Disrupted structural connectome is associated with both psychometric and real-world neuropsychological impairment in diffuse traumatic brain injury.

Traumatic brain injury (TBI) is likely to disrupt structural network properties due to diffuse white matter pathology. The present study aimed to detect alterations in structural network topology in TBI and relate them to cognitive and real-world behavioral impairment. Twenty-two people with moderate to severe TBI with mostly diffuse pathology and 18 demographically matched healthy controls were included in the final analysis. Graph theoretical network analysis was applied to diffusion tensor imaging (DTI) data to characterize structural connectivity in both groups. Neuropsychological functions were assessed by a battery of psychometric tests and the Frontal Systems Behavior Scale (FrSBe). Local connection-wise analysis demonstrated reduced structural connectivity in TBI arising from subcortical areas including thalamus, caudate, and hippocampus. Global network metrics revealed that shortest path length in participants with TBI was longer compared to controls, and that this reduced network efficiency was associated with worse performance in executive function and verbal learning. The shortest path length measure was also correlated with family-reported FrSBe scores. These findings support the notion that the diffuse form of neuropathology caused by TBI results in alterations in structural connectivity that contribute to cognitive and real-world behavioral impairment.

Fast forward: supramarginal gyrus stimulation alters time measurement.

The neural basis of temporal processing is unclear. We addressed this important issue by performing two experiments in which repetitive transcranial magnetic stimulation (rTMS) was administered in different sessions to the left or right supramarginal gyrus (SMG) or vertex; in both tasks, two visual stimuli were presented serially and subjects were asked to judge if the second stimulus was longer than the first (standard) stimulus. rTMS was presented on 50% of trials. Consistent with a previous literature demonstrating the effect of auditory clicks on temporal judgment, rTMS was associated with a tendency to perceive the paired visual stimulus as longer in all conditions. Crucially, rTMS to the right SMG was associated with a significantly greater subjective prolongation of the associated visual stimulus in both experiments. These findings demonstrate that the right SMG is an important element of the neural system underlying temporal processing and, as discussed, have implications for neural and cognitive models of temporal perception and attention.

The image of time: a voxel-wise meta-analysis.

Although there has been an explosion of interest in the neural correlates of time perception during the past decade, substantial disagreement persists regarding the structures that are relevant to interval timing. We addressed this important issue by conducting a comprehensive, voxel-wise meta-analysis using the activation likelihood estimation algorithm; this procedure models each stereotactic coordinate as a 3D Gaussian distribution, then tests the likelihood of activation across all voxels in the brain (Turkeltaub et al., 2002). We included 446 sets of activation foci across 41 studies of timing that report whole-brain analyses. We divided the data set along two dimensions: stimulus duration (sub- vs. supra-second) and nature of response (motor vs. perceptual). Our meta-analyses revealed dissociable neural networks for the processing of duration with motor or perceptual components. Sub-second timing tasks showed a higher propensity to recruit sub-cortical networks, such as the basal ganglia and cerebellum, whereas supra-second timing tasks were more likely to activate cortical structures, such as the SMA and prefrontal cortex. We also detected a differential pattern of activation likelihood in basal ganglia structures, depending on the interval and task design. Finally, a conjunction analysis revealed the SMA and right inferior frontal gyrus as the only structures with significant voxels across all timing conditions. These results suggest that the processing of temporal information is mediated by a distributed network that can be differentially engaged depending on the task requirements.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Semantic Feature Training in Combination with Transcranial Direct Current Stimulation (tDCS) for Progressive Anomia.

We examined the effectiveness of a 2-week regimen of a semantic feature training in combination with transcranial direct current stimulation (tDCS) for progressive naming impairment associated with primary progressive aphasia (N = 4) or early onset Alzheimer's Disease (N = 1). Patients received a 2-week regimen (10 sessions) of anodal tDCS delivered over the left temporoparietal cortex while completing a language therapy that consisted of repeated naming and semantic feature generation. Therapy targets consisted of familiar people, household items, clothes, foods, places, hygiene implements, and activities. Untrained items from each semantic category provided item level controls. We analyzed naming accuracies at multiple timepoints (i.e., pre-, post-, 6-month follow-up) via a mixed effects logistic regression and individual differences in treatment responsiveness using a series of non-parametric McNemar tests. Patients showed advantages for naming trained over untrained items. These gains were evident immediately post tDCS. Trained items also showed a shallower rate of decline over 6-months relative to untrained items that showed continued progressive decline. Patients tolerated stimulation well, and sustained improvements in naming accuracy suggest that the current intervention approach is viable. Future implementation of a sham control condition will be crucial toward ascertaining whether neurostimulation and behavioral treatment act synergistically or alternatively whether treatment gains are exclusively attributable to either tDCS or the behavioral intervention.

Male sexual function. Impairment after right hemisphere stroke.

If the right hemisphere is dominant for activation and this capacity is critical for normal sexual function, one might expect to find a greater incidence of impaired sexual function after right than after left hemisphere stroke. We found that the prevalence of major sexual dysfunction was significantly greater after right (9/12) than after left (4/14) hemisphere stroke in 26 men with unilateral stroke. These data are consistent with the hypothesis that activation is critical for sexual function as well as the hypothesis that the right hemisphere is dominant for sexual function.

Repetition of affective prosody in mixed transcortical aphasia.

Two patients with mixed transcortical aphasia could repeat propositional speech but not affective prosody. These findings suggest that the intact perisylvian region responsible for propositional speech does not mediate effective prosody. We propose that affective prosody is incorporated into propositional speech by means of an interhemispheric mechanism and that the failure of these patients to repeat affective prosody was caused by a disconnection of the left perisylvian structures from the right hemisphere structures thought to mediate affective prosody.

Frontal verbal amnesia. Phonological amnesia.

Although aphasic patients with frontal lobe damage may demonstrate impaired retention of verbal material, significant anterograde memory disturbances have not, to our knowledge, been reported with a minor Broca's aphasia. We describe a patient with minor Broca's aphasia who exhibited an unusual and profound anterograde memory disturbance, especially for phonologically specified stimuli. We suggest that this disturbance is attributable to an impairment in the volitional, controlled search of stored phonological information.

Reduction in cerebral activation after right hemisphere stroke.

Destruction or disconnection of specific neuronal structures or failure to activate those structures may impair brain function. Because the right hemisphere seems dominant for mediating arousal, which is an important determinant of the capacity for cerebral activation, we predicted that subjects with right hemisphere damage would have a greater reduction in the capacity for cerebral activation than subjects with left hemisphere damage. A paradigm requiring that two simple tasks be performed singly and simultaneously was used to assess the capacity for activation. Subjects with right hemisphere damage had significantly greater impairment in the capacity for cerebral activation than subjects with left hemisphere damage. This impairment may partly explain the associations between right hemisphere damage and decreased ability to perform certain analytic and linguistic tasks.

Comprehension of affective and nonaffective prosody.

We studied patients with damage of either the right (RHD) or left hemisphere (LHD) and control subjects to determine whether the RHD patients had a global or limited prosodic defect. Compared with LHD patients and controls, RHD subjects had decreased comprehension of emotional prosody. Both LHD and RHD groups had more impaired comprehension of propositional prosody than controls, but the RHD and LHD groups did not differ. The right hemisphere, therefore, seems to be dominant for comprehending emotional prosody but not propositional prosody.

Reading: selective sparing of closed-class words in Wernicke's aphasia.

One aspect of Broca's aphasia, induced by anterior perisylvian lesions, is an inability to read closed-class words (eg, articles, prepositions) with a preserved ability to read open-class words (eg, nouns, verbs). We examined a man with profound Wernicke's aphasia induced by an infarct of the posterior portion of the superior temporal gyrus (Wernicke's area). He could not read substantive words or pronounceable nonwords but could read closed-class words. These observations suggest that the reading of closed- and open-class words is mediated by separable systems. Whereas the anterior perisylvian region appears to be important in reading functional words, the posterior perisylvian region is important in reading substantive words.

Pure word deafness after bilateral primary auditory cortex infarcts.

In pure word deafness, comprehension and repetition of speech are impaired, but reading, writing, and spontaneous speech are preserved. Pure word deafness is distinguished from generalized auditory agnosia by the preserved ability to recognize environmental sounds. We examined a patient with pure word deafness associated with bilateral infarctions of the primary auditory cortex, who could use auditory affective intonation to enhance comprehension. The primary auditory cortex seems to be essential for comprehending speech, but comprehension of nonverbal sounds and affective prosody may be mediated by other cerebral structures such as the auditory association cortex.

Pain and the body schema: effects of pain severity on mental representations of movement.

Previous research suggests that response times for imagined movements provide a sensitive measure of the integrity of the motor system. In a group of 12 patients with chronic unilateral arm pain, the authors demonstrate that response times for imagined movements are influenced by the severity of pain. Simulated large-amplitude arm movements were slower for the painful as compared with the unaffected arms before, but not after, effective music therapy entrainment, suggesting that mental representations of movement are influenced by the current state of nociceptive feedback.

Directional hypokinesia: prolonged reaction times for leftward movements in patients with right hemisphere lesions and neglect.

Patients with hemispatial neglect perform activities poorly in the hemispace contralateral to the lesion. We postulate that hemispatial neglect induced by right hemisphere lesions may be associated with a directional hypokinesia: initiation of movements toward the hemispace contralateral to the lesion is affected more than movements toward the lesion. We tested 6 patients with hemispatial neglect caused by right hemisphere damage, 7 with left hemisphere damage and no neglect, and 12 controls. Patients with left hemispatial neglect initiated responses to left hemispace more slowly than toward right hemispace.

Spatial influences on motor and language function.

In subjects with parietal lobe lesions, performance on motor and language tasks differed as a function of the side of space to which subjects directed their attention or acted. Subjects with left parietal lesions performed better when attention was directed to stimuli in left hemispace (that is, the left side of their environment), and those with right parietal lesions showed a similar effect when attending to stimuli in right hemispace. Hemispace effects were not observed in subjects with lesions located elsewhere in the cerebral hemispheres, or in subjects with subcortical lesions. These data are consistent with the view that not only motor but also cognitive operations such as language, which do not appear to have any intrinsic spatial organization, are maintained in registration with spatial systems, and that this attention-requiring linkage confers a processing advantage.

Neglect of chimeric figures: two halves are better than a whole.

From a group of 22 patients with neglect, we identified five patients who neglected the left sides of "chimeric" figures composed of the conjoined right and left halves of drawings of two different objects; these subjects reported the left half-drawing significantly more accurately when a gap was introduced between the chimeric halves. The improvement in the "gap" condition cannot be attributed to the subjects' recognition that the right-sided stimuli were incomplete, as when whole figures were presented on the right along with left-sided half figures, the enhancement in reporting accuracy was maintained. For at least one patient, sufficient information was available about the neglected stimuli to support accurate recognition in a forced-choice task with foils visually similar to the targets. On the basis of these and other data, we propose that for these patients with neglect, visual processing systems subserving the registration of discrete object markers in a spatial map are at least relatively intact, but that there is an impairment in the allocation of attention to the left sides of these markers.

Impaired face and word recognition without object agnosia.

A leading account of high-level visual recognition proposes that the recognition of faces, objects, and words is mediated by two processing capacities. Words are assumed to require the capacity to represent numerous parts, whereas faces are processed wholistically. and hence require the representation of complex units. Object recognition requires the capacity to represent both numerous and complex parts. As object recognition depends upon the same processing capacities underlying face and word recognition, this account predicts that patients with severe alexia and prosopagnosia should be deficient in tests of object recognition. We report a patient who is unable to recognize words or faces, yet performs relatively well on tests of object recognition. The two-capacity theory cannot accommodate this pattern of performance without additional assumptions.

Phasic arousal in response to auditory warnings after traumatic brain injury.

Traumatic brain injury (TBI) is believed to have adverse effects on attention, but because of the multifaceted nature of the arousal and attentional network, the precise impact of TBI on various subcomponents of this network remains controversial. As part of a larger program of research on attention in TBI, we studied the effects of auditory warning signals on accuracy, reaction time, and response bias, as indices of phasic arousal in a visual go/no-go task. Warnings were presented randomly at various pre-stimulus intervals to a sample of recently injured patients and control subjects. For each subject and performance index, we examined the time interval required to reach maximal phasic arousal, the degree of performance change occurring at this maximal point, and the ability to maintain this state of increased arousal over longer warning intervals. After adjustment for baseline differences, there were no significant differences between patients and controls in any aspect of performance. Examination of effect sizes suggested that this was not due to limited statistical power, but that any differences between groups, if present, must have been small. In contrast, in our prior research on sustained attention and observable behaviors related to attention, large group differences have been found. These data suggest that mechanisms responsible for auditorily-induced phasic arousal responses are largely preserved in severe TBI.

Sustained arousal and attention after traumatic brain injury.

Clinicians report that patients with traumatic brain injury (TBI) often have difficulty with tasks requiring sustained attention, and there are neuroanatomical and neurophysiological reasons to expect such deficits. Nevertheless, laboratory measures of sustained attention or vigilance in TBI have produced conflicting results. These inconsistencies may be due to patient heterogeneity as well as the fact that vigilance performance is dependent on highly specific features of the task design. We developed a visual vigilance task in which the influence of non-attentional factors was minimized and task difficulty for patients and controls made comparable. Performance was characterized with respect to vigilance level as well as vigilance decrement, using measures of perceptual discrimination, response bias, reaction time and reaction time variability. Twenty-six patients with recent TBI and 18 control subjects were tested on this task. A MANOVA of ranked scores revealed significantly different patient and control performance overall. Initial level of performance (vigilance level) was slower and more variable for patients than controls, and patients showed more conservative response biases. Deterioration over time (vigilance decrement) was steeper for patients than controls for reaction time, reaction time variability, and response bias. Deterioration in accuracy (D') did not differ significantly between patients and controls. Performance was not related to available measures of injury severity. Hypotheses relating arousal mechanisms to vigilance performance are discussed.

Comprehension of emotional prosody following unilateral hemispheric lesions: processing defect versus distraction defect.

Two studies were conducted in order to determine whether the poor performance of RHD patients on emotional prosody tasks could be attributed to a defect in perceiving/categorizing emotional prosody (processing defect) or to a problem in being distracted by the semantic content of affectively intoned sentences (distraction defect). In one study, patients with RHD, LHD or NHD listened to affectively intoned sentences in which the semantic content was congruent or incongruent with the emotional prosody. In a second study, the patients listened to affectively intoned sentences that had been speech filtered or unfiltered. Findings from these studies indicate that both processing and distraction defects are present in RHD patients.