The way to "left" Piazza del Popolo: damage to white matter tracts in representational neglect for places.

The ability of seeing with the mind's eye, the visual mental imagery, is peculiarly compromised in patients with representational neglect. Representational neglect affects the processing of the left side of a mental image and may selectively concern the ability to imagine places and/or objects. Right-brain damaged patients with representational neglect for places (RN+) lose the ability to imagine themselves within a familiar place and fail in transforming an egocentric representation of the environment into an allocentric one and vice-versa. A peak region located at the posterior junction between the parietal and temporal lobes has emerged as pivotal in determining representational neglect for places. Here we aimed at verifying whether white matter disconnections affecting parietal lobe, by preventing the integration of egocentric information with the allocentric one, play a role in representational neglect for places. A track-wise statistical analysis on 58 right brain damaged patients, with and without extrapersonal perceptual neglect and/or representational neglect for places, suggests that the disconnection of the superior longitudinal fasciculus and that of the posterior arcuate segment, together with the disconnection of a fronto-parietal u-shaped tract, may be crucial in determining the representational neglect for places. These results suggest that representational neglect for places emerges from a complex pattern of lesion location and disconnection that involves parietal, temporal and frontal lobes.

Cortico-thalamic disconnection in a patient with supernumerary phantom limb.

Supernumerary phantom limb (SPL) designates the experience of an illusory additional limb occurring after brain damage. Functional neuroimaging during SPL movements documented increased response in the ipsilesional supplementary motor area (SMA), premotor cortex (PMC), thalamus and caudate. This suggested that motor circuits are important for bodily related cognition, but anatomical evidence is sparse. Here, we tested this hypothesis by studying an extremely rare patient with chronic SPL, still present 3 years after a vascular stroke affecting cortical and subcortical right-hemisphere structures. Anatomical analysis included an advanced in vivo reconstruction of white matter tracts using diffusion-based spherical deconvolution. This reconstruction demonstrated a massive and relatively selective disconnection between anatomically preserved SMA/PMC and the thalamus. Our results provide strong anatomical support for the hypothesis that cortico-thalamic loops involving motor-related circuits are crucial to integrate sensorimotor processing with bodily self-awareness.

Lesion-symptom mapping of a complex figure copy task: A large-scale PCA study of the BCoS trial.

Complex figure copying is a commonly used neuropsychological test. Here we explored the neural basis of the factors underlying complex figure copying (CFC), using data from the Birmingham Cognitive Screen (BCoS) in a large group of sub-acute, ischemic stroke patients (239). We computed two analyses: in the first we assessed the contribution of co-morbid deficits (i.e. in gesture processing, object use, visual neglect, pictures naming and sustained attention) to the lesions associated with CFC. In a second analysis a Principle Component Analysis (PCA) was used to isolate different underlying task components and to link to clinical neuroimaging scans. A voxel-based morphometry (VBM) analysis showed that poor CFC performance was associated with lesions to bi-lateral thalamus, lingual, right fusiform and right inferior parietal cortices (rIPC). The latter association with the posterior parietal cortex was diminished after controlling for neglect. Follow up analysis showed the neglect partially mediated the correlation of CFC and rIPC. The PCA revealed three main underlying components: (1) a component associated with high-level motor control common to different measures of apraxia and linked to the left postcentral gyrus, the right thalamus and middle frontal gyrus; (2) a visuo-motor transformation component unique to the CFC and associated with lesions to the posterior occipital and sensory cortices; (3) a component associated with multistep object use tasks which was correlated with lesions to the left inferior frontal orbital gyrus, the right fusiform and cerebellum. Using clinical symptoms, cognitive profiles and lesion mapping we showed that beyond visual perception, CFC performance is supported by three functional networks: one for high-level motor control, a visuo-motor transformation component, and multistep object use network.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.

Clock desynchronisation: why and how?

The internal clock located in the suprachiasmatic nuclei of the anterior hypothalamus is controlled by external (environment and social life) and genetic factors. Desynchronisation of the organism occurs when the clock does no longer work in harmony with the environ- mentalfactors. Rhythm desynchronization can be related to a conflict between the clock and environmentalfactors (shift work, night shift, transmeridianflight), to inefficient synchro- nizers (aging, psychiatric diseases..), to badly received synchronizers (circadian rhythm sleep disorders with e.g delayed or advanced sleep phase syndromes), or to the use of some drugs (lithium, propofol, alcohol...). In the long term rhythm desynchronisation can result in serious illnesses and the use of resynchronizing agents like melatonin or bright light are useful to the clock resynchronization.

Mirror therapy in unilateral neglect after stroke (MUST trial): a randomized controlled trial.

OBJECTIVE: We explored the effectiveness of mirror therapy (MT) in the treatment of unilateral neglect in stroke patients. METHODS: This is an open, blinded endpoint, randomized controlled trial carried out from January 2011 to August 2013. We included stroke patients with thalamic and parietal lobe lesions with unilateral neglect 48 hours after stroke. Patients were randomized to the MT group or the control group (sham MT), and both the groups received limb activation. Patients received treatment for 1-2 hours a day 5 days a week for 4 weeks. The primary outcome was unilateral neglect assessed by a blinded assessor using the star cancellation test, the line bisection test, and a picture identification task at 1, 3, and 6 months. This study was registered at http://clinicaltrials.gov (NCT 01735877). RESULTS: Forty-eight patients were randomized to MT (n = 27) or the control group (n = 21). Improvement in scores on the star cancellation test over 6 months was greater in the MT group (mean difference 23, 95% confidence interval [CI] 19-28; p < 0.0001). Similarly, improvement in the MT group was observed in the scores on the picture identification task (mean difference 3.2, 95% CI 2.4-4.0; p < 0.0001) and line bisection test (mean difference 8.6, 95% CI 2.7-14.6; p = 0.006). CONCLUSIONS: In patients with stroke, MT is a simple treatment that improves unilateral neglect. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with neglect from thalamic and parietal lobe strokes, MT improves neglect.

In search of the disappeared half of it: 35 years of studies on representational neglect.

OBJECTIVE: Representational neglect (RN) is a neuropsychological deficit mostly occurring after right brain damage affecting the mental imagery domain. Patients suffering from RN are unable to represent, describe, or explore the contralesional side of their mental images. Since its first description in 1978, RN has been explored using different theoretical frameworks and experimental paradigms. After 35 years, the nature of its behavioral and anatomical correlates is still unclear. METHOD: We reviewed studies on RN published from 1978-2013 to systematize available knowledge and to shed light on future research directions. RESULTS: The huge variety of tests used to diagnose RN reflects the different clinical features of the deficit, which can compromise space sectors and memory storage, depending on the stimulus to be imagined, even in a dissociated fashion. RN has been frequently described after parietal, temporal, and frontal right brain lesions, even though reliable group studies are scanty. CONCLUSION: A number of priorities concerning RN were identified. Future studies might take into account several aspects of RN that are still poorly explored, starting from a more systematized investigation of RN using larger group studies. RESULTS might add pieces to the puzzle of spatial cognition and its neural basis in mental imagery, paving the way for tailored motor and cognitive rehabilitation programs.

Comparison of auditory deficits associated with neglect and auditory cortex lesions.

In contrast to lesions of the visual and somatosensory cortex, lesions of the auditory cortex are not associated with self-evident contralesional deficits. Only when two or more stimuli are presented simultaneously to the left and right, contralesional extinction has been observed after unilateral lesions of the auditory cortex. Because auditory extinction is also considered a sign of neglect, clinical separation of auditory neglect from deficits caused by lesions of the auditory cortex is challenging. Here, we directly compared a number of tests previously used for either auditory-cortex lesions or neglect in 29 controls and 27 patients suffering from unilateral auditory-cortex lesions, neglect, or both. The results showed that a dichotic-speech test revealed similar amounts of extinction for both auditory cortex lesions and neglect. Similar results were obtained for words lateralized by inter-aural time differences. Consistent extinction after auditory cortex lesions was also observed in a dichotic detection task. Neglect patients showed more general problems with target detection but no consistent extinction in the dichotic detection task. In contrast, auditory lateralization perception was biased toward the right in neglect but showed considerably less disruption by auditory cortex lesions. Lateralization of auditory-evoked magnetic fields in auditory cortex was highly correlated with extinction in the dichotic target-detection task. Moreover, activity in the right primary auditory cortex was somewhat reduced in neglect patients. The results confirm that auditory extinction is observed with lesions of the auditory cortex and auditory neglect. A distinction can nevertheless be made with dichotic target-detection tasks, auditory-lateralization perception, and magnetoencephalography.

Cognitive maps in imagery neglect.

Patients with imagery neglect (RI+) show peculiar difficulties in orienting themselves in the environment. Navigational impairments could be due to a deficit in creating or using a mental representation of the environment (Guariglia, Piccardi, Iaria, Nico, & Pizzamiglio, 2005) or, according to the BBB model (Burgess, Becker, King, & O'Keefe, 2001), to a specific deficit in a mechanism that transforms an allocentric representation into an egocentric one and vice versa. Previous studies, however, do not allow discerning between a deficit in forming or in using a cognitive map, taking no notice of the fact that these are two different abilities underlain by different neuroanatomical areas, which could be independently impaired. Furthermore, the BBB model has never been verified in a population of brain-damaged patients. Therefore, we administered two tasks that separately assess the ability to create and use a cognitive map of the environment to 28 right brain-damaged patients (4 patients with imagery neglect and 4 patients with perceptual neglect) and 11 healthy participants. RI+ patients showed no specific deficit in creating or using a cognitive map, but failed to transform an egocentric representation of the environment into an allocentric one and vice versa, as predicted by the BBB model.

Neurophysiological investigation of idiopathic acquired auditory-visual synesthesia.

We present a case of acquired auditory-visual synesthesia and its neurophysiological investigation in a healthy 42-year-old woman. She started experiencing persistent positive and intermittent negative visual phenomena at age 37 followed by auditory-visual synesthesia. Her neurophysiological investigation included video-EEG, fMRI, and MEG. Auditory stimuli (700 Hz, 50 ms duration, 0.5 s ISI) were presented binaurally at 60 db above the hearing threshold in a dark room. The patient had bilateral symmetrical auditory-evoked neuromagnetic responses followed by an occipital-evoked field 16.3 ms later. The activation of occipital cortex following auditory stimuli may represent recruitment of existing cross-modal sensory pathways.

Electrostimulation mapping of spatial neglect.

BACKGROUND: Cortical and subcortical electrostimulation mapping during awake brain surgery for tumor removal is usually used to minimize deficits. OBJECTIVE: To use electrostimulation to study neuronal substrates involved in spatial awareness in humans. METHODS: Spatial neglect was studied using a line bisection task in combination with electrostimulation mapping of the right hemisphere in 50 cases. Stimulation sites were identified with Talairach coordinates. The behavioral effects induced by stimulation, especially eye movements and deviations from the median, were quantified and compared with preoperative data and a control group. RESULTS: Composite and highly individualized spatial neglect maps were generated. Both rightward and leftward deviations were induced, sometimes in the same patient but for different stimulation sites. Group analysis showed that specific and reproducible line deviations were induced by stimulation of discrete cortical areas located in the posterior part of the right superior and middle temporal gyri, inferior parietal lobe, and inferior postcentral and inferior frontal gyri (P < .05). Fiber tracking identified stimulated subcortical areas important to spare as sections of fronto-occipital and superior longitudinal II fascicles. According to preoperative and postoperative neglect battery tests, the specificity and sensitivity of intraoperative line bisection tests were 94% and 83%, respectively. CONCLUSION: In humans, discrete cortical areas that are variable in location between individuals but mainly located within the right posterior Sylvian fissure sustain visuospatial attention specifically toward the contralateral or ipsilateral space direction. Line bisection mapping was found to be a reliable method for minimizing spatial neglect caused by brain tumor surgery.

Attention deficits following ADEM ameliorated by guanfacine.

The authors report here the case of a patient with severe deficits in arousal and sustained attention, associated with hemispatial neglect. These impairments were secondary to acute disseminated encephalomyelitis, with bilateral involvement of the medial nuclei and pulvinar of the thalamus. Treatment with the noradrenergic agonist guanfacine, previously used for attention deficits in attention deficit/hyperactivity disorder and stroke, was associated with a significant amelioration of both the spatial and sustained attention impairments in neglect. Guanfacine may prove to be a useful tool in the treatment of disorders of attention associated with neurological conditions.

Alterations in visual and auditory processing in hemispatial neglect: an evoked potential follow-up study.

Hemispatial neglect is common after cerebrovascular stroke in the right hemisphere. Cortical electrophysiological studies, especially investigations of both visual and auditory processing in subjects with neglect are sparse. Our purpose was to assess whether and to which extent subjects with neglect may show impairments in both visual and auditory processing. Thereby, we assessed the evolution of changes in sensory processing and neglect symptoms over a 6 month follow-up period. Twenty-one stroke subjects with hemispatial neglect were studied at baseline, 3 weeks later and at 6 months follow-up. At enrollment, 12 patients were in Acute/subacute and 9 were in the chronic stage of stroke. Visual and auditory evoked potentials (EP) were elicited with unilateral stimulations and electrophysiologic data were registered with high-density EEG. Primary visual and auditory cortex activations seen in EP components were analyzed at three time points in order to detect alterations. Both sensory modalities revealed differences between hemispheres in processing stimuli coming from a unilateral source. Amplitudes of visual and auditory EP components elicited by left-sided stimuli were smaller compared to those elicited by right-sided stimuli in the Acute/subacute group. The behavioral neglect was more severe in those who had smaller EP amplitudes (e.g. EP amplitude after the right auditory stimulus was significantly associated with total behavioral neglect score, r=0.57). The main hemispheric differences diminished by the follow-up 6 months later along with the decreasing severity of neglect in the Acute/subacute group.

Environment and object mental images in patients with representational neglect: two case reports.

The aim of this study was to shed light on the nature of the imagery deficits in two patients with representational neglect and to determine whether representational neglect is affected by the content of the mental images the patients have to generate, inspect and manipulate. In particular, we submitted two patients with different types of representational neglect to a battery of visual mental imagery tests to assess the different kinds of imagery processes. We found that Patient 1, whose performance was asymmetrical on the O'Clock Test, performed poorly on tasks involving the mental generation, inspection and manipulation of objects but showed no deficit on tasks involving the mental generation, inspection and manipulation of environments. On the other hand, Patient 2, whose performance was asymmetrical on the Familiar Squares Description Test, performed poorly on tasks involving the mental generation, inspection and manipulation of environments, but not on tasks involving the mental generation, inspection and manipulation of objects. Our results demonstrate that environments and objects in the imagery domain can be represented separately and can be selectively affected by damage following brain lesions.

Effect of prism adaptation on left dichotic listening deficit in neglect patients: glasses to hear better?

Unilateral neglect is a disabling syndrome frequently observed following right hemisphere brain damage. Symptoms range from visuo-motor impairments through to deficient visuo-spatial imagery, but impairment can also affect the auditory modality. A short period of adaptation to a rightward prismatic shift of the visual field is known to improve a wide range of hemispatial neglect symptoms, including visuo-manual tasks, mental imagery, postural imbalance, visuo-verbal measures and number bisection. The aim of the present study was to assess whether the beneficial effects of prism adaptation may generalize to auditory manifestations of neglect. Auditory extinction, whose clinical manifestations are independent of the sensory modalities engaged in visuo-manual adaptation, was examined in neglect patients before and after prism adaptation. Two separate groups of neglect patients (all of whom exhibited left auditory extinction) underwent prism adaptation: one group (n = 6) received a classical prism treatment ('Prism' group), the other group (n = 6) was submitted to the same procedure, but wore neutral glasses creating no optical shift (placebo 'Control' group). Auditory extinction was assessed by means of a dichotic listening task performed three times: prior to prism exposure (pre-test), upon prism removal (0 h post-test) and 2 h later (2 h post-test). The total number of correct responses, the lateralization index (detection asymmetry between the two ears) and the number of left-right fusion errors were analysed. Our results demonstrate that prism adaptation can improve left auditory extinction, thus revealing transfer of benefit to a sensory modality that is orthogonal to the visual, proprioceptive and motor modalities directly implicated in the visuo-motor adaptive process. The observed benefit was specific to the detection asymmetry between the two ears and did not affect the total number of responses. This indicates a specific effect of prism adaptation on lateralized processes rather than on general arousal. Our results suggest that the effects of prism adaptation can extend to unexposed sensory systems. The bottom-up approach of visuo-motor adaptation appears to interact with higher order brain functions related to multisensory integration and can have beneficial effects on sensory processing in different modalities. These findings should stimulate the development of therapeutic approaches aimed at bypassing the affected sensory processing modality by adapting other sensory modalities.

Aging and the interaction of sensory cortical function and structure.

Even the healthiest older adults experience changes in cognitive and sensory function. Studies show that older adults have reduced neural responses to sensory information. However, it is well known that sensory systems do not act in isolation but function cooperatively to either enhance or suppress neural responses to individual environmental stimuli. Very little research has been dedicated to understanding how aging affects the interactions between sensory systems, especially cross-modal deactivations or the ability of one sensory system (e.g., audition) to suppress the neural responses in another sensory system cortex (e.g., vision). Such cross-modal interactions have been implicated in attentional shifts between sensory modalities and could account for increased distractibility in older adults. To assess age-related changes in cross-modal deactivations, functional MRI studies were performed in 61 adults between 18 and 80 years old during simple auditory and visual discrimination tasks. Results within visual cortex confirmed previous findings of decreased responses to visual stimuli for older adults. Age-related changes in the visual cortical response to auditory stimuli were, however, much more complex and suggested an alteration with age in the functional interactions between the senses. Ventral visual cortical regions exhibited cross-modal deactivations in younger but not older adults, whereas more dorsal aspects of visual cortex were suppressed in older but not younger adults. These differences in deactivation also remained after adjusting for age-related reductions in brain volume of sensory cortex. Thus, functional differences in cortical activity between older and younger adults cannot solely be accounted for by differences in gray matter volume.

Crossed aphasia and visuo-spatial neglect following a right thalamic stroke: a case study and review of the literature.

Crossed aphasia in dextrals (CAD) following pure subcortical lesions is rare. This study describes a right-handed patient with an ischemic lesion in the right thalamus. In the post-acute phase of the stroke, a unique combination of 'crossed thalamic aphasia' was found with left visuo-spatial neglect and constructional apraxia. On the basis of the criteria used in Mariën et al. [67], this case-report is the first reliable representative of vascular CAD following an isolated lesion in the right thalamus. Furthermore, this paper presents a detailed analysis of linguistic and cognitive impairments of 'possible' and 'reliable' subcortical CAD-cases published since 1975. Out of 25 patients with a pure subcortical lesion, nine cases were considered as 'possibly reliable or reliable'. A review of these cases reveals that: 1) demographic data are consistent with the general findings for the entire group of vascular CAD, 2) the neurolinguistic findings do not support the data in the general CAD-population with regard to a) the high prevalence of transcortical aphasia and b) the tendency towards a copresence of an oral versus written language dissociation and a 'mirror-image' lesion-aphasia profile, 3) subcortical CAD is not a transient phenomenon, 4) the lesion-aphasia correlations are not congruent with the high incidence of anomalous cases in the general CAD-population, 5) neuropsychological impairments may accompany subcortical CAD.

Left ipsilesional neglect for visual imagery: a mental image generation impairment?

In this article, we describe a patient, CN, with unilateral left posterior brain damage, who shows a rare occurrence of left ipsilesional neglect limited to mental representations. CN's clinical pattern is consistent with the hypothesis that different mechanisms underlie perceptual and representational neglect. We also discuss an interpretation of representational neglect based on the different involvement of the two hemispheres in visual imagery processes. In particular, left brain lesions do not present the typical strong contralesional bias and may lead to an impairment of mental generation of either side of the image, depending on pre-morbid and methodological factors.

Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort.

OBJECTIVE: To delineate the frequency, course, risk factors, and neuroanatomy of hemispatial neglect in a large stroke cohort. METHODS: One thousand two hundred eighty-one patients with acute stroke were enrolled in a multicenter trial of an anticoagulant. Presence and severity of neglect were assessed with the NIH Stroke Scale (NIHSS) neglect item, assessing tactile extinction and visuospatial neglect at entry, daily for 1 week, and at 3 months. Head CT scans were obtained on day 7, and infarct location and size were characterized. RESULTS: Neglect was common at presentation, occurring in 43% of right brain-lesioned (RBL) patients and 20% of left brain-lesioned (LBL) patients (p < 0.001). At 3 months, neglect was present in 17% of RBL patients and in 5% of LBL patients (p < 0.001). In RBL patients, neglect was most frequently associated with lesions involving the (in descending order) temporal, parietal, frontal, occipital lobes, basal ganglia, and thalamus. Neglect was more common and persistent with cortical than with subcortical lesions. Increasing age was associated with increased risk of neglect in RBL patients, whereas gender and handedness did not significantly affect neglect frequency. CONCLUSIONS: This series confirms that hemispatial neglect may occur with damage to several supratentorial structures but is most common and persistent with lesions of the right temporoparietal cortex. Increasing age is associated with neglect, particularly after right brain lesions. Gender and handedness do not exert a marked effect on the likelihood of the occurrence of neglect.

Neurobiology of perceptual and motor timing in children with spina bifida in relation to cerebellar volume.

The cerebellum is important for perceptual and motor timing in the mature brain, but the timing function of the cerebellum in the immature brain is less well understood. We investigated timing in children with spina bifida meningomyelocele (SB), a neural tube defect that involves cerebellar dysgenesis, and in age-matched controls. Specifically, we studied perceptual timing (judgements of 400 ms duration) and motor timing (isochronous motor tapping); measured cerebellar volumes; and related perceptual and motor timing to each other and to cerebellar volume measurements. Children with SB had impairments in the perception of duration (around 400 ms) but not frequency (around 3000 Hz), showing that their perceptual timing deficit was not a generalized auditory impairment. Children with SB had motor timing deficits on unpaced but not paced isochronous tapping, and their unpaced timing performance was associated with clock variance rather than with motor implementation. Perceptual and motor timing were correlated, suggesting that children with SB have impairments in a central timing mechanism. Children with SB, especially those with upper spinal cord lesions, had significant cerebellar volume reductions in grey and white matter, as well as different regional patterns of grey matter, white matter and CSF. Duration perception was correlated with cerebellar volumes, and the number of valid tapping trials was correlated with cerebellar volumes in the SB group, which data demonstrate structure-function relations between timing and cerebellar volumes.