Processing of Positive and Negative Feedback in Patients with Cerebellar Lesions.

It is well accepted that the cerebellum plays a crucial role in the prediction of the sensory consequences of movements. Recent findings of altered error processing in patients with selective cerebellar lesions led to the hypothesis that feedback processing and feedback-based learning might be affected by cerebellar damage as well. Thus, the present study investigated learning from and processing of positive and negative feedback in 12 patients with selective cerebellar lesions and healthy control subjects. Participants performed a monetary feedback learning task. The processing of positive and negative feedback was assessed by means of event-related potentials (ERPs) during the learning task and during a separate task in which the frequencies of positive and negative feedback were balanced. Patients did not show a general learning deficit compared to controls. Relative to the control group, however, patients with cerebellar lesions showed significantly higher ERP difference wave amplitudes (rewards-losses) in a time window between 250 and 450 ms after feedback presentation, possibly indicating impaired outcome prediction. The analysis of the original waveforms suggested that patients and controls primarily differed in their pattern of feedback-related negativity and P300 amplitudes. Our results add to recent findings on altered performance monitoring associated with cerebellar damage and demonstrate, for the first time, alterations of feedback processing in patients with cerebellar damage. Unaffected learning performance appears to suggest that chronic cerebellar lesions can be compensated in behaviour.

The involvement of the thalamus in semantic retrieval: a clinical group study.

There is increasing attention about the role of the thalamus in high cognitive functions, including memory. Although the bulk of the evidence refers to episodic memory, it was recently proposed that the mediodorsal (MD) and the centromedian-parafascicular (CM-Pf) nuclei of the thalamus may process general operations supporting memory performance, not only episodic memory. This perspective agrees with other recent fMRI findings on semantic retrieval in healthy participants. It can therefore be hypothesized that lesions to the MD and the CM-Pf impair semantic retrieval. In this study, 10 patients with focal ischemic lesions in the medial thalamus and 10 healthy controls matched for age, education, and verbal IQ performed a verbal semantic retrieval task. Patients were assigned to a target clinical group and a control clinical group based on lesion localization. Patients did not suffer from aphasia and performed in the range of controls in a categorization and a semantic association task. However, target patients performed poorer than healthy controls on semantic retrieval. The deficit was not because of higher distractibility but of an increased rate of false recall and, in some patients, of a considerably increased rate of misses. The latter deficit yielded a striking difference between the target and the control clinical groups and is consistent with anomia. Follow-up high-resolution structural scanning session in a subsample of patients revealed that lesions in the CM-Pf and MD were primarily associated with semantic retrieval deficits. We conclude that integrity of the MD and the CM-Pf is required for semantic retrieval, possibly because of their role in the activation of phonological representations.

Cortical processing of saccade-related efference copy signals in patients with cerebellar lesion.

The updating of visual space across saccades is thought to rely on efference copies of motor commands. In humans, thalamic lesions impair performance on a saccadic double-step task, which requires the use of efference copy information, and the altering of saccade-related efference copy processing. This deficit is attributed to disruption of a pathway from the superior colliculus to the frontal eye field. However, the cerebellum is probably also involved in efference copy processing, due to its pivotal role for predictive motor control. The present study investigated the processing of efference copy information in eight patients with focal cerebellar lesions and 22 healthy controls by means of a saccadic double-step task with simultaneous event-related potential recording. Despite intact behavioural performance, a positive event-related potential component between 150 and 450 ms after first saccade onset in the updating condition, which has been interpreted in terms of the integration of efference copy signals with motor intentions for a subsequent saccade, was markedly reduced in the patients. These findings suggest that the cerebellum contributes to on-line saccade monitoring, and that cerebellar lesions alter saccade-related efference copy processing. However, given the intact behavioural performance, the reduced positivity in the patients may indicate that cerebellar damage is accounted for by either exploiting reduced saccade-related information, or making use of compensatory strategies to circumvent a deficit in using efference copy information procured by the cerebellum. The present study extends previous findings on the neural underpinnings of saccadic updating and further elucidates the mechanisms underlying cerebellar predictive motor control.

Updating of visual space across horizontal saccades in cerebellar and thalamic lesion patients.

Efference copies of motor commands are used to update visual space across saccades, ultimately ensuring transsaccadic constancy of space. Thalamic lesions have been shown to impair efference copy-based saccadic updating in an oculomotor context, i.e., when two successive saccades are required. Moreover, the cerebellum has also been discussed as one possible source of saccade-related efference copy signals. The present study aimed to investigate the effects of thalamic and cerebellar lesions on saccadic updating in a perceptual context. To this end, seven patients with focal cerebellar lesions, seven patients with focal thalamic lesions and 11 healthy controls completed a perceptual localisation task in which the position of a target had to be updated across a single horizontal saccade, while saccade-related event-related potentials (ERPs) were recorded. Contrary to the expectations, localisation precision in both patient groups did not differ from the respective controls. A positive ERP component with centroparietal distribution occurring from about 300 to 500 ms after saccade onset in the updating condition was observed equally pronounced in controls and thalamic lesion patients. In cerebellar lesion patients, there was evidence of a reduction of this relative positivity in the updating condition, particularly for leftward saccades. This finding suggests that cerebellar damage altered the neural processes underlying saccadic updating in a perceptual context without causing overt behavioural deficits.

Differential impairment of remembering the past and imagining novel events after thalamic lesions.

Vividly remembering the past and imagining the future (mental time travel) seem to rely on common neural substrates and mental time travel impairments in patients with brain lesions seem to encompass both temporal domains. However, because future thinking-or more generally imagining novel events-involves the recombination of stored elements into a new event, it requires additional resources that are not shared by episodic memory. We aimed to demonstrate this asymmetry in an event generation task administered to two patients with lesions in the medial dorsal thalamus. Because of the dense connection with pFC, this nucleus of the thalamus is implicated in executive aspects of memory (strategic retrieval), which are presumably more important for future thinking than for episodic memory. Compared with groups of healthy matched control participants, both patients could only produce novel events with extensive help of the experimenter (prompting) in the absence of episodic memory problems. Impairments were most pronounced for imagining personal fictitious and impersonal events. More precisely, the patients' descriptions of novel events lacked content and spatio-temporal relations. The observed impairment is unlikely to trace back to disturbances in self-projection, scene construction, or time concept and could be explained by a recombination deficit. Thus, although memory and the imagination of novel events are tightly linked, they also partly rely on different processes.

Working memory and verbal fluency deficits following cerebellar lesions: relation to interindividual differences in patient variables.

Findings concerning cognitive impairment in patients with focal cerebellar lesions tend to be inconsistent and usually reflect a mild deficit. Patient variables such as lesion age and the age at lesion onset might affect functional reorganization and contribute to the variability of the findings. To assess this issue, 14 patients with focal vascular cerebellar lesions and 14 matched healthy control subjects performed a verbal working memory and a verbal long-term memory task as well as verbal fluency tasks. Patients showed deficits in working memory and verbal fluency, while recall of complex narrative material was intact. Verbal fluency performance correlated significantly with age in the patient group, with more severe impairments in older patients, suggesting that age at lesion onset is a critical variable for cognitive outcome. In controls, no significant correlations with age were observed. Taken together, our findings support the idea of cerebellar involvement in nonmotor functions and indicate the relevance of interindividual differences in regard to clinical parameters after focal cerebellar damage.

Separate and overlapping functional roles for efference copies in the human thalamus.

How the perception of space is generated from the multiple maps in the brain is still an unsolved mystery in neuroscience. A neural pathway ascending from the superior colliculus through the medio-dorsal (MD) nucleus of thalamus to the frontal eye field has been identified in monkeys that conveys efference copy information about the metrics of upcoming eye movements. Information sent through this pathway stabilizes vision across saccades. We investigated whether this motor plan information might also shape spatial perception even when no saccades are performed. We studied patients with medial or lateral thalamic lesions (likely involving either the MD or the ventrolateral (VL) nuclei). Patients performed a double-step task testing motor updating, a trans-saccadic localization task testing visual updating, and a localization task during fixation testing a general role of motor signals for visual space in the absence of eye movements. Single patients with medial or lateral thalamic lesions showed deficits in the double-step task, reflecting insufficient transfer of efference copy. However, only a patient with a medial lesion showed impaired performance in the trans-saccadic localization task, suggesting that different types of efference copies contribute to motor and visual updating. During fixation, the MD patient localized stationary stimuli more accurately than healthy controls, suggesting that patients compensate the deficit in visual prediction of saccades - induced by the thalamic lesion - by relying on stationary visual references. We conclude that partially separable efference copy signals contribute to motor and visual stability in company of purely visual signals that are equally effective in supporting trans-saccadic perception.

Impairment of verbal recollection following ischemic damage to the right anterior hippocampus.

Damage to the left medial temporal lobe (MTL) leads to an impairment of verbal recognition memory, affecting both the process of conscious recollection and familiarity-based recognition. Neuroimaging evidence, on the other hand, suggests a bilateral MTL contribution to verbal recollection. We investigated verbal recognition memory in three patients with focal ischemic lesions to the right MTL. The dual-process signal detection model and the process-dissociation procedure were applied to assess the contributions of recollection and familiarity to recognition memory. Compared to a group of 27 healthy age-matched controls, patients were impaired at recollection while familiarity was intact, and this effect was found for both estimation procedures. Detailed single-case analyses confirmed this pattern in two of the three right MTL patients. The findings suggest that, when task demands are high, as during recollective recognition, the right anterior hippocampus may also contribute to verbal recollection, thereby confirming neuroimaging evidence of a joint involvement of the left and the right MTL in verbal recollection.

Focal basal ganglia lesions are associated with impairments in reward-based reversal learning.

The basal ganglia (BG) are thought to play a key role in learning from feedback, with mesencephalic dopamine neurons coding errors in reward prediction, thereby mediating information processing in the BG and the prefrontal cortex. In the present study, reward-based learning was assessed in patients with focal BG lesions, by studying outcome-based acquisition and reversal of stimulus-stimulus associations with different reward magnitudes in two probabilistic learning tasks. Eleven patients with selective BG lesions (three females) and 18 healthy control subjects (six females) participated in this study. Two cognitive transfer tasks provided a measure of declarative learning strategy application. On the group level, BG patients showed deficits in reversal learning, with dorsal striatum lesion patients being most severely affected. While basic mechanisms of learning from feedback such as the processing of different reward magnitudes appeared to be intact, patients needed more trials than controls to learn a second reward-based task, suggesting reduced carry-over effects in learning. A patient with a bilateral BG lesion showed better performance than controls on most learning tasks, applying a compensatory declarative learning strategy. The results are discussed in terms of the implication of different BG subregions in different aspects of learning from feedback.

Involvement of the human thalamus in relational and non-relational memory.

Damage to the human thalamus has been associated with selective anterograde recognition memory impairments. Recently, recognition memory has been subdivided into relational and non-relational memory. The aim of the present study was to assess the potentially differential involvement of the human thalamus in relational and non-relational memory. Ten patients with focal ischemic thalamic lesions were compared to individualized control groups of healthy subjects matched to each individual patient on age and IQ. Six patients showed poorer relational memory than their respective control samples. None of the 10 patients showed a significant deficit on the non-relational memory task. These observations suggest an involvement of the thalamus in relational memory, and are discussed in terms of disruption of mediotemporal-thalamic and thalamic-fronto-striatal circuits.

The cerebellum is involved in reward-based reversal learning.

The cerebellum has recently been discussed in terms of a possible involvement in reward-based associative learning. To clarify the cerebellar contribution, eight patients with focal vascular lesions of the cerebellum and a group of 24 healthy subjects matched for age and IQ were compared on a range of different probabilistic outcome-based associative learning tasks, assessing acquisition, reversal, cognitive transfer, and generalization as well as the effect of reward magnitude. Cerebellar patients showed intact acquisition of stimulus contingencies, while reward-based reversal learning was significantly impaired. In addition, the patients showed slower acquisition of new stimulus contingencies in a second reward-based learning task, which might reflect reduced carry-over effects. Reward magnitude affected learning only during initial acquisition, with better learning on trials with high rewards in patients and control subjects. Overall, the findings suggest that the cerebellum is implicated in reversal learning as a dissociable component of reward-based learning.

Subcortical contributions to multitasking and response inhibition.

The involvement of the prefrontal cortex in executive control has been well established. It is, however, as yet unclear whether the basal ganglia and the cerebellum as components of frontostriatal/frontocerebellar networks also contribute to the executive domains multitasking and response inhibition. To investigate this issue, groups of patients with selective vascular lesions of the basal ganglia (n=13) or the cerebellum (n=14) were compared with matched healthy control groups. Several paradigms assessing the ability to process concurrent visual and auditory input and to simultaneously perform verbal and manual responses as well as the inhibition of habitual or newly acquired response tendencies were administered. Basal ganglia patients showed marked response slowing during coordination of sensory input from different modalities and high error rates during the inhibition of overlearned responses. There was no clear evidence of a cerebellar involvement in multitasking or response suppression. Taken together, the findings provided evidence for a striatal involvement in both multitasking and response inhibition, emphasizing the functional implication of subcortical components in frontostriatal circuits.

Fornix and medial temporal lobe lesions lead to comparable deficits in complex visual perception.

Recent research dealing with the structures of the medial temporal lobe (MTL) has shifted away from exclusively investigating memory-related processes and has repeatedly incorporated the investigation of complex visual perception. Several studies have demonstrated that higher level visual tasks can recruit structures like the hippocampus and perirhinal cortex in order to successfully perform complex visual discriminations, leading to a perceptual-mnemonic or representational view of the medial temporal lobe. The current study employed a complex visual discrimination paradigm in two patients suffering from brain lesions with differing locations and origin. Both patients, one with extensive medial temporal lobe lesions (VG) and one with a small lesion of the anterior fornix (HJK), were impaired in complex discriminations while showing otherwise mostly intact cognitive functions. The current data confirmed previous results while also extending the perceptual-mnemonic theory of the MTL to the main output structure of the hippocampus, the fornix.

Do normal D-dimer levels reliably exclude cerebral sinus thrombosis?

BACKGROUND AND PURPOSE: Cerebral sinus thrombosis (CST) needs to be considered in the differential diagnosis of all patients with acute headache. Early diagnosis is essential because early treatment may prevent morbidity and may even be life-saving. Definite exclusion, however, needs advanced neuroradiologic diagnostics, which are not readily available in many hospitals. Because measurement of D-dimers has been demonstrated to be helpful in excluding thromboembolic disease, our aim was to investigate whether D-dimers would be also sensitive enough to exclude CST. METHODS: We undertook a prospective multicenter study over a 2.5-year period including all patients who came to the emergency departments with symptoms suggestive of CST. All patients were diagnosed either by magnetic resonance venography, spiral computed tomography scan venography, or intra-arterial digital subtraction angiography. D-dimer levels were measured at admission and analyzed by the same method in all patients. RESULTS: A total of 343 patients were included. CST was diagnosed in 35 patients, of whom 34 had D-dimers above the cutoff value (>500 microg/L). From the 308 patients not having CST, D-dimers were elevated in 27. Sensitivity of D-dimers was 97.1%, with a negative predictive value of 99.6%. Specificity was 91.2%, with a positive predictive value of 55.7%. D-dimers were positively correlated with the extent of the thrombosis and negatively correlated with the duration of symptoms (Spearman rank correlation coefficients 0.76, -0.58, respectively). CONCLUSIONS: D-dimer measurement is useful in patients with suspected CST. Normal D-dimers make the presence of CST very unlikely.

Involvement of the mediodorsal thalamic nucleus in mediating recollection and familiarity.

The mediodorsal (MD) thalamic nucleus is thought to play an important role in memory processes. Distinct hippocampal-thalamic-prefrontal connections have been described as the potential neural substrate for both, recollection and familiarity. The aim of this study was to investigate whether the MD is part of the circuits underlying these two memory components. We assessed the effects of ischemic thalamic lesions with or without MD involvement on performance in a word list discrimination task and standard tests of memory and executive function. Estimates of recollection and familiarity were derived using the dual-process signal-detection model (DPSD). The results revealed impairments in both, recollection and familiarity, after unilateral thalamic damage, with recollection being more affected than familiarity. There were no significant differences in the memory performance of patients with MD lesions compared to patients with ventrolateral-thalamic lesions except for familiarity estimates, which were lower for the latter group. Lesions involving the MD led to recollection deficits, although inspection of individual cases suggested a decrease in both memory components after damage in the medial part of this nucleus. Executive dysfunction was associated with lateral MD lesions and also ventrolateral-thalamic damage. The findings suggest that MD contributes to recollection, with some preliminary evidence of a contribution of the medial MD to familiarity. The small sample size does, however, not yet allow any clear conclusions in this regard. Since damage in the ventrolateral thalamus leads to memory and executive dysfunction, further research is needed to elucidate the role of this thalamic region in cognition.

Recall deficits in stroke patients with thalamic lesions covary with damage to the parvocellular mediodorsal nucleus of the thalamus.

The functional role of the mediodorsal thalamic nucleus (MD) and its cortical network in memory processes is discussed controversially. While Aggleton and Brown (1999) suggested a role for recognition and not recall, Van der Werf et al. (2003) suggested that this nucleus is functionally related to executive function and strategic retrieval, based on its connections to the prefrontal cortices (PFC). The present study used a lesion approach including patients with focal thalamic lesions to examine the functions of the MD, the intralaminar nuclei and the midline nuclei in memory processing. A newly designed pair association task was used, which allowed the assessment of recognition and cued recall performance. Volume loss in thalamic nuclei was estimated as a predictor for alterations in memory performance. Patients performed poorer than healthy controls on recognition accuracy and cued recall. Furthermore, patients responded slower than controls specifically on recognition trials followed by successful cued recall of the paired associate. Reduced recall of picture pairs and increased response times during recognition followed by cued recall covaried with the volume loss in the parvocellular MD. This pattern suggests a role of this thalamic region in recall and thus recollection, which does not fit the framework proposed by Aggleton and Brown (1999). The functional specialization of the parvocellular MD accords with its connectivity to the dorsolateral PFC, highlighting the role of this thalamocortical network in explicit memory (Van der Werf et al., 2003).

Cerebellar lesions alter performance monitoring on the antisaccade task--an event-related potentials study.

Error processing is associated with distinct event-related potential components (ERPs), i.e. the error-related negativity (ERN) which occurs within approximately 150 ms and is typically more pronounced than the correct-response negativity (CRN), and the error positivity (Pe) emerging from about 200 to 400 ms after an erroneous response. The short latency of the ERN suggests that the internal error monitoring system acts on rapidly available central information such as an efference copy signal rather than slower peripheral feedback. The cerebellum has been linked to an internal forward-model which enables online performance monitoring by predicting the sensory consequences of actions, most probably by making use of efference copies. In the present study it was hypothesized that the cerebellum is involved in the fast evaluation of saccadic response accuracy as reflected by the ERN. Error processing on an antisaccade task was investigated in eight patients with focal vascular lesions to the cerebellum and 22 control subjects using ERPs. While error rates were comparable between groups, saccadic reaction times (SRTs) were enhanced in the patients, and the error-correct difference waveforms showed reduced amplitudes for patients relative to controls in the ERN time window. Notably, this effect was mainly driven by an increased CRN in the patients. In the later Pe time window, the difference signal yielded higher amplitudes in patients compared to controls mainly because of smaller Pe amplitudes on correct trials in patients. The altered ERN/CRN pattern suggests that the cerebellum is critically involved in fast classification of saccadic accuracy. Largely intact performance accuracy together with increased SRTs and the altered Pe pattern may indicate a compensatory mechanism presumably related to slower, more conscious aspects of error processing in the patients.

Altered error processing following vascular thalamic damage: evidence from an antisaccade task.

Event-related potentials (ERP) research has identified a negative deflection within about 100 to 150 ms after an erroneous response--the error-related negativity (ERN)--as a correlate of awareness-independent error processing. The short latency suggests an internal error monitoring system acting rapidly based on central information such as an efference copy signal. Studies on monkeys and humans have identified the thalamus as an important relay station for efference copy signals of ongoing saccades. The present study investigated error processing on an antisaccade task with ERPs in six patients with focal vascular damage to the thalamus and 28 control subjects. ERN amplitudes were significantly reduced in the patients, with the strongest ERN attenuation being observed in two patients with right mediodorsal and ventrolateral and bilateral ventrolateral damage, respectively. Although the number of errors was significantly higher in the thalamic lesion patients, the degree of ERN attenuation did not correlate with the error rate in the patients. The present data underline the role of the thalamus for the online monitoring of saccadic eye movements, albeit not providing unequivocal evidence in favour of an exclusive role of a particular thalamic site being involved in performance monitoring. By relaying saccade-related efference copy signals, the thalamus appears to enable fast error processing. Furthermore early error processing based on internal information may contribute to error awareness which was reduced in the patients.

Domain-specific impairment of source memory following a right posterior medial temporal lobe lesion.

This single case analysis of memory performance in a patient with an ischemic lesion affecting posterior but not anterior right medial temporal lobe (MTL) indicates that source memory can be disrupted in a domain-specific manner. The patient showed normal recognition memory for gray-scale photos of objects (visual condition) and spoken words (auditory condition). While memory for visual source (texture/color of the background against which pictures appeared) was within the normal range, auditory source memory (male/female speaker voice) was at chance level, a performance pattern significantly different from the control group. This dissociation is consistent with recent fMRI evidence of anterior/posterior MTL dissociations depending upon the nature of source information (visual texture/color vs. auditory speaker voice). The findings are in good agreement with the view of dissociable memory processing by the perirhinal cortex (anterior MTL) and parahippocampal cortex (posterior MTL), depending upon the neocortical input that these regions receive.

Altered processing of corollary discharge in thalamic lesion patients.

Accumulating evidence suggests that thalamic nuclei relay corollary discharge information of saccadic eye movements, enabling the visual system to update the representation of visual space. The present study aimed to explore the effect of thalamic lesions in humans on updating-related cortical processing. Event-related potentials were recorded while four patients with impairments in using corollary discharge information and 12 healthy control subjects performed a saccadic double-step task. In the experimental condition, which required the use of corollary discharge information, control subjects showed a pronounced positivity over the parietal cortex starting about 150 ms after first saccade onset, reflecting the updating process. In the patients, parietal processing related to updating was altered. Three patients showed evidence of reduced updating event-related potential effects, consistent with a unilateral deficit in using corollary discharge information. In two patients, the event-related potential topography differed significantly from the topography pattern observed in controls. Thalamic damage affects updating-related processing, presumably due to insufficient transfer of saccade-related information to parietal areas. This study thus provides further evidence for thalamic involvement in relaying corollary discharge information related to saccadic eye movements. Our data suggest that integration of corollary discharge and motor information occurs directly before the second saccade in a double-step task.