Mechanical pinprick pain in patients with unilateral spatial neglect: The influence of space representation on the perception of nociceptive stimuli.

BACKGROUND: Crossing the hands over the midline can reduce the perceived intensity of nociceptive stimuli applied onto the hands. It remains unclear to what extent intact representation of peripersonal space influences this effect. Here we used the crossed-hands paradigm in patients with unilateral spatial neglect, a neuropsychological condition characterized by the inability to detect, attend and respond to contralesional (most often left) stimuli, and spared ability to process stimuli in the non-affected space. METHODS: Sixteen post-stroke patients without unilateral neglect and 11 patients with unilateral spatial neglect received punctate mechanical pinprick stimuli onto their crossed or uncrossed hands. We tested: (i) whether deficits in space representation reduce the possibility of observing 'crossed-hands analgesia', and; (ii) whether placing the contralesional hand, normally lying in the affected space in the healthy space would increase the number of detected stimuli. RESULTS: Our results showed that neglect patients did not exhibit 'crossed-hands' analgesia, but did not provide strong evidence for an improvement in the number of detected stimuli when the contralesional hand was in the healthy space. CONCLUSION: These findings uphold the notion that the perception of nociceptive stimuli is modulated by the relative position of the hands in space, but raise questions about the conditions under which these effects may arise. SIGNIFICANCE: We show that deficits in space representation can influence the processing of mechanical pinprick stimuli. Our results raise several questions on the mechanisms underlying these effects, which are relevant for the clinical practice.

Nucleus accumbens functional connectivity discriminates medication-overuse headache.

Medication-overuse headache (MOH) is a secondary form of headache related to the overuse of triptans, analgesics and other acute headache medications. It is believed that MOH and substance addiction share some similar pathophysiological mechanisms. In this study we examined the whole brain resting state functional connectivity of the dorsal and ventral striatum in 30 patients (15 MOH and 15 non-MOH patients) to investigate if classification algorithms can successfully discriminate between MOH and non-MOH patients on the basis of the spatial pattern of resting state functional connectivity of the dorsal and ventral striatal region of interest. Our results indicated that both nucleus accumbens and dorsal rostral putamen functional connectivity could discriminate between MOH and non-MOH patients, thereby providing possible support to two interpretations. First, that MOH patients show altered reward functionality in line with drug abusers (alterations in functional connectivity of the nucleus accumbens). Second, that MOH patients show inability to break habitual behavior (alterations in functional connectivity of the dorsal striatum). In conclusion, our data showed that MOH patients were characterized by an altered functional connectivity of motivational circuits at rest. These differences could permit the blind discrimination between the two conditions using classification algorithms. Considered overall, our findings might contribute to the development of novel diagnostic measures.

Cerebellar Clustering and Functional Connectivity During Pain Processing.

The cerebellum has been traditionally considered a sensory-motor structure, but more recently has been related to other cognitive and affective functions. Previous research and meta-analytic studies suggested that it could be involved in pain processing. Our aim was to distinguish the functional networks subserved by the cerebellum during pain processing. We used functional magnetic resonance imaging (fMRI) on 12 subjects undergoing mechanical pain stimulation and resting state acquisition. For the analysis of data, we used fuzzy c-mean to cluster cerebellar activity of each participant during nociception. The mean time courses of the clusters were used as regressors in a general linear model (GLM) analysis to explore brain functional connectivity (FC) of the cerebellar clusters. We compared our results with the resting state FC of the same cluster and explored with meta-analysis the behavior profile of the FC networks. We identified three significant clusters: cluster V, involving the culmen and quadrangular lobules (vermis IV-V, hemispheres IV-V-VI); cluster VI, involving the posterior quadrangular lobule and superior semilunar lobule (hemisphere VI, crus 1, crus 2), and cluster VII, involving the inferior semilunar lobule (VIIb, crus1, crus 2). Cluster V was more connected during pain with sensory-motor areas, cluster VI with cognitive areas, and cluster VII with emotional areas. Our results indicate that during the application of mechanical punctate stimuli, the cerebellum is not only involved in sensory functions but also with areas typically associated with cognitive and affective functions. Cerebellum seems to be involved in various aspects of nociception, reflecting the multidimensionality of pain perception.

Unawareness of bipolar disorder: the role of the cingulate cortex.

Reduced awareness of illness is a well-known phenomenon that has been understudied in remitted patients with bipolar disorder. In particular, the relationship between reduced awareness and executive dysfunction is an intriguing question that has yet to be resolved. The aim of the current study is to analyze the link between reduced awareness, brain dysfunction, and concomitant cognitive-behavioral disturbances from a neurocognitive perspective. In previous studies, we demonstrated the role of the anterior cingulate cortex (ACC) in the unawareness of distinct pathologies that exhibit overlapping symptoms in the context of overlapping circuit-specific dysfunction. Given the clinical importance of the results obtained, the present study considers six aware and four unaware remitted bipolar disorder patients. Cingulate functionality was assessed with functional magnetic resonance imaging while patients performed a go/no-go task. Patients were also studied on an overall cognitive task battery and with behavioral assessment of mood changes in terms of apathy and disinhibited behavior. Unaware patients showed frontoparietal hypo-perfusion, with a significant reduction of task-sensitive activity in the bilateral superior and middle frontal gyrus, putamen, insular, and ACCs.

The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients.

AIM: A growing number of neuropsychological studies reported that chemotherapy may impair brain functions, inducing persistent cognitive changes in a subset of cancer survivors. The aim of this paper was to investigate the neural basis of the chemotherapy induced neurobehavioral changes by means of metabolic imaging and neuropsychological testing. METHODS: We studied the resting brain [¹8F]FDG-PET/CT images of 50 adult cancer patients with diagnosis of lymphoma: 18 patients were studied prior and 32 after to chemotherapy. All patients underwent to a neuropsychological examination assessing cognitive impairment (tests for shifting attention, verbal memory, phonemic fluency), depression, anxiety and distress. RESULTS: Compared to no chemotherapy patients, the treated group showed significant bilateral lower rate of glucose metabolism in prefrontal cortices, cerebellum, medial cortices and limbic brain areas. The metabolism of these regions negatively correlated with number of cycles and positively with post-chemotherapy time. The treated group showed a poorer performance in many frontal functions, but similar level of depression, anxiety and distress. CONCLUSIONS: Chemotherapy induced significant long-term changes in metabolism of multiple regions with a prevailing involvement of the prefrontal cortex. The observed cognitive dysfunctions could be explained by these changes. The recovery from chemotherapy is probably affected by treatment duration and by the time elapsed after its end. We speculated that the mechanism could be an accelerating ageing / oxidative stress that, in some patients at risk, could result in an early and persistent cognitive impairment.

Virtual navigation for memory rehabilitation in a traumatic brain injured patient.

The use of 3D video games in memory rehabilitation has been explored very little. A virtual navigation task allows participants to encode the spatial layout of the virtual environment and activate areas involved in memory processing. We describe the rehabilitation of a 24-year-old man with traumatic brain injury presenting memory deficits, and evaluate the efficacy of a navigational training program measuring neuropsychological changes and fMRI modification cerebral activations. Memory improvement appears to be present both after navigational training and in follow-up testing. Furthermore, fMRI data suggest that this training may increase activation of the hippocampal and parahippocampal brain regions. The results suggest that intensive training in virtual navigational tasks may result in an enhancement of memory function in brain-damaged adults.

Altered resting state attentional networks in diabetic neuropathic pain.

BACKGROUND: Chronic pain can be considered as a highly salient stimulus that continuously taxes the attentional and salience processing networks, thus interfering with cognitive abilities and, more specifically, consuming attentional resources. The aim of the paper was to explore whether and how diabetic neuropathic pain (NP) affects attentional networks. METHODS: The authors sought to achieve this by investigating resting state functional connectivity (rsFC) in diabetic NP patients and comparing it with that of matched healthy controls. RESULTS: NP patients showed a widespread reduction in connectivity in both the dorsal and ventral attentional networks, as well as in the dorsal anterior cingulated cortex (ACC), typically implicated in salience processing. The authors also found a generalised reduction in the length of functional connections in the NP group: in all the examined networks, the Euclidean distance between connected voxels was significantly shorter in patients than in controls. CONCLUSION: In diabetic NP, a parieto-fronto-cingulate network controlling attention to external stimuli is impaired. In line with previous studies, chronic pain can disrupt the synchrony of a common pool of brain areas, involved in self-monitoring, pain processing and salience detection.

Disrupted intrinsic functional connectivity in the vegetative state.

It is debatable as to whether the spontaneous blood-oxygen-level dependent fluctuations that are observed in the resting brain in turn reflect consciously directed mental activity or, alternatively, constitute an intrinsic property of functional brain organisation persisting in the absence of consciousness. This report shows for the first time, in three patients, that the persistent vegetative state (PVS) is marked by a dysfunctional default mode network, with decreased connectivity in several brain regions, including the dorsolateral prefrontal cortex and anterior cingulated cortex, especially in the right hemisphere. This finding supports the view that the resting state is involved in self-consciousness, and that the right-hemisphere default state may play a major role in conscious processes. It is speculated that the default state may act as a surrogate marker of PVS with awareness contents and, therefore, could replace a more complex activation paradigm.

Motor imagery of walking following training in locomotor attention. The effect of "the tango lesson".

The hypothesis of this study is that focusing attention on walking motor schemes could modify sensorimotor activation of the brain. Indeed, gait is a learned automated process, mostly regulated by subcortical and spinal structures. We examined the functional changes in the activity of the cerebral areas involved in locomotor imagery tasks, before and after one week of training consisting of physical and mental practice. The aim of the training was to focus the subject's conscious attention on the movements involved in walking. In our training, subjects were asked to perform basic tango steps, which require specific ways of walking; each tango lesson ended with motor imagery training of the performed steps. The results show that training determines an expansion of active bilateral motor areas during locomotor imagery. This finding, together with a reduction of visuospatial activation in the posterior right brain, suggests a decreased role of visual imagery processes in the post-training period in favor of motor-kinesthetic ones.

A study of arm movements in Huntington's disease under visually controlled and blindfolded conditions.

The so-called bradykinesia of Huntington's disease (HD) seems not due to reduced movement speed alone but may also be task-dependent. We therefore investigated the influence of visual control on the ability of HD patients to perform a motor task. Ten HD patients, never treated with neuroleptic drugs and with mild functional impairment in activities of daily living, performed the task blindfolded and not blindfolded, as did 10 age- and education-matched healthy controls. The task was to use the dominant hand to trace out the contours of a 20 x 20 cm square in a clockwise direction, pausing at each corner. The square was marked on the table at which the subject sat. Accuracy was stressed rather than speed. A videocamerabased system recorded movement trajectories, from which kinematic and error parameters were derived. Patients and controls moved at comparable speeds but patients took longer to complete the task due to more curvilinear and hence longer trajectories. Patients spent more time in the deceleration phase of the movement, and in the blindfold condition had more variable movements as indicated by greater error variability scores. Correlation analysis showed that kinematic parameters in patients did not correlate with involuntary movement scores. These findings indicate that abnormalities of motor control are present in HD when movement accuracy (and not velocity) is required. HD patients are more dependent on visual control than normal subjects.

Acute effects of bilateral subthalamic nucleus stimulation on clinical and kinematic parameters in Parkinson's disease.

After implantation with subthalamic stimulators, nine patients with advanced Parkinson's disease were studied on the task of tracing out, as accurately as possible, the four corners of a square with the dominant hand. The task was performed in four treatment conditions: on stimulation-off medication, off stimulation-off medication, off stimulation-on medication, and on stimulation-on medication. Movement times and peak velocities improved significantly only in the on stimulation-on medication condition compared to off stimulation-off medication. The improvement in clinical parameters with stimulation only (relative to off stimulation off medication) was of borderline significance, while consistent and significant clinical improvement was only obtained with addition of medication (on medication-on stimulation). This study provides quantitative evidence of the effect of subthalamic stimulation on kinematic measures in Parkinson's disease (PD) and suggests that combined treatment (medication and stimulation) is superior to either treatment alone.

Development and decay of extra-linguistic communication.

Cognitive Pragmatics theory is concerned with analyzing the cognitive processes underlying communication. In previous works we have explained the emergence of communication in context, as revealed by very young children, and the communicative deficits shown by closed head injury patients. The aim of the present work is an extension of Cognitive Pragmatics to the emergence and the decay of extra-linguistic communication. In particular, we investigate the performance of 2- to 7-year-old children and that of Alzheimer's patients in standard and nonstandard (irony and deceit) pragmatic tasks. The predictions derived by Cognitive Pragmatics are confirmed. Comprehension of pragmatic phenomena which are more complex according to the theory emerges later in the development (Experiment 1), and their decay is most severe in Alzheimer's patients (Experiment 2). We conclude that the framework provided by Cognitive Pragmatics can accommodate both the development and the decay of extra-linguistic communication.

Dopaminergic stimulation in unilateral neglect.

OBJECTIVE: To explore the hypothesis that dopaminergic circuits play a part in the premotor components of the unilateral neglect syndrome, the effects of acute dopaminergic stimulation in patients with neglect were studied. METHODS: Two tasks were evaluated before and after subcutaneous administration of apomorphine and placebo: a circle crossing test and a test of target exploration (a modified version of the bell test), performed both in perceptual (counting) and in perceptual-motor (pointing) conditions. SUBJECTS: Four patients with left neglect. RESULTS: After dopaminergic stimulation, a significant improvement was found compared with placebo administration and baseline evaluation, in the performance of the two tests. Three of the patients had a more marked improvement in the perceptual-motor condition (pointing) of the task than the perceptual condition (counting). CONCLUSIONS: The findings suggest that dopaminergic neuronal networks may mediate, in different ways, both perceptive and premotor components of the unilateral neglect syndrome.

Cabergoline in Parkinson's disease complicated by motor fluctuations.

Cabergoline is a long-acting D2 dopamine (DA) agonist. We conducted an open study to investigate the effectiveness and tolerability of cabergoline, administered once a day orally, in 50 consecutive patients with Parkinson's disease complicated by motor fluctuations and dyskinesias. In 15 patients cabergoline replaced another direct DA agonist. Evaluation after 6 months of treatment (also including patients who dropped out during this period), showed an improvement in off or on hours, or both, in excess of 50% in 27 patients, comprising 20 of the 35 patients (57%) previously untreated with DA agonists and seven of the 15 patients (47%) already on DA agonists when the study began. Of the 22 patients who received the treatment for 1 year, the improvement was maintained up to final evaluation in the patients not on DA agonists at admission (n = 16), whereas a slight deterioration in clinical condition was observed in the patients already on DA agonists at admission (n = 6). Only six patients showed a detectable increase in dyskinesias. The most common side effects were gastric upset (n = 12), orthostatic hypotension (n = 3), and ankle edema (n = 3), all mild; also observed were two cases of pleural effusion/pulmonary fibrosis. Twenty patients (40%) failed to complete the treatment; of these, five (10% of total) dropped out because of adverse effects. It is concluded that once-daily administrations of cabergoline are useful for treating patients with Parkinson's disease with motor fluctuations and may advantageously substitute other DA agonists. The side effects of the drug are generally mild, although two cases involving pleuropulmonary complications did emerge.

Analogical representation and language structure.

Severe impairment of the analogue of mental representation is not compensated for by putative language-based cognitive processes in non-dysphasic brain-damaged patients. This undermines the hypothesis of an independent role for language in the generation of thought. Against this view it may be contended that there seems to be no obvious way in which analogical mental representation can decide between alternative syntactical structures available for the expression of thought. We performed a visual imagery experiment in which we asked 40 subjects to imagine visual scenes representing the meanings of simple utterances presented to them. The subjects then had to indicate the relative position, in each visual image, of two objects mentioned in each utterance. Series of utterances were presented differing syntactically (active or passive phrase) and semantically (specifying in different ways the spatial and temporal relations between the objects mentioned). The results of this mental imagery experiment indirectly support the hypothesis that syntactical structures can be represented in a nonlinguistic analogue medium.

Anatomical correlates of visual and tactile extinction in humans: a clinical CT scan study.

The anatomical correlates of tactile and visual extinction with double simultaneous stimulation were investigated in a series of 159 patients with right brain damage caused by stroke. Forty six patients showed extinction (22 tactile, 14 visual, 10 tactile and visual). Over 50% of the patients with extinction had deep lesions, which were found in about 25% of the patients with visuospatial neglect not associated with extinction. In the patients with extinction and cortico-subcortical damage the paraventricular occipital white matter and the dorsolateral frontal cortex were most often involved. By contrast, when neglect was also present, the lesions clustered in the inferior parietal lobule. These data suggest, from an anatomical perspective, that partly different neural mechanisms may underlie neglect and extinction. The comparatively high frequency of subcortical lesions involving the ascending pathways may be a neural correlate of a sensory component of extinction.

Response to L-DOPA in multiple system atrophy.

A poor response to L-DOPA in addition to parkinsonian, cerebellar, and autonomic signs is commonly regarded as indicative of clinical multiple system atrophy (MSA). We compared the motor response to a single oral administration of 250 mg L-DOPA/25 mg carbidopa in eight MSA patients and eight Parkinson's disease (PD) patients with the "on-off" phenomenon, evaluating L-DOPA peripheral pharmacokinetics. Motor response was consistently good in all PD patients, but only four MSA patients had a (moderate) response. Pharmacokinetic parameters did not differ between the groups. The varying extent of putaminal damage could be responsible for the differing motor response to L-DOPA in MSA patients.