Functional Contributions of the Arcuate Fasciculus to Language Processing.

Current evidence strongly suggests that the arcuate fasciculus (AF) is critical for language, from spontaneous speech and word retrieval to repetition and comprehension abilities. However, to further pinpoint its unique and differential role in language, its anatomy needs to be explored in greater detail and its contribution to language processing beyond that of known cortical language areas must be established. We address this in a comprehensive evaluation of the specific functional role of the AF in a well-characterized cohort of individuals with chronic aphasia (n = 33) following left hemisphere stroke. To evaluate macro- and microstructural integrity of the AF, tractography based on the constrained spherical deconvolution model was performed. The AF in the left and right hemispheres were then manually reconstructed using a modified 3-segment model (Catani et al., 2005), and a modified 2-segment model (Glasser and Rilling, 2008). The normalized volume and a measure of microstructural integrity of the long and the posterior segments of the AF were significantly correlated with language indices while controlling for gender and lesion volume. Specific contributions of AF segments to language while accounting for the role of specific cortical language areas - inferior frontal, inferior parietal, and posterior temporal - were tested using multiple regression analyses. Involvement of the following tract segments in the left hemisphere in language processing beyond the contribution of cortical areas was demonstrated: the long segment of the AF contributed to naming abilities; anterior segment - to fluency and naming; the posterior segment - to comprehension. The results highlight the important contributions of the AF fiber pathways to language impairments beyond that of known cortical language areas. At the same time, no clear role of the right hemisphere AF tracts in language processing could be ascertained. In sum, our findings lend support to the broader role of the left AF in language processing, with particular emphasis on comprehension and naming, and point to the posterior segment of this tract as being most crucial for supporting residual language abilities.

Neural Underpinnings of Proactive Interference in Working Memory: Evidence From Patients With Unilateral Lesions.

Proactive interference in working memory refers to the fact that memory of past experiences can interfere with the ability to hold new information in working memory. The left inferior frontal gyrus (LIFG) has been proposed to play an important role in resolving proactive interference in working memory. However, the role of white matter pathways and other cortical regions has been less investigated. Here we investigated proactive interference in working memory using the Recent Probes Test (RPT) in 15 stroke patients with unilateral chronic lesions in left (n = 7) or right (n = 2) prefrontal cortex (PFC), or left temporal cortex (n = 6). We examined the impact of lesions in both gray and white matter regions on the size of the proactive interference effect. We found that patients with left PFC lesions performed worse overall, but the proactive interference effect in this patient group was comparable to that of patients with right PFC lesions, temporal lobe lesions, and controls. Interestingly, the size of the interference effect was significantly correlated with the degree of damage in the extreme/external capsule and marginally correlated with the degree of damage in the inferior frontal occipital fasciculus (IFOF). These findings suggests that ventral white matter pathways connecting the LIFG to left posterior regions play a role in resolving proactive interference in working memory. This effect was particularly evident in one patient with a very large interference effect (>3 SDs above controls) who had mostly spared LIFG, but virtually absent ventral white matter pathways (i.e., passing through the extreme/external capsules and IFOF). This case study further supports the idea that the role of the LIFG in resolving interference in working memory is dependent on connectivity with posterior regions via ventral white matter pathways.

Voxel-based lesion analysis of brain regions underlying reading and writing.

The neural basis of reading and writing has been a source of inquiry as well as controversy in the neuroscience literature. Reading has been associated with both left posterior ventral temporal zones (termed the "visual word form area") as well as more dorsal zones, primarily in left parietal cortex. Writing has also been associated with left parietal cortex, as well as left sensorimotor cortex and prefrontal regions. Typically, the neural basis of reading and writing are examined in separate studies and/or rely on single case studies exhibiting specific deficits. Functional neuroimaging studies of reading and writing typically identify a large number of activated regions but do not necessarily identify the core, critical hubs. Last, due to constraints on the functional imaging environment, many previous studies have been limited to measuring the brain activity associated with single-word reading and writing, rather than sentence-level processing. In the current study, the brain correlates of reading and writing at both the single- and sentence-level were studied in a large sample of 111 individuals with a history of chronic stroke using voxel-based lesion symptom mapping (VLSM). VLSM provides a whole-brain, voxel-by-voxel statistical analysis of the role of distinct regions in a particular behavior by comparing performance of individuals with and without a lesion at every voxel. Rather than comparing individual cases or small groups with particular behavioral dissociations in reading and writing, VLSM allowed us to analyze data from a large, well-characterized sample of stroke patients exhibiting a wide range of reading and writing impairments. The VLSM analyses revealed that reading was associated with a critical left inferior temporo-occipital focus, while writing was primarily associated with the left supramarginal gyrus. Separate VLSM analyses of single-word versus sentence-level reading showed that sentence-level reading was uniquely associated with anterior to mid-portions of the middle and superior temporal gyri. Both single-word and sentence-level writing overlapped to a great extent in the left supramarginal gyrus, but sentence-level writing was associated with additional underlying white matter pathways such as the internal capsule. These findings suggest that critical aspects of reading and writing processes diverge, with reading relying critically on the ventral visual recognition stream and writing relying on a dorsal visuo-spatial-motor stream.

Dissociation between working memory performance and proactive interference control in post-traumatic stress disorder.

Deficits in working memory (WM) and cognitive control processes have been reported in post-traumatic stress disorder (PTSD), in addition to clinical symptoms such as hypervigilance, re-experiencing, and avoidance of trauma reminders. Given the uncontrollable nature of intrusive memories, an important question is whether PTSD is associated with altered control of interference in WM. Some studies also suggest that episodic memory shows a material-specific dissociation in PTSD, with greater impairments in verbal memory and relative sparing of nonverbal memory. It is unclear whether this dissociation applies to WM, as no studies have used identical task parameters across material. Here we tested 29 combat Veterans with PTSD and 29 age-matched control Veterans on a recent probes WM task with words and visual patterns in separate blocks. Participants studied four-item sets, followed by a probe stimulus that had been presented in the previous set (recent probe) or not (nonrecent probe). Participants with PTSD made more errors than controls, and this decrement was similar for verbal and visual stimuli. Proactive interference from items recently presented, but no longer relevant, was not significantly different in the PTSD group and showed no relationship to re-experiencing symptom severity. These results demonstrate that PTSD is not reliably associated with increased intrusions of irrelevant representations into WM when non-emotional stimuli are used. Future studies that use trauma-related material may provide insight into the flashbacks and intrusive thoughts that plague those with PTSD.

Not Just Language: Persisting Lateralized Visuospatial Impairment after Left Hemisphere Stroke.

OBJECTIVES: Imbalances in spatial attention are most often associated with right hemisphere brain injury. This report assessed 25 chronic left hemisphere stroke patients for attentional bias. METHODS: Participants were evaluated with a computerized visual search task and a standardized neuropsychological assessment known as the Behavioral Inattention Test (BITC). Twenty age-matched controls were also tested. RESULTS: Although little to no attentional impairment was observed on the BITC, the computerized visual search task revealed statistically significant contralesional attentional impairment in the left hemisphere stroke group. Specifically, these participants required 208 ms more viewing time, on average, to reliably detect visual targets on the right side of the display compared to detection on the left side, while controls showed a difference of only 8 ms between the two sides. CONCLUSIONS: The observation of significant leftward visuospatial bias in this chronic stroke group provides further evidence that the left hemisphere also plays a role in the balance of visual attention across space. These results have implications for left hemisphere patients who are often not screened for visuospatial problems, as well as for theories of visual attention which have primarily emphasized the role of the right hemisphere. (JINS, 2016, 22, 695-704).

Diffusion properties of cortical and pericortical tissue: regional variations, reliability and methodological issues.

Characterizing the diffusion properties of cortical tissue is complicated by intersubject variability in the relative locations of gyri and sulci. Here we extend methods of measuring the average diffusion properties of gyral and sulcal structures after they have been aligned to a common template of cortical surface anatomy. Diffusion tensor image (DTI) data were gathered from 82 young subjects and co-registered with high-resolution T1 images that had been inflated and co-registered to a hemispherically unified spherical coordinate system based on FreeSurfer. We analyzed fractional anisotropy (FA), mean diffusivity (MD) and the novel quantity of cortical primary diffusion direction (cPDD) at five surfaces parallel to the white/gray junction, spanning approximately 5 mm from the pial surface into white matter. FA increased with increasing depth, whereas MD and cPDD were reduced. There were highly significant and reliable regional differences in FA, MD and cPDD as well as systematic differences between cortical lobes and between the two hemispheres. The influence of nearby cortical spinal fluid (CSF), local cortical curvature and thickness, and sulcal depth was also investigated. We found that FA correlated significantly with cortical curvature and sulcal depth, while MD was strongly influenced by nearby CSF. The measurement of FA, MD and cPDD near the cortical surface clarifies the organization of fiber projections to and from the cortex.

The neural architecture of the language comprehension network: converging evidence from lesion and connectivity analyses.

While traditional models of language comprehension have focused on the left posterior temporal cortex as the neurological basis for language comprehension, lesion and functional imaging studies indicate the involvement of an extensive network of cortical regions. However, the full extent of this network and the white matter pathways that contribute to it remain to be characterized. In an earlier voxel-based lesion-symptom mapping analysis of data from aphasic patients (Dronkers et al., 2004), several brain regions in the left hemisphere were found to be critical for language comprehension: the left posterior middle temporal gyrus, the anterior part of Brodmann's area 22 in the superior temporal gyrus (anterior STG/BA22), the posterior superior temporal sulcus (STS) extending into Brodmann's area 39 (STS/BA39), the orbital part of the inferior frontal gyrus (BA47), and the middle frontal gyrus (BA46). Here, we investigated the white matter pathways associated with these regions using diffusion tensor imaging from healthy subjects. We also used resting-state functional magnetic resonance imaging data to assess the functional connectivity profiles of these regions. Fiber tractography and functional connectivity analyses indicated that the left MTG, anterior STG/BA22, STS/BA39, and BA47 are part of a richly interconnected network that extends to additional frontal, parietal, and temporal regions in the two hemispheres. The inferior occipito-frontal fasciculus, the arcuate fasciculus, and the middle and inferior longitudinal fasciculi, as well as transcallosal projections via the tapetum were found to be the most prominent white matter pathways bridging the regions important for language comprehension. The left MTG showed a particularly extensive structural and functional connectivity pattern which is consistent with the severity of the impairments associated with MTG lesions and which suggests a central role for this region in language comprehension.

Multimodal surface-based morphometry reveals diffuse cortical atrophy in traumatic brain injury.

BACKGROUND: Patients with traumatic brain injury (TBI) often present with significant cognitive deficits without corresponding evidence of cortical damage on neuroradiological examinations. One explanation for this puzzling observation is that the diffuse cortical abnormalities that characterize TBI are difficult to detect with standard imaging procedures. Here we investigated a patient with severe TBI-related cognitive impairments whose scan was interpreted as normal by a board-certified radiologist in order to determine if quantitative neuroimaging could detect cortical abnormalities not evident with standard neuroimaging procedures. METHODS: Cortical abnormalities were quantified using multimodal surfaced-based morphometry (MSBM) that statistically combined information from high-resolution structural MRI and diffusion tensor imaging (DTI). Normal values of cortical anatomy and cortical and pericortical DTI properties were quantified in a population of 43 healthy control subjects. Corresponding measures from the patient were obtained in two independent imaging sessions. These data were quantified using both the average values for each lobe and the measurements from each point on the cortical surface. The results were statistically analyzed as z-scores from the mean with a p < 0.05 criterion, corrected for multiple comparisons. False positive rates were verified by comparing the data from each control subject with the data from the remaining control population using identical statistical procedures. RESULTS: The TBI patient showed significant regional abnormalities in cortical thickness, gray matter diffusivity and pericortical white matter integrity that replicated across imaging sessions. Consistent with the patient's impaired performance on neuropsychological tests of executive function, cortical abnormalities were most pronounced in the frontal lobes. CONCLUSIONS: MSBM is a promising tool for detecting subtle cortical abnormalities with high sensitivity and selectivity. MSBM may be particularly useful in evaluating cortical structure in TBI and other neurological conditions that produce diffuse abnormalities in both cortical structure and tissue properties.

Left inferior frontal gyrus is critical for response inhibition.

BACKGROUND: Lesion studies in human and non-human primates have linked several different regions of prefrontal cortex (PFC) with the ability to inhibit inappropriate motor responses. However, recent functional neuroimaging studies have specifically implicated right inferior PFC in response inhibition. Right frontal dominance for inhibitory motor control has become a commonly accepted view, although support for this position has not been consistent. Particularly conspicuous is the lack of data on the importance of the homologous region in the left hemisphere. To investigate whether the left inferior frontal gyrus (IFG) is critical for response inhibition, we used neuropsychological methodology with carefully characterized brain lesions in neurological patients. RESULTS: Twelve individuals with damage in the left IFG and the insula were tested in a Go/NoGo response inhibition task. In alternating blocks, the difficulty of response inhibition was easy (50% NoGo trials) or hard (10% NoGo trials). Controls showed the predicted pattern of faster reaction times and more false alarm errors in the hard condition. Left IFG patients had higher error rates than controls in both conditions, but were more impaired in the hard condition, when a greater degree of inhibitory control was required. In contrast, a patient control group with orbitofrontal cortex lesions showed intact performance. CONCLUSION: Recent neuroimaging studies have focused on a highly specific association between right IFG and inhibitory control. The present results indicate that the integrity of left IFG is also critical for successful implementation of inhibitory control over motor responses. Our findings demonstrate the importance of obtaining converging evidence from multiple methodologies in cognitive neuroscience.

Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging.

BACKGROUND: Schizophrenia is associated with deficits in using context to establish prepotent responses in complex paradigms and failures to inhibit prepotent responses once established. OBJECTIVE: To assess prepotent response establishment and inhibition in patients with schizophrenia using event-related brain potential (ERP) and functional magnetic resonance imaging (fMRI) in a simple NoGo task. To combine fMRI and ERP data to focus on fMRI activations associated with the brief (approximately 200 ms) moment of context updating reflected in the NoGo P300 ERP component. DESIGN AND SETTING: We collected ERP and fMRI data while subjects performed a NoGo task requiring a speedy button press to X stimuli (P=.88) but not to K stimuli (P=.12). The ERPs were collected at the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif; fMRIs were collected at Stanford University, Stanford, Calif. PARTICIPANTS: We recruited patients with DSM-IV schizophrenia (n=11) from the community and the VA hospital and sex- and age-matched healthy control subjects (n=11) from the community. MAIN OUTCOME MEASURES: Behavioral accuracy, P300 amplitudes and latencies, and fMRI activations suggested that patients with schizophrenia did not establish as strong a prepotent tendency to respond to the Go stimulus as healthy subjects. In healthy subjects, NoGo P300 was related to activations in the anterior cingulate cortex, dorsal lateral prefrontal cortex, and right inferior parietal lobule and caudate nucleus, perhaps reflecting conflict experienced when withholding a response, control needed to inhibit a response, and stopping a response in action, respectively. In patients with schizophrenia, NoGo P300 was modestly related to activations in the anterior cingulate cortex, which is consistent with experiencing conflict. CONCLUSIONS: The difference in ERP and fMRI responses to Go and NoGo stimuli suggested that inhibiting a response was easier for patients with schizophrenia than for healthy subjects. Correlations of P300 and fMRI data suggested that patients with schizophrenia and healthy subjects used different neural structures to inhibit responses, with healthy subjects using a more complex system.

Are impairments of action monitoring and executive control true dissociative dysfunctions in patients with schizophrenia?

OBJECTIVE: Impaired self-monitoring is considered a critical deficit of schizophrenia. The authors asked whether this is a specific and isolable impairment or is part of a global disturbance of cognitive and attentional functions. METHOD: Internal monitoring of erroneous actions, as well as three components of attentional control (conflict resolution, set switching, and preparatory attention) were assessed during performance of a single task by eight high-functioning patients with schizophrenia and eight comparison subjects. RESULTS: The patients exhibited no significant dysfunction of attentional control during task performance. In contrast, their ability to correct errors without external feedback and, by inference, to self-monitor their actions was markedly compromised. CONCLUSIONS: This finding suggests that dysfunction of self-monitoring in schizophrenia does not necessarily reflect a general decline in cognitive function but is evidence of disproportionately pronounced impairment of action monitoring, which may be mediated by a distinct subsystem within the brain's executive attention networks.

Dissociation between conflict detection and error monitoring in the human anterior cingulate cortex.

The relative importance of the anterior cingulate cortex (ACC) for the detection and resolution of response conflicts versus its role in error monitoring remains under debate. One disputed issue is whether conflict detection and error monitoring can be viewed as unitary functions performed by the same region of the ACC, or whether these processes can be dissociated functionally and anatomically. We used a combination of electrophysiological and neuropsychological methods to assess these competing hypotheses. A neurological patient with a rare focal lesion of rostral-to-middorsal ACC was tested in an event-related potential study designed to track the time course of neural activity during conflicts and erroneous responses. Compared with controls, the error-related negativity component after incorrect responses was attenuated in the patient, accompanied by lower error-correction rates. Conversely, the stimulus-locked component on correct conflict trials, the N450, was enhanced, and behavioral performance was impaired. We hypothesize that intact regions of lateral prefrontal cortex were able to detect response conflict, but damage to the dorsal ACC impaired response inhibition, which may be due to disconnection from cingulate and supplementary motor areas. The results implicate rostral-dorsal ACC in error monitoring and suggest this function can be dissociated from conflict-detection processes.