Reliability of White Matter Microstructural Changes in HIV Infection: Meta-Analysis and Confirmation.

BACKGROUND: Diffusion tensor imaging has been widely used to measure HIV effects on white matter microarchitecture. While many authors have reported reduced fractional anisotropy and increased mean diffusivity in HIV, quantitative inconsistencies across studies are numerous. PURPOSE: Our aim was to evaluate the consistency across studies of HIV effects on DTI measures and then examine the DTI reliability in a longitudinal seropositive cohort. DATA SOURCES: Published studies and investigators. STUDY SELECTION: The meta-analysis included 16 cross-sectional studies reporting fractional anisotropy and 12 studies reporting mean diffusivity in the corpus callosum. DATA ANALYSIS: Random-effects meta-analysis was used to estimate study standardized mean differences and heterogeneity. DTI longitudinal reliability was estimated in seropositive participants studied before and 3 and 6 months after beginning treatment. DATA SYNTHESIS: Meta-analysis revealed lower fractional anisotropy (standardized mean difference, -0.43; P < .001) and higher mean diffusivity (standardized mean difference, 0.44; P < .003) in seropositive participants. Nevertheless, between-study heterogeneity accounted for 58% and 66% of the observed variance (P < .01). In contrast, the longitudinal cohort fractional anisotropy was higher and mean diffusivity was lower in seropositive participants (both, P < .001), and fractional anisotropy and mean diffusivity measures were very stable during 6 months, with intraclass correlation coefficients all >0.96. LIMITATIONS: Many studies pooled participants with varying treatments, ages, and disease durations. CONCLUSIONS: HIV effects on WM microstructure had substantial variations that could result from acquisition, processing, or cohort-selection differences. When acquisition parameters and processing were carefully controlled, the resulting DTI measures did not show high temporal variation. HIV effects on WM microstructure may be age-dependent. The high longitudinal reliability of DTI WM microstructure measures makes them promising disease-activity markers.

An adaptive randomized trial of dialectical behavior therapy and cognitive behavior therapy for binge-eating.

BACKGROUND: Early weak treatment response is one of the few trans-diagnostic, treatment-agnostic predictors of poor outcome following a full treatment course. We sought to improve the outcome of clients with weak initial response to guided self-help cognitive behavior therapy (GSH). METHOD: One hundred and nine women with binge-eating disorder (BED) or bulimia nervosa (BN) (DSM-IV-TR) received 4 weeks of GSH. Based on their response, they were grouped into: (1) early strong responders who continued GSH (cGSH), and early weak responders randomized to (2) dialectical behavior therapy (DBT), or (3) individual and additional group cognitive behavior therapy (CBT+). RESULTS: Baseline objective binge-eating-day (OBD) frequency was similar between DBT, CBT+ and cGSH. During treatment, OBD frequency reduction was significantly slower in DBT and CBT+ relative to cGSH. Relative to cGSH, OBD frequency was significantly greater at the end of DBT (d = 0.27) and CBT+ (d = 0.31) although these effects were small and within-treatment effects from baseline were large (d = 1.41, 0.95, 1.11, respectively). OBD improvements significantly diminished in all groups during 12 months follow-up but were significantly better sustained in DBT relative to cGSH (d = -0.43). At 6- and 12-month follow-up assessments, DBT, CBT and cGSH did not differ in OBD. CONCLUSIONS: Early weak response to GSH may be overcome by additional intensive treatment. Evidence was insufficient to support superiority of either DBT or CBT+ for early weak responders relative to early strong responders in cGSH; both were helpful. Future studies using adaptive designs are needed to assess the use of early response to efficiently deliver care to large heterogeneous client groups.

Efficacy of Double-Blind Peer Review in an Imaging Subspecialty Journal.

BACKGROUND AND PURPOSE: Many scientific journals use double-blind peer review to minimize potential reviewer bias concerning publication recommendations. However, because neuroradiology is a relatively small subspecialty, this process may be limited by prior knowledge of the authors' work or associated institutions. We sought to investigate the efficacy of reviewer blinding and determine the impact that unblinding may have on manuscript acceptance. MATERIALS AND METHODS: For manuscripts submitted to the American Journal of Neuroradiology (AJNR) from January through June 2015, reviewers completed a brief anonymous questionnaire after submitting their evaluations, assessing whether they were familiar with the research or had knowledge of the authors or institutions from which the work originated. RESULTS: The response rate for 1079 questionnaires was 98.8%; 12.9% of reviewers knew or suspected that they knew authors, and 15.3% knew or suspected that they knew the associated institutions. Reviewers correctly identified the authors in 90.3% of cases and correctly stated the institutions in 86.8% of cases. Unblinding resulted from self-citation in 34.1% for both authorship and institutions. The acceptance rate when reviewers knew or suspected that they knew the authors was 57/137 (41.6%) and 262/929 (28.2%) when reviewers did not. The acceptance rate when reviewers knew or suspected that they knew the institutions was 60/163 (36.8%) and 259/903 (28.7%) when they did not. The Fisher exact test showed that author (P < .038) and institution (P < .039) familiarity was associated with greater manuscript acceptance. CONCLUSIONS: While the AJNR process of double-blind peer review minimizes reviewer bias, perceived knowledge of the author and institution is associated with a higher rate of manuscript acceptance.

Speech acquisition predicts regions of enhanced cortical response to auditory stimulation in autism spectrum individuals.

A continuum of phenotypes makes up the autism spectrum (AS). In particular, individuals show large differences in language acquisition, ranging from precocious speech to severe speech onset delay. However, the neurological origin of this heterogeneity remains unknown. Here, we sought to determine whether AS individuals differing in speech acquisition show different cortical responses to auditory stimulation and morphometric brain differences. Whole-brain activity following exposure to non-social sounds was investigated. Individuals in the AS were classified according to the presence or absence of Speech Onset Delay (AS-SOD and AS-NoSOD, respectively) and were compared with IQ-matched typically developing individuals (TYP). AS-NoSOD participants displayed greater task-related activity than TYP in the inferior frontal gyrus and peri-auditory middle and superior temporal gyri, which are associated with language processing. Conversely, the AS-SOD group only showed enhanced activity in the vicinity of the auditory cortex. We detected no differences in brain structure between groups. This is the first study to demonstrate the existence of differences in functional brain activity between AS individuals divided according to their pattern of speech development. These findings support the Trigger-threshold-target model and indicate that the occurrence of speech onset delay in AS individuals depends on the location of cortical functional reallocation, which favors perception in AS-SOD and language in AS-NoSOD.

Enhanced mental image mapping in autism.

The formation and manipulation of mental images represents a key ability for successfully solving visuospatial tasks like Wechsler's Block Design or visual reasoning problems, tasks where autistics perform at higher levels than predicted by their Wechsler IQ. Visual imagery can be used to compare two mental images, allowing judgment of their relative properties. To examine higher visual processes in autism, and their possible role in explaining autistic visuospatial peaks, we carried out two mental imagery experiments in 23 autistic and 14 age and IQ matched, non-autistic adolescents and adults. Among autistics, 11 had significantly higher Block Design scores than predicted by their IQ. Experiment 1 involved imagining a letter inside a circle, followed by a decision concerning which of two highlighted portions of the circle would contain the greater proportion of the letter. Experiment 2 involved four classic mental rotation tasks utilizing two- and three-dimensional geometric figures, hands and letters. Autistics were more accurate in the formation and comparison of mental images than non-autistics. Autistics with a Block Design peak outperformed other participants in both speed and accuracy of mental rotation. Also, Performance IQ and Block Design scores were better predictors of mental rotation accuracy in autistic compared to non-autistic participants. The ability to form, access and manipulate visual mental representations may be more developed in autistics. We propose two complementary mechanisms to explain these processing advantages: (1) a global advantage in perceptual processing, discussed in the framework of the enhanced perceptual functioning model, and (2) particular strengths in veridical mapping, the ability to efficiently detect isomorphisms among entities and then to use these mappings to process stimulus characteristics, thereby facilitating judgments about their differences.

Attention to single letters activates left extrastriate cortex.

Brain imaging studies examining the component processes of reading using words, non-words, and letter strings frequently report task-related activity in the left extrastriate cortex. Processing of these linguistic materials involves varying degrees of semantic, phonological, and orthographic analysis that are sensitive to individual differences in reading skill and history. In contrast, single letter processing becomes automatized early in life and is not modulated by later linguistic experience to the same degree as are words. In this study, skilled readers attended to different aspects (single letters, symbols, and colors) of an identical stimulus set during separate sessions of functional magnetic resonance imaging (fMRI). Whereas activation in some portions of ventral extrastriate cortex was shared by attention to both alphabetic and non-alphabetic features, a letter-specific area was identified in a portion of left extrastriate cortex (Brodmann's Area 37), lateral to the visual word form area. Our results demonstrate that while minimizing activity related to word-level lexical properties, cortical responses to letter recognition can be isolated from figural and color characteristics of simple stimuli. The practical utility of this finding is discussed in terms of early identification of reading disability.

Activation of language cortex with automatic speech tasks.

OBJECTIVE: To identify automatic speech tasks that reliably demonstrate increased regional cerebral blood flow (rCBF) in Broca's and Wernicke's areas of the cortex using PET. BACKGROUND: Localizing language with direct cortical stimulation mapping requires that patients have a stable baseline on tests that engage eloquent cortex. For dysphasic patients or younger children, automatic speech tasks such as counting are often used in lieu of more complex language tests. Evidence from both lesion and neuroimaging studies suggests that these tasks may not adequately engage language cortices. In this study, we examined rCBF during automatic oromotor and speech tasks of varying complexity to identify those eliciting increased CBF in Broca's and Wernicke's areas. METHODS: Eight normal volunteers underwent PET during rest, tongue movements, and three automatic speech tasks: repeating a phoneme sequence, repeating the months of the year, and reciting a memorized prose passage. Images were averaged across subjects and compared across tasks for regional localization and laterality. RESULTS: Whereas all activation tasks produced increased relative CBF in brain regions that correlated with articulation and auditory processing, only the two tasks that used real words (versus phonemes) showed left-lateralized rCBF increases in posterior superior temporal lobe (Wernicke's area), and only the prose repetition task produced left lateralized activity in Broca's area. CONCLUSIONS: Whereas automatic speech typically does not engage language cortex, repeating a memorized prose passage showed unambiguous activation in both Broca's and Wernicke's areas. These results caution against the use of common automatic speech tasks for mapping eloquent cortex and suggest an alternative task for those with poor language abilities or acquired dysphasia who cannot perform standardized language tests reliably.

Utilizing hemodynamic delay and dispersion to detect fMRI signal change without auditory interference: the behavior interleaved gradients technique.

A major problem associated with the use of functional magnetic resonance imaging (fMRI) is the attendant gradient noise, which causes undesirable auditory system stimulation. A method is presented here that delays data acquisition to a period immediately after task completion, utilizing the physiological delay and dispersion between neuronal activity and its resulting hemodynamic lag. Subjects performed finger movements with the gradients off, followed by a rest period with the gradients on. This resulted in task-related signals comparable to those obtained with concurrent task performance and image data acquisition. This behavior interleaved gradients technique may be particularly useful for the studies involving auditory stimulation or overt verbal responses.

Neural systems underlying learning and representation of global motion.

We demonstrate performance-related changes in cortical and cerebellar activity. The largest learning-dependent changes were observed in the anterior lateral cerebellum, where the extent and intensity of activation correlated inversely with psychophysical performance. After learning had occurred (a few minutes), the cerebellar activation almost disappeared; however, it was restored when the subjects were presented with a novel, untrained direction of motion for which psychophysical performance also reverted to chance level. Similar reductions in the extent and intensity of brain activations in relation to learning occurred in the superior colliculus, anterior cingulate, and parts of the extrastriate cortex. The motion direction-sensitive middle temporal visual complex was a notable exception, where there was an expansion of the cortical territory activated by the trained stimulus. Together, these results indicate that the learning and representation of visual motion discrimination are mediated by different, but probably interacting, neuronal subsystems.

Regional cerebral blood flow during auditory responsive naming: evidence for cross-modality neural activation.

One issue of continuing debate in language research concerns whether the brain holds separate representations for semantic information through the auditory vs visual modalities. Regardless of whether we hear, see or read meaningful information, our brains automatically activate both auditory and visual semantic associations to the sensory input. The prominent models for how the brain makes these cross-modality associations holds that semantic information conveyed through either sensory input modality is represented in a shared semantic system comprising the traditionally identified language areas in the brain. A few recent case reports as well as activation imaging studies, have challenged this notion by demonstrating category-specific organization within the semantic system in spatially discrete brain regions. Neither view posits a role for primary sensory cortices in semantic processing. We obtained positron emission tomographic (PET) images while subjects performed an auditory responsive naming task, an auditory analog to visual object naming. Subjects heard and responded to descriptions of concrete objects while blindfolded to prevent visual stimulation. Our results showed that, in addition to traditional language centers, auditory language input produced reciprocal activation in primary and secondary visual brain regions, just as if the language stimuli had entered in the visual modality. These findings provide evidence for a distributed semantic system in which sensory-specific semantic modules are mutually interactive, operating directly onto early sensory processing centers.

Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET.

The PET H2 15O-bolus method was used to image regional brain activity in normal human subjects during intense pain induced by intradermal injection of capsaicin and during post-capsaicin mechanical allodynia (the perception of pain from a normally non-painful stimulus). Images of regional cerebral blood flow were acquired during six conditions: (i) rest; (ii) light brushing of the forearm; (iii) forearm intradermal injection of capsaicin, (iv) and (v) the waning phases of capsaicin pain; and (vi) allodynia. Allodynia was produced by light brushing adjacent to the capsaicin injection site after ongoing pain from the capsaicin injection had completely subsided. Capsaicin treatment produced activation in many discrete brain regions which we classified as subserving four main functions: sensation-perception (primary somatosensory cortex, thalamus and insula); attention (anterior cingulate cortex); descending pain control (periaqueductal grey); and an extensive network related to sensory-motor integration (supplementary motor cortex, bilateral putamen and insula, anterior lobe and vermis of the cerebellum and superior colliculus). Comparison of the noxious and non-noxious stimuli yielded several new insights into neural organization of pain and tactile sensations. Capsaicin pain, which had no concomitant tactile component, produced little or no activation in secondary somatosensory cortex (SII), whereas light brushing produced a prominent activation of SII, suggesting a differential sensitivity of SII to tactile versus painful stimuli. The cerebellar vermis was strongly activated by capsaicin, whereas light brush and experimental allodynia produced little or no activation, suggesting a selective association with C-fibre stimulation and nociceptive second-order spinal neurons. The experimental allodynia activated a network that partially overlapped those activated by both pain and light brush alone. Unlike capsaicin-induced pain, allodynia was characterized by bilateral activation of inferior prefrontal cortex, suggesting that prefrontal responses to pain are context dependent.

A direct comparison of PET activation and electrocortical stimulation mapping for language localization.

Mapping eloquent language cortex in presurgical patients typically is accomplished using highly invasive direct cortical stimulation techniques. Functional imaging during language activation using positron emission tomography (PET) is a promising, noninvasive alternative that requires validation. In seven patients undergoing surgical evaluation for intractable epilepsy, we performed both direct cortical stimulation and PET activation mapping of language cortex using identical tasks. MRI, PET, and CT scans were coregistered to directly compare the location of language centers determined by cortical stimulation versus activation PET. We found that cortical regions that showed increased cerebral blood flow during both visual and auditory naming tasks were located in the same regions as subdural electrodes which disrupted language during electrical stimulation. Cortical regions underlying electrodes that did not disrupt language also showed no consistent changes in regional cerebral blood flow during PET activation. Used cautiously, PET activation produces language maps similar to those obtained with direct cortical stimulation, with more complete brain coverage and considerably less invasion.

The role of posterior parietal cortex in visually guided reaching movements in humans.

Positron emission tomography (PET) was used to identify the brain areas involved in visually guided reaching by measuring regional cerebral blood flow (rCBF) in six normal volunteers while they were fixating centrally and reaching with the left or right arm to targets presented in either the right or the left visual field. The PET images were registered with magnetic resonance images from each subject so that increases in rCBF could be localized with anatomical precision in individual subjects. Increased neural activity was examined in relation to the hand used to reach, irrespective of field of reach (hand effect), and the effects of target field of reach, irrespective of hand used (field effect). A separate analysis on intersubject, averaged PET data was also performed. A comparison of the results of the two analyses showed close correspondence in the areas of activation that were identified. We did not find a strict segregation of regions associated exclusively with either hand or field. Overall, significant rCBF increases in the hand and field conditions occurred bilaterally in the supplementary motor area, premotor cortex, cuneus, lingual gyrus, superior temporal cortex, insular cortex, thalamus, and putamen. Primary motor cortex, postcentral gyrus, and the superior parietal lobule (intraparietal sulcus) showed predominantly a contralateral hand effect, whereas the inferior parietal lobule showed this effect for the left hand only. Greater contralateral responses for the right hand were observed in the secondary motor areas. Only the anterior and posterior cingulate cortices exhibited strong ipsilateral hand effects. Field of reach was more commonly associated with bilateral patterns of activation in the areas with contralateral or ipsilateral hand effects. These results suggest that the visual and motor components of reaching may have a different functional organization and that many brain regions represent both limb of reach and field of reach. However, since posterior parietal cortex is connected with all of these regions, we suggest that it plays a crucial role in the integration of limb and field coordinates.

The visual deficit theory of developmental dyslexia.

Dyslexia is an impairment in reading that can result from an abnormal developmental process in the case of developmental dyslexia or cerebral insult in the case of acquired dyslexia. It has long been known that the clinical manifestations of developmental dyslexia are varied. In addition to their reading difficulties, individuals with developmental dyslexia exhibit impairments in their ability to process the phonological features of written or spoken language. Recently, it has been demonstrated with a variety of experimental approaches that these individuals are also impaired on a number of visual tasks involving visuomotor, visuospatial, and visual motion processing. The results of these studies, as well as the anatomical and physiological anomalies seen in the brains of individuals with dyslexia, suggest that the pathophysiology of developmental dyslexia is more complex than originally thought, extending beyond the classically defined language areas of the brain. Functional neuroimaging is a useful tool to more precisely delineate the pathophysiology of this reading disorder.

Abnormal processing of visual motion in dyslexia revealed by functional brain imaging.

It is widely accepted that dyslexics have deficits in reading and phonological awareness, but there is increasing evidence that they also exhibit visual processing abnormalities that may be confined to particular portions of the visual system. In primate visual pathways, inputs from parvocellular or magnocellular layers of the lateral geniculate nucleus remain partly segregated in projections to extrastriate cortical areas specialized for processing colour and form versus motion. In studies of dyslexia, psychophysical and anatomical evidence indicate an anomaly in the magnocellular visual subsystem. To investigate the pathophysiology of dyslexia, we used functional magnetic resonance imaging (fMRI) to study visual motion processing in normal and dyslexic men. In all dyslexics, presentation of moving stimuli failed to produce the same task-related functional activation in area V5/MT (part of the magnocellular visual subsystem) observed in controls. In contrast, presentation of stationary patterns resulted in equivalent activations in V1/V2 and extrastriate cortex in both groups. Although previous studies have emphasized language deficits, our data reveal differences in the regional functional organization of the cortical visual system in dyslexia.

Functional mapping of human learning: a positron emission tomography activation study of eyeblink conditioning.

Regional cerebral blood flow (rCBF) was measured using positron emission tomography during eyeblink conditioning in young adults. Subjects were scanned in three experimental conditions: delay conditioning, in which binaural tones preceded air puffs to the right eye by 400 msec; pseudoconditioning, in which presentations of tone and air puff stimuli were not correlated in time; and fixation rest, which served as a baseline control. Compared with fixation, pseudoconditioning produced rCBF increases in frontal and temporal cortex, basal ganglia, left hippocampal formation, and pons. Learning-specific activations were observed in conditioning as compared with pseudoconditioning in bilateral frontal cortex, left thalamus, right medial hippocampal formation, left lingual gyrus, pons, and bilateral cerebellum; decreases in rCBF were observed for bilateral temporal cortex, and in the right hemisphere in putamen, cerebellum, and the lateral aspect of hippocampal formation. Blood flow increased as the level of learning increased in the left hemisphere in caudate, hippocampal formation, fusiform gyrus, and cerebellum, and in right temporal cortex and pons. In contrast, activation in left frontal cortex decreased as learning increased. These functional imaging results implicate many of the same structures identified by previous lesion and recording studies of eyeblink conditioning in animals and humans and suggest that the same brain regions in animals and humans mediate multiple forms of associative learning that give meaning to a previously neutral stimulus.

Functional mapping of human memory using PET: comparisons of conceptual and perceptual tasks.

An experiment is reported in which regional cerebral blood flow (rCBF) as measured using positron emission tomography (PET) as participants performed conceptual and perceptual memory tasks. Blood flow during two conceptual tests of semantic cued recall and semantic association was compared to a control condition in which participants made semantic associations to nonstudied words. Analogously, rCBF during two perceptual tasks of word fragment cued recall and word fragment completion was compared to a word fragment nonstudied control condition. A direct comparison of conceptual and perceptual tasks showed that conceptual tasks activated medial and lateral left hemisphere in frontal and temporal regions as well as the lateral aspect of bilateral inferior parietal lobule. Perceptual tasks, in contrast, produced relatively greater activation in right frontal and temporal cortex as well as bilateral activation in more posterior regions. Comparisons of the memory tasks with their control conditions revealed memory-specific deactivations in left medial and superior temporal cortex as well as left frontal cortex for both conceptual tasks. In contrast, memory-specific deactivations for both perceptual fragment completion tests were localized in posterior regions including occipital cortex. Results from this and other functional imaging experiments provide evidence that conceptual and perceptual memory processes are subserved, at least in part, by different neurological structures in the human brain.

Locating the motor cortex on the MRI with transcranial magnetic stimulation and PET.

Transcranial magnetic stimulation with a focal coil was used to map the cortical representation of a hand muscle in four healthy subjects. In each subject, the three-dimensional locations of the magnetic stimulation positions and about 400 positions on the surface of the head were digitized. The amplitude-weighted center of gravity of each subject's map was found, and a line perpendicular to the local head surface was projected inward. The digitized heads were registered with the subjects' MRIs using the scalp contours. The coordinate transformations yielded by this process were used to map the stimulation positions and the perpendicular line into the MRIs. Brain areas imaged with positron emission tomography (PET) and 15O-labeled water, activated by movement of the same muscle, were registered with the MRIs using the brain contours. In all cases, the magnetic stimulation lines encountered the surface of the brain at the anterior lip of the central sulcus and ran along the precentral gyrus a few millimeters anterior to the central sulcus, coming within 5-22 mm of all the PET activation maxima. This technique demonstrates the accuracy of transcranial magnetic stimulation for locating the primary motor area.