Disentangling the Role of Cortico-Basal Ganglia Loops in Top-Down and Bottom-Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease.

It is solidly established that top-down (goal-driven) and bottom-up (stimulus-driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top-down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control.

Time-frequency modulation of ERD and EEG coherence in robot-assisted hand performance.

A better understanding of cortical modifications related to movement preparation and execution after robot-assisted training could aid in refining rehabilitation therapy protocols for stroke patients. Electroencephalography (EEG) modifications of cortical activity in healthy subjects were evaluated using time-frequency event-related EEG and task-related coherence (TRCoh). Twenty-one channel EEG was recorded in eight subjects during protocols of active, passive, and imagined movements. The subjects performed robot-assisted tasks using the Bi-Manu-Track robot-assisted arm trainer. We applied time-frequency event-related synchronization/desynchronization (ERS/ERD) and TRCoh approaches to investigate where movement-related decreases in power were localized and to study the functional relationships between areas. Our results showed ERD of sensorimotor (SM) area over the contralateral side before the movement and bilateral ERD during execution of the movement. ERD during passive movements was similar in topography to that observed during voluntary movements, but without pre-movement components. No significant difference in time course ERD was observed among the three types of movement over the two SM areas. The TRCoh topography was similar for active and imagined movement; before passive movement, the frontal regions were uncoupled from the SM regions and did not contribute to task performance. This study suggests new perspectives for the evaluation of brain oscillatory activity and the neurological assessment of motor performance by means of quantitative EEG to better understand the planning and execution of movement.

Investigation of brain hemodynamic changes induced by active and passive movements: a combined arterial spin labeling-BOLD fMRI study.

PURPOSE: To assess the applicability of arterial spin labeling (ASL) in comparison to blood-oxygenation-level-dependent (BOLD) contrast fMRI in detecting brain activations elicited by active and passive hand movements. MATERIALS AND METHODS: A block design for ASL and BOLD fMRI was applied in 8 healthy subjects using active and passive hand tasks. Data analyses were performed at individual and group level, comparing both the different movements and the performance of the two techniques. RESULTS: Group analyses showed involvement of the same areas during both tasks, as the contralateral sensorimotor cortex, supplementary motor area, cerebellum, inferior parietal lobes, thalamus. ASL detected smaller activation volumes than BOLD, but the areas had a high degree of colocalization. Few significant differences (P < 0.05) were found when the two tasks were compared for the number of activated voxels, coordinates of center of mass, and CBF estimates. Considering together all the areas, the mean %BOLD change was 0.79 ± 0.27 and 0.73 ± 0.24 for the active and passive movements respectively, while the mean %CBF changes were 34.1 ± 8.9 and 27.1 ± 14.8. CONCLUSION: Our findings confirm passive and active tasks are strongly coupled, supporting the importance of passive tasks as a diagnostic tool in the clinical setting. ASL fMRI proved suitable for functional mapping and quantifying CBF changes, making it a promising technique for patient cohort applications.

Effect of voluntary repetitive long-lasting muscle contraction activity on the BOLD signal as assessed by optimal hemodynamic response function.

OBJECTIVE: Among other neuroimaging techniques, functional magnetic resonance imaging (fMRI) can be useful for studying the development of motor fatigue. The aim of this study was to identify differences in cortical neuronal activation in nine subjects on three motor tasks: right-hand movement with minimum, maximum, and post-fatigue maximum finger flexion. MATERIALS AND METHODS: fMRI activation maps for each subject and during each condition were obtained by estimating the optimal model of the hemodynamic response function (HRF) out of four standard HRF models and an individual-based HRF model (ibHRF). RESULTS: ibHRF was selected as the optimal model in six out of nine subjects for minimum movement, in five out of nine for maximum movement, and in eight out of nine for post-fatigue maximum movement. As compared to maximum movement, a large reduction in the total number of active voxels (primary sensorimotor area, supplementary motor area and cerebellum) was observed in post-fatigue maximum movement. CONCLUSION: This is the first approach to the evaluation of long-lasting contraction effort in healthy subjects by means of the fMRI paradigm with the use of an individual-based hemodynamic response. The results may be relevant for defining a baseline in future studies on central fatigue in patients with neuropathological disorders.

Visual cortex hyperexcitability in idiopathic generalized epilepsies with photosensitivity: a TMS pilot study.

BACKGROUND: The current understanding of the mechanisms underlying photosensitivity is still limited, although most studies point to a hyperexcitability of the visual cortex. METHODS: Using transcranial magnetic stimulation, we determined the resting motor threshold (rMT) and the phosphene threshold (PT) in 33 patients with IGEs (8 with photosensitivity) compared with 12 healthy controls. RESULTS: Eleven controls (92%) reported phosphenes compared with fifteen (46%) patients with idiopathic generalized epilepsy (p=0.015). Phosphenes were reported more frequently among patients with epilepsy with photosensitivity (87.5%) than in patients with active epilepsy without photosensitivity (30.8%) (p=0.038) and patients with epilepsy in remission without photosensitivity (33.3%) (p=0.054); no differences were found between patients with epilepsy with photosensitivity and controls (p=0.648). Resting motor threshold and phosphene threshold were significantly higher among patients with epilepsy (active epilepsy or epilepsy in remission without photosensitivity) compared to healthy controls (p<0.01). Conversely, patients with active epilepsy and photosensitivity had significantly lower values than controls (p=0.03). CONCLUSIONS: The marked decrease in PT and the high phosphene prevalence in patients with IGE with photosensitivity indicate a regional hyperexcitability of the primary visual cortex. Results of this study also suggest that the PT may serve as a biomarker for excitability in patients with IGE and photosensitivity.

Factors predicting functional and cognitive recovery following severe traumatic, anoxic, and cerebrovascular brain damage.

OBJECTIVES: To compare demographic data, clinical data, and rate of functional and cognitive recovery in patients with severe traumatic, cerebrovascular, or anoxic acquired brain injury (ABI) and to identify factors predicting discharge home. PARTICIPANTS: Three hundred twenty-nine patients with severe ABI (192 with traumatic, 104 with cerebrovascular, and 33 with anoxic brain injury). DESIGN: Longitudinal prospective study of inpatients attending the intensive Rehabilitation Department of the "Sacro Cuore" Don Calabria Hospital (Negrar, Verona, Italy). MAIN MEASURES: Etiology, sex, age, rehabilitation admission interval, rehabilitation length of stay, discharge destination, Glasgow Coma Scale, Disability Rating Scale (DRS), Glasgow Outcome Scale, Levels of Cognitive Functioning, and Functional Independence Measure. RESULTS: Predominant etiology was traumatic; male gender was prevalent in all the etiologic groups; patients with traumatic brain injury were younger than the patients in the other groups and had shorter rehabilitation admission interval, greater functional and cognitive outcomes on all considered scales, and a higher frequency of returning home. Patients with anoxic brain injury achieved the lowest grade of functional and cognitive recovery. Age, etiology, and admission DRS score predicted return home. CONCLUSIONS: Patients with traumatic brain injury achieved greater functional and cognitive improvements than patients with cerebrovascular and anoxic ABI. Age, etiology, and admission DRS score can assist in predicting discharge destination.

Modulation of event-related desynchronization in robot-assisted hand performance: brain oscillatory changes in active, passive and imagined movements.

BACKGROUND: Robot-assisted therapy in patients with neurological disease is an attempt to improve function in a moderate to severe hemiparetic arm. A better understanding of cortical modifications after robot-assisted training could aid in refining rehabilitation therapy protocols for stroke patients. Modifications of cortical activity in healthy subjects were evaluated during voluntary active movement, passive robot-assisted motor movement, and motor imagery tasks performed under unimanual and bimanual protocols. METHODS: Twenty-one channel electroencephalography (EEG) was recorded with a video EEG system in 8 subjects. The subjects performed robot-assisted tasks using the Bi-Manu Track robot-assisted arm trainer. The motor paradigm was executed during one-day experimental sessions under eleven unimanual and bimanual protocols of active, passive and imaged movements. The event-related-synchronization/desynchronization (ERS/ERD) approach to the EEG data was applied to investigate where movement-related decreases in alpha and beta power were localized. RESULTS: Voluntary active unilateral hand movement was observed to significantly activate the contralateral side; however, bilateral activation was noted in all subjects on both the unilateral and bilateral active tasks, as well as desynchronization of alpha and beta brain oscillations during the passive robot-assisted motor tasks. During active-passive movement when the right hand drove the left one, there was predominant activation in the contralateral side. Conversely, when the left hand drove the right one, activation was bilateral, especially in the alpha range. Finally, significant contralateral EEG desynchronization was observed during the unilateral task and bilateral ERD during the bimanual task. CONCLUSIONS: This study suggests new perspectives for the assessment of patients with neurological disease. The findings may be relevant for defining a baseline for future studies investigating the neural correlates of behavioral changes after robot-assisted training in stroke patients.

Time-frequency analysis of short-lasting modulation of EEG induced by intracortical and transcallosal paired TMS over motor areas.

Dynamic changes in spontaneous electroencephalogram (EEG) rhythms can be seen to occur with a high rate of variability. An innovative method to study brain function is by triggering oscillatory brain activity with transcranial magnetic stimulation (TMS). EEG-TMS coregistration was performed on five healthy subjects during a 1-day experimental session that involved four steps: baseline acquisition, unconditioned single-pulse TMS, intracortical inhibition (ICI, 3 ms) paired-pulse TMS, and transcallosal stimulation over left and right primary motor cortex (M1). A time-frequency analysis based on the wavelet method was used to characterize rapid modifications of oscillatory EEG rhythms induced by TMS. Single, paired, and transcallosal TMS applied on the sensorimotor areas induced rapid desynchronization over the frontal and central-parietal electrodes mainly in the alpha and beta bands, followed by a rebound of synchronization, and rapid synchronization of delta and theta activity. Wavelet analysis after a perturbation approach is a novel way to investigate modulation of oscillatory brain activity. The main findings are consistent with the concept that the human motor system may be based on networklike oscillatory cortical activity and might be modulated by single, paired, and transcallosal magnetic pulses applied to M1, suggesting a phenomenon of fast brain activity resetting and triggering of slow activity.

Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective.

Tongue biting (TB) may occur both in seizures and in psychogenic non-epileptic events (PNEEs). We undertook a systematic review to determine sensitivity, specificity, and likelihood ratios (LR) of TB. Five studies (222 epilepsy patients and 181 subjects with PNEEs) were included. There was a statistically significant higher prevalence of TB (both without further specifications on site of lesions and lateral TB) in patients with seizures. Pooled accuracy measures of TB (no further specifications) were sensitivity 38%, specificity 75%, pLR 1.479 (95% CI 1.117-1.957), and nLR 0.837 (95% CI 0.736-0.951). Pooled measures of lateral TB were sensitivity 22%, specificity 100%, pLR 21.386 (95% CI 1.325-345.169), and nLR 0.785 (95% CI 0.705-0.875). Only a pooled analysis of data demonstrated a statistically significant pLR for lateral TB. Lateral TB but not 'any' TB has diagnostic significance in distinguishing seizures from PNEEs, supporting the diagnosis of seizures. Tongue biting without further specifications has, therefore, no value in the differential diagnosis between seizures and PNEEs.

Focal nonconvulsive seizures during detoxification for benzodiazepine abuse.

Chronic benzodiazepine (BDZ) abuse is currently treated with detoxification using a low-dose flumazenil infusion, a relatively recently developed and promising procedure. Given the possibility reported in the literature of the occurrence of generalized seizures during therapeutic BDZ detoxification, we usually administer preventive antiepileptic drug (AED) therapy. We describe two patients with no previous history of seizures or evidence of intracerebral lesions who, during detoxification for benzodiazepine abuse, developed repetitive focal nonconvulsive seizures instead of generalized seizures, even with appropriate doses of preventive AED therapy. There are no previous reported cases of focal nonconvulsive seizures occurring during this procedure or, more generally, during abrupt BDZ discontinuation. The cases we describe suggest that during detoxification for BDZ abuse, not only generalized, but also focal nonconvulsive seizures may occur. In this context, the focal seizures probably result from a diffuse decrease in the seizure threshold (caused by a generalized excitatory rebound), which may trigger focal seizures arising from cortical regions with higher intrinsic epileptogenicity. Detoxification for benzodiazepine abuse, even if performed with adequate-dosage AED treatment, may not be as safe a procedure as previously considered, because not only convulsive, but also nonconvulsive seizures may occur and go unnoticed. It is therefore strongly advisable to perform this detoxification under close medical supervision and to maintain a low threshold for EEG monitoring in the event of sudden onset of behavioral changes.

A multimodal imaging approach to the evaluation of post-traumatic epilepsy.

OBJECT: Electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration and high-density EEG (hdEEG) can be combined to map noninvasively abnormal brain activation elicited by epileptic processes. By combining noninvasive imaging techniques in a multimodal approach, we sought to investigate pathophysiological mechanisms underlying epileptic activity in seven patients with severe traumatic brain injury. MATERIALS AND METHODS: Standard EEG and fMRI data were acquired during a single scanning session. The EEG-fMRI data were analyzed using the general linear model and independent component analysis. Source localization of interictal epileptiform discharges (IEDs) was performed using 256-channel hdEEG. Blood oxygenation level dependent (BOLD) localizations were then compared to EEG source reconstruction. RESULTS: On hdEEG, focal source localization was detected in all seven patients; in six out of seven it was concordant with the expected epileptic activity as defined by EEG data and clinical evaluation; and in four out of seven in whom IEDs were recorded, BOLD signal changes were observed. These activities were partially concordant with the source localization. CONCLUSION: Multimodal integration of EEG-fMRI and hdEEG combining two different methods to localize the same epileptic foci appears to be a promising tool to noninvasively map abnormal brain activation in patients with post-traumatic brain injury.

Transcranial magnetic stimulation of visual cortex in migraine patients: a systematic review with meta-analysis.

We systematically reviewed the literature to evaluate the prevalence of phosphenes and the phosphene threshold (PT) values obtained during single-pulse transcranial magnetic stimulation (TMS) in adults with migraine. Controlled studies measuring PT by single-pulse TMS in adults with migraine with or without aura (MA, MwA) were systematically searched. Prevalence of phosphenes and PT values were assessed calculating mean difference (MD) and odds ratio (OR) with 95 % confidence intervals (CI). Ten trials (277 migraine patients and 193 controls) were included. Patients with MA had statistically significant lower PT compared with controls when a circular coil was used (MD -28.33; 95 % CI -36.09 to -20.58); a similar result was found in MwA patients (MD -17.12; 95 % CI -23.81 to -10.43); using a figure-of-eight coil the difference was not statistically significant. There was a significantly higher phosphene prevalence in MA patients compared with control subjects (OR 4.21; 95 % CI 1.18-15.01). No significant differences were found either in phosphene reporting between patients with MwA and controls, or in PT values obtained with a figure-of-eight coil in MA and MwA patients versus controls. Overall considered, these results support the hypothesis of a primary visual cortex hyper-excitability in MA, providing not enough evidence for MwA. A significant statistical heterogeneity reflects clinical and methodological differences across studies, and higher temporal variabilities among PT measurements over time, related to unstable excitability levels. Patients should therefore be evaluated in the true interictal period with an adequate headache-free interval. Furthermore, skull thickness and ovarian cycle should be assessed as possible confounding variables, and sham stimulation should be performed to reduce the rate of false positives. Phosphene prevalence alone cannot be considered a measure of cortical excitability, but should be integrated with PT evaluation.

Integrating EEG and fMRI in epilepsy.

Integrating electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) studies enables to non-invasively investigate human brain function and to find the direct correlation of these two important measures of brain activity. Presurgical evaluation of patients with epilepsy is one of the areas where EEG and fMRI integration has considerable clinical relevance for localizing the brain regions generating interictal epileptiform activity. The conventional analysis of EEG-fMRI data is based on the visual identification of the interictal epileptiform discharges (IEDs) on scalp EEG. The convolution of these EEG events, represented as stick functions, with a model of the fMRI response, i.e. the hemodynamic response function, provides the regressor for general linear model (GLM) analysis of fMRI data. However, the conventional analysis is not automatic and suffers of some subjectivity in IEDs classification. Here, we present an easy-to-use and automatic approach for combined EEG-fMRI analysis able to improve IEDs identification based on Independent Component Analysis and wavelet analysis. EEG signal due to IED is reconstructed and its wavelet power is used as a regressor in GLM. The method was validated on simulated data and then applied on real data set consisting of 2 normal subjects and 5 patients with partial epilepsy. In all continuous EEG-fMRI recording sessions a good quality EEG was obtained allowing the detection of spontaneous IEDs and the analysis of the related BOLD activation. The main clinical finding in EEG-fMRI studies of patients with partial epilepsy is that focal interictal slow-wave activity was invariably associated with increased focal BOLD responses in a spatially related brain area. Our study extends current knowledge on epileptic foci localization and confirms previous reports suggesting that BOLD activation associated with slow activity might have a role in localizing the epileptogenic region even in the absence of clear interictal spikes.

Fear as the only clinical expression of affective focal status epilepticus.

Affective seizures consist of fear, depression, joy, and (rarely) anger. A correct diagnosis is often delayed as the behavioral features, like fear, are interpreted as psychiatric disorders. We describe a patient with affective focal status epilepticus (AFSE) in which fear was the only clinical manifestation. We present electroencephalographic correlates and discuss the diagnostic difficulties that can be encountered in similar cases. AFSE with fear as the only clinical expression may represent a diagnostic challenge. When fear is the only or the prominent behavioral feature, seizures may be diagnosed as panic attacks, leading to erroneous therapy. In such situations, electroencephalography is an essential tool in differentiating between psychiatric disorders and epileptic events.

Highly focal BOLD activation on functional MRI in a patient with progressive myoclonic epilepsy and diffuse giant somatosensory evoked potentials.

We analyzed the effect of afferent input on patterns of brain electrical activation in a 31-year-old man with progressive myoclonic epilepsy (PME) by measuring the somatosensory evoked potential (SSEP) amplitude at the scalp after median nerve stimulation and examining the changes in the functional magnetic resonance imaging blood oxygen level-dependent (fMRI BOLD) signal. High-amplitude SSEPs were elicited at the wrist in association with highly focal BOLD activation of the contralateral sensorimotor areas. By contrast, no diffuse activation of either the frontal or the posterior parietal cortical areas was observed, as seen in previously recorded data on SSEPs from a healthy control group. The highly focal BOLD activation in this patient suggests that cortex hyperexcitability might be limited to the sensorimotor cortex in PME. The combined EEG-fMRI findings highlight a dissociation between BOLD activation and neurophysiological findings.

Multiple radiculopathy as the presenting manifestation of primary spinal leptomeningeal B cell lymphoma detected by flow cytometry of cerebrospinal fluid.

Primary leptomeningeal lymphoma is a rare syndrome characterized by lymphomatous meningeal infiltration without identification of systemic lymphoma or parenchymal central nervous system lymphoma. We report a case of a 62-year-old immunocompetent woman with primary spinal leptomeningeal lymphoma presenting as cervical and lumbar radiculopathy who is rare because of particularly unusual onset site of B cell lymphoma. Interestingly, the diagnosis was possible only by cerebrospinal fluid flow cytometry.

Coexistence of two distinct benign EEG variants in the same subject.

Rhythmic temporal theta bursts of drowsiness (RTTD), also known as "psychomotor variant", and subclinical rhythmic EEG discharge of adults (SREDA) are two EEG patterns of uncertain significance that occur without any correlation with epilepsy. Each of these patterns has been described to occur alone and in the literature there are no previous reports of co-occurrence of the two distinct benign EEG variants in the same patient. We describe the coexistence of RTTD and SREDA in EEG recordings from the same subject. Although the coexistence of two distinct EEG variants in the same patient is a rarity, these patterns are not so infrequently encountered when present alone and should thus be promptly recognised in order to avoid misdiagnosis of epilepsy due to an over-interpretation of normal sharp patterns.

Infliximab-related seizures: a first case study.

Seizures following infliximab treatment are very rare and, to date, there is no detailed description of EEG abnormalities with cerebral radiological findings reported in cases with infliximab-related seizures. We describe a patient who acutely developed seizures temporally related to infliximab treatment, which disappeared after drug withdrawal. MRI showed encephalopathy involving mainly cortical regions and EEGs showed focal paroxysmal activity which completely disappeared a few days after infliximab withdrawal. No other plausible cause of the seizures was identified. The clear temporal association between seizure onset and infliximab treatment as well as the clinical improvement and disappearance of focal epileptiform activity after drug withdrawal indicated an evident correlation between seizures and infliximab therapy. The coexistence of pathological findings on MRI suggested that seizures were secondary to the encephalopathy. Further studies are required to evaluate whether infliximab per se has an epileptogenic effect or whether the seizures are caused by encephalopathy involving cortico-subcortical regions.

ECG myogenic artifacts during clonic seizures: a disturbing (and interesting) finding.

During motor seizures myogenic artifacts may appear on ECG. We report a patient with recurring convulsive seizures involving left side of his body in whom ECG served as a surrogate of electromyography (EMG), showing myogenic artifacts strongly correlated with clonic jerks. The possibility of standard ECG of recording myogenic potentials when clonic seizures occur is something intriguing, being at the same time both disturbing and informative. In such cases standard ECG works as an EMG, although ECG filter, sensitivity and paper speed is different from EMG currently used in neurophysiological laboratory. However, using standard ECG acquisition parameters, muscular activity may be recorded without excessive attenuation of high-frequency myogenic potentials, permitting to indicate the frequency of clonic movements. On the other hand, whenever possible, positioning of ECG surface electrodes on limbs not (or less) involved in clonic epileptic movements may permit to obtain a sufficiently informative ECG recording with less amount of myogenic artifacts, thus providing essential information on heart rate and rhythm.

Muscular pain in Parkinson's disease and nociceptive processing assessed with CO2 laser-evoked potentials.

Muscular pain is the most frequent kind of nondystonic pain associated with Parkinson's disease (PD). It might be related not only to peripheral factors but also to an abnormal nociceptive input processing in the central nervous system. To test this hypothesis, we recorded CO(2) laser-evoked potentials (LEPs) in response to shoulder stimulation (skin over deltoid muscle) in 11 hemiparkinsonian PD patients complaining of muscular pain in the shoulder (ipsilateral to motor symptoms) and compared the results with those obtained in 12 pain-free PD patients with hemiparkinson and in 11 normal subjects. N2/P2 LEP, which is thought to originate from the cingulate cortex and insula, was significantly lower in amplitude in both groups of PD patients than in controls, regardless of the clinically affected body side. In both groups of PD patients, no significant correlation was observed between the severity of motor symptoms and N2/P2 amplitude abnormalities. In PD patients with muscular pain, the N2/P2 amplitude obtained following stimulation of the painful shoulder was significantly reduced compared with that obtained in response to nonpainful shoulder stimulation and compared with the values obtained in pain-free PD patients. No significant correlation was observed between the intensity of muscular pain and N2/P2 amplitude abnormalities in this group of PD patients. These results suggest abnormal nociceptive input processing in PD, which appears to be independent of clinical expression of parkinsonian motor signs. These alterations are more evident in the presence of muscular pain.