were identified with spatial independent component analysis conducted using the Infomax algorithm and employing Icasso procedures to enhance component robustness. Network spatial focus and spectral power were not generally significantly affected by preterm birth. By contrast, Granger-causality analysis of the time courses of network activity revealed widespread reductions in between-network connectivity in the preterm group, particularly along paths including salience-network features. The potential clinical relevance of these Granger-causal measurements was suggested by linear discriminant analysis of topological representations of connection strength, which classified individuals by group with a maximal accuracy of 86%. Functional connections from the striatal salience network to the posterior default mode network informed this classification most powerfully. In the VPT-born group it was additionally found that perinatal factors significantly moderated the relationship between executive function (which was reduced in the VPT-born as compared with the term-born group) and generalised partial directed coherence. Together these findings show that resting-state functional connectivity of preterm-born individuals remains compromised in adulthood; and present consistent evidence that the striatal salience network is preferentially affected. Therapeutic practices directed at strengthening within-network cohesion and fine-tuning between-network inter-relations may have the potential to mitigate the cognitive, behavioural and psychiatric repercussions of preterm birth.

Binge drinking is now considered a central public health issue and is associated with emotional and interpersonal problems, but the neural implications of these deficits remain unexplored. The present study aimed at offering the first insights into the effects of binge drinking on the neural processing of vocal affect. On the basis of an alcohol-consumption screening phase (204 students), 24 young adults (12 binge drinkers and 12 matched controls, mean age: 23.8 years) were selected and performed an emotional categorisation task on morphed vocal stimuli (drawn from a morphed fear-anger continuum) during fMRI scanning. In comparison to controls, binge drinkers presented (1) worse behavioural performance in emotional affect categorisation; (2) reduced activation of bilateral superior temporal gyrus; and (3) increased activation of right middle frontal gyrus. These results constitute the first evidence of altered cerebral processing of emotional stimuli in binge drinking and confirm that binge drinking leads to marked cerebral changes, which has important implications for research and clinical practice.