Cerebellum's Contribution to Attention, Executive Functions and Timing: Psychophysiological Evidence from Event-Related Potentials.

Since 1998, when Schmahmann first proposed the concept of the "cognitive affective syndrome" that linked cerebellar damage to cognitive and emotional impairments, a substantial body of literature has emerged. Anatomical, neurophysiological, and functional neuroimaging data suggest that the cerebellum contributes to cognitive functions through specific cerebral-cerebellar connections organized in a series of parallel loops. The aim of this paper is to review the current findings on the involvement of the cerebellum in selective cognitive functions, using a psychophysiological perspective with event-related potentials (ERPs), alone or in combination with non-invasive brain stimulation techniques. ERPs represent a very informative method of monitoring cognitive functioning online and have the potential to serve as valuable biomarkers of brain dysfunction that is undetected by other traditional clinical tools. This review will focus on the data on attention, executive functions, and time processing obtained in healthy subjects and patients with varying clinical conditions, thus confirming the role of ERPs in understanding the role of the cerebellum in cognition and exploring the potential diagnostic and therapeutic implications of ERP-based assessments in patients.

Role of Functional Neuroimaging with 123I-MIBG and 123I-FP-CIT in De Novo Parkinson's Disease: A Multicenter Study.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder, with incidence and prevalence rates of 8-18 per 100,000 people per year and 0.3-1%, respectively. As parkinsonian symptoms do not appear until approximately 50-60% of the nigral DA-releasing neurons have been lost, the impact of routine structural imaging findings is minimal at early stages, making Parkinson's disease an ideal condition for the application of functional imaging techniques. The aim of this multicenter study is to assess whether 123I-FP-CIT (DAT-SPECT), 123I-MIBG (mIBG-scintigraphy) or an association of both exams presents the highest diagnostic accuracy in de novo PD patients. METHODS: 288 consecutive patients with suspected diagnoses of Parkinson's disease or non- Parkinson's disease syndromes were analyzed in the present Italian multicenter retrospective study. All subjects were de novo, drug-naive patients and met the inclusion criteria of having undergone both DAT-SPECT and mIBG-scintigraphy within one month of each other. RESULTS: The univariate analysis including age and both mIBG-SPECT and DAT-SPECT parameters showed that the only significant values for predicting Parkinson's disease in our population were eH/M, lH/M, ESS and LSS obtained from mIBG-scintigraphy (p < 0.001). CONCLUSIONS: mIBG-scintigraphy shows higher diagnostic accuracy in de novo Parkinson's disease patients than DAT-SPECT, so given the superiority of the MIBG study, the combined use of both exams does not appear to be mandatory in the early phase of Parkinson's disease.

Fatigue in fluctuating Parkinson's disease patients: possible impact of safinamide.

Fatigue is a common non-motor symptom in Parkinson's disease (PD). Among other pathophysiological mechanisms, neuroinflammation, a pathological PD hallmark associated with changes in glutamatergic transmission in basal ganglia, has been proposed as a crucial factor closely related to fatigue. To test the hypothesis that safinamide could represent an effective treatment of fatigue in PD patients, given its dual mechanism of action (it selectively and reversibly inhibits MAOB and modulates glutamate release), we administered the validated versions of fatigue severity scale (FSS) and Parkinson fatigue scale-16 (PFS-16) to 39 fluctuating PD patients with fatigue before and after a 24-week treatment period with safinamide as add-on therapy. An assessment of secondary variables such as depression, quality of life (QoL), and motor and non-motor symptoms (NMS) was conducted. After 24 weeks of treatment with safinamide, both FSS (p < 0.001) and PF-S16 (p = 0.02) scores were significantly lower than at baseline. Moreover, 46.2% and 41% of patients scored below the cut-off for the presence of fatigue according to FSS and PFS-16, respectively (responders). At follow-up, a significant difference emerged between responders and non-responders in mood, QoL, and NMS. Fatigue improved in fluctuating PD, and more than 40% of patients were "fatigue-free" after a 6 month treatment with safinamide. Patients without fatigue at follow-up displayed significantly better scores in QoL domains, such as mobility or activities of daily living, although disease severity remained stable, supporting the hypothesis that fatigue could considerably affect QoL. Drugs that interact with multiple neurotransmission systems, such as safinamide, could be useful in reducing this symptom.

The role of cerebellum in timing processing: A contingent negative variation study.

Time management is an important aspect of human behaviour and cognition. Several brain regions are thought to be involved in motor timing and time estimation tasks. However, subcortical regions such as the basal nuclei and cerebellum seem to play a role in timing control. The aim of this study was to investigate the role of the cerebellum in temporal processing. For this purpose, we transitorily inhibited cerebellar activity by means of cathodal transcranial direct current stimulation (tDCS) and studied the effects of this inhibition on contingent negative variation (CNV) parameters elicited during a S1-S2 motor task in healthy subjects. Sixteen healthy subjects underwent a S1-S2 motor task prior to and after cathodal and sham cerebellar tDCS in separate sessions. The CNV task consisted of a duration discrimination task in which subjects had to determine whether the duration of a probe interval trial was shorter (800 ms), longer (1600 ms), or equal to the target interval of 1200 ms. A reduction in total CNV amplitude emerged only after cathodal tDCS for short and target interval trials, while no differences were detected for the long interval trial. Errors were significantly higher after cathodal tDCS than at baseline evaluation of short and target intervals. No reaction time differences were found for any time interval after the cathodal and sham sessions. These results point to a role of the cerebellum in time perception. In particular, the cerebellum seems to regulate temporal interval discrimination for second and sub-second ranges.

Serotonergic central tone in Parkinson's disease with fatigue: Evidence from the loudness dependence of auditory evoked potentials (LDAEP).

Central fatigue in Parkinson's disease (PD) is a common and disabling symptom that further worsens the patients' quality of life. A deficit in the serotonergic system may be implicated in the occurrence of fatigue in patients with PD as well as in those with other chronic conditions characterized by fatigue. The loudness dependence of auditory evoked potentials (LDAEP) is a neurophysiological tool that has proved to be effective in measuring the serotonergic central function in vivo. The aim of the present study was to assess central serotonergic activity in PD patients and to explore its possible association with the presence of fatigue. LDAEP was recorded in 38 PD patients (26 without fatigue - PDnF and 12 with fatigue - PDF) and 34 healthy controls. A significant difference between parkinsonian patients and controls emerged, with patients displaying stronger LDAEP values (which reflect a lower serotonergic central tone) than controls. By contrast, no differences in LDAEP emerged between PDF and PDnF. Our electrophysiological data confirmed the presence of a deficit in serotonergic central transmission in PD. An association between this deficit and fatigue was not demonstrated. It is likely that an altered dopamine/serotonin balance, rather than a serotonin deficit alone, is involved in the genesis of central fatigue. This complex and multifaceted symptom is related above all to a dysfunction in the striato-thalamo-cortical loop that connects the neostriatum to the frontal lobe and is strongly affected by motivation.

Effects of Cerebellar tDCS on Inhibitory Control: Evidence from a Go/NoGo Task.

Response inhibition as an executive function refers to the ability to suppress inappropriate but prepotent responses. Several brain regions have been implicated in the process underlying inhibitory control, including the cerebellum. The aim of the present study was to explore the role of the cerebellum in executive functioning, particularly in response inhibition. For this purpose, we transitorily inhibited cerebellar activity by means of cathodal tDCS and studied the effects of this inhibition on ERP components elicited during a Go/NoGo task in healthy subjects. Sixteen healthy subjects underwent a Go/NoGo task prior to and after cathodal and sham cerebellar tDCS in separate sessions. A reduction in N2-NoGo amplitude and a prolongation in N2-NoGo latency emerged after cathodal tDCS whereas no differences were detected after sham stimulation. Moreover, commission errors in NoGo trials were significantly higher after cathodal tDCS than at the basal evaluation. No differences emerged between performances in Go trials and those after sham stimulation. These data indicate that cerebellar inhibition following cathodal stimulation alters the ability to allocate attentional resources to stimuli containing conflict information and the inhibitory control. The cerebellum may regulate the attentional mechanisms of stimulus orientation and inhibitory control both directly, by making predictions of errors or behaviors related to errors, and indirectly, by controlling the functioning of the cerebral cortical areas involved in the perception of conflict signals and of the basal ganglia involved in the inhibitory control of movement.

Pearls and pitfalls in brain functional analysis by event-related potentials: a narrative review by the Italian Psychophysiology and Cognitive Neuroscience Society on methodological limits and clinical reliability-part I.

Event-related potentials (ERPs) are obtained from the electroencephalogram (EEG) or the magnetoencephalogram (MEG, event-related fields (ERF)), extracting the activity that is time-locked to an event. Despite the potential utility of ERP/ERF in cognitive domain, the clinical standardization of their use is presently undefined for most of procedures. The aim of the present review is to establish limits and reliability of ERP medical application, summarize main methodological issues, and present evidence of clinical application and future improvement. The present section of the review focuses on well-standardized ERP methods, including P300, Contingent Negative Variation (CNV), Mismatch Negativity (MMN), and N400, with a chapter dedicated to laser-evoked potentials (LEPs). One section is dedicated to proactive preparatory brain activity as the Bereitschaftspotential and the prefrontal negativity (BP and pN). The P300 and the MMN potentials have a limited but recognized role in the diagnosis of cognitive impairment and consciousness disorders. LEPs have a well-documented usefulness in the diagnosis of neuropathic pain, with low application in clinical assessment of psychophysiological basis of pain. The other ERP components mentioned here, though largely applied in normal and pathological cases and well standardized, are still confined to the research field. CNV, BP, and pN deserve to be largely tested in movement disorders, just to explain possible functional changes in motor preparation circuits subtending different clinical pictures and responses to treatments.

Central fatigue and attentional processing in Parkinson's disease: An event-related potentials study.

OBJECTIVE: To verify whether central fatigue in patients with Parkinson's disease (PD) is associated with the presence of a more severe selective cognitive impairment. METHODS: Twenty-four PD patients without fatigue-PDnF, 11 with fatigue-PDF and 32 healthy volunteers underwent a P300 novelty task that elicits both the P3a and the P3b components. RESULTS: P3b latency was significantly longer in both PDF and PDnF than in controls. P3b amplitudes were comparable between groups. P3a latency and P3a amplitude were respectively significantly longer and lower in PDF than in either PDnF or controls. CONCLUSION: The ability to discriminate the significant target stimulus, which requires the integrity of the dorsal attentional network and top-down control mechanisms, is compromised in parkinsonian patients irrespective of the presence of fatigue. PDF exhibited a difficulty in attentional orienting to salient novel stimuli, a bottom-up attentional control mechanism that is related to the functioning of the ventral attention network. SIGNIFICANCE: Fatigue seems to be specifically related to an impairment in the processing of novel stimuli, which is an essential part of adaptive decision-making behavior.

The Cerebellum Modulates Attention Network Functioning: Evidence from a Cerebellar Transcranial Direct Current Stimulation and Attention Network Test Study.

The functional domain of the cerebellum extends beyond its traditional role in motor control. In recent years, this structure has increasingly been considered to play a crucial role even in cognitive performance and attentional processes. Attention is defined as the ability to appropriately allocate processing resources to relevant stimuli. According to the Posnerian model, three interacting networks modulate attentive processes: the alerting, orienting, and executive networks. The aim of this study was to investigate the role played by the cerebellum in the functioning of the attentive networks using the Attention Network Test (ANT). We studied the effects of transcranial direct current stimulation (tDCS), delivered over the cerebellum in cathodal, anodal, and sham sessions, on ANT parameters in healthy subjects. After anodal and sham tDCS, the efficiency of the three attention networks remained stable, and a significant reduction in reaction time (RT) following the task repetition was observed for both congruent and incongruent targets, indicating a learning effect. After cathodal stimulation, instead, while the efficiency of the alerting and orienting networks remained stable, the efficiency of the executive network was significantly reduced. Moreover, a significant reduction in RT was observed for the congruent target alone, with no difference being detected for the incongruent target, indicating that cerebellar inhibition caused an attentive executive dysfunction specifically related to the ability to process complex stimuli in which conflict signals or errors are present. These results point to a role of the cerebellum, a subcortical structure that is thought to affect error processing both directly, by making predictions of errors or behaviors related to errors, and indirectly, by managing the functioning of brain cortical areas involved in the perception of conflicting signals, in the functioning of the attentional networks, particularly the executive network.

Attentional functioning in individuals with 22q11 deletion syndrome: insight from ERPs.

The 22q11 deletion syndrome (22q11DS), or DiGeorge syndrome (DG), is one of the most common genetic deletion syndromes. DG also carries a high risk for psychiatric disorders, with learning disabilities frequently being reported. Impairments in specific cognitive domains, such as executive functioning and attention, have also been described. The aim of this study was to investigate attentional functioning in a group of subjects with DG using ERPs, and in particular the P300 and CNV components. We studied ten patients with DG and ten healthy subjects that performed a P300 Novelty task and a CNV motor task. P3b amplitude was significantly lower in patients than in controls, while P3b latency was comparable in patients and controls. The P3a parameters were similar in both groups. All CNV amplitudes were significantly lower in DG patients than in controls. DG patients displayed slower reaction times in the CNV motor task than healthy subjects. These results point to a cognitive dysfunction related above all to executive attentional processing in DG patients. In particular, a specific difficulty emerged in selective attention and in the ability to orient and to sustain the anticipatory attention required for an executive motor response.

Selective attentional impairment in chronic tinnitus: Evidence from an event-related potentials study.

OBJECTIVE: Tinnitus is an auditory phantom sensation experienced in the absence of a sound source. Cognitive dysfunctions, especially in working memory and attention, are frequently reported to be associated with tinnitus. The aim of this study was to investigate attentional functioning in a group of subjects with chronic tinnitus using ERPs, and in particular the P300 components. METHODS: We studied 20 patients with chronic tinnitus and 20 healthy subjects that performed a P300 Novelty task. RESULTS: P3a amplitude was significantly lower in tinnitus subjects than in controls. P3a latency was comparable in patients and controls. The P3b parameters were similar in the two groups. N1 latency for all the stimuli was significantly longer in tinnitus subjects than in controls. CONCLUSION: These results point to a general slowing in early stimulus perception in tinnitus subjects. Moreover, a specific difficulty emerged in attentional switching to unexpected events during an orienting response, probably owing to a dysfunction in the ventral attention network. SIGNIFICANCE: Psychophysiological approach reveals selective attentional impairment and could provide useful data for rehabilitative strategies in chronic tinnitus.

Prefronto-cerebellar tDCS enhances neurocognition in euthymic bipolar patients. Findings from a placebo-controlled neuropsychological and psychophysiological investigation.

OBJECTIVES: The present double blind placebo-controlled study aimed at investigating the efficacy of 3-weeks prefronto-cerebellar transcranial direct current stimulation (tDCS) on neurocognitive functioning in euthymic BD patients. METHODS: Forty-two outpatients with BD were randomly assigned to receive either active (n=21) or sham (n=21) prefronto-cerebellar tDCS for 3 consecutive weeks. Neurocognitive abilities were assessed with both neuropsychological testing and psychophysiological evaluation with a P300 novelty task. RESULTS: Our results showed that (i) Trail Making Test-B, a measure of executive functioning, decreased significantly in the active but not in the sham group, (ii) Rey Complex Figure Test Delay Recall, a measure of visuospatial memory, increased significantly in both groups with a greater increase in the active compared to the sham group, and (iii) P3b latency, a measure of brain information processing stream, decreased significantly in the active but not in the sham group. No significant changes were observed in the other explored neuropsychological and psychophysiological measures. CONCLUSIONS: The study suggests that concomitant prefrontal-excitatory and cerebellar-inhibitory tDCS in euthymic BD patients may lead to better neurocognitive performance, quantified through neuropsychological and psychophysiological measures.

Attention in Parkinson's disease with fatigue: evidence from the attention network test.

Fatigue is a non-specific symptom that is common in chronic diseases and represents one of the most disabling symptoms in Parkinson's disease. PD patients often experience cognitive deficits related above all to executive functions. The relationship between cognitive changes and fatigue in PD patients has not been explored in depth. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e., alerting, orienting, and executive, by evaluating reaction times (RTs) in response to visual stimuli. To assess the association between fatigue and the efficiency of the attentional networks, according to the Posnerian view, ANT was administered to 15 parkinsonian patients with fatigue (PFS-16 > 2.95), 17 parkinsonian patients without fatigue, and 37 age- and sex-matched healthy controls. Anxiety, depression, quality of sleep, and quality of life were also assessed. Parkinsonian patients displayed significantly longer RTs and lower executive network efficiency than controls. Patients with fatigue displayed significantly lower executive network efficiency than patients without fatigue. Moreover, patients with fatigue exhibited a lower accuracy than either patients without fatigue or controls. Finally, patients without fatigue displayed a more efficient alerting network than either patients with fatigue or controls. Although the pathogenesis of fatigue is multifactorial, our results indicate that fatigue may be closely related to an alteration of the striato-thalamo-cortical loop connecting the neostriatum to the prefrontal cortex, which is also responsible for the executive dysfunction that is typical of Parkinson's disease.

Effects of cerebellar transcranial direct current stimulation on attentional processing of the stimulus: Evidence from an event-related potentials study.

Attentional processing consists of a set of processes that manage the flow of information through the nervous system and appropriately allocate attentional resources to relevant stimuli. Specific networks in the frontal and parietal regions appear to be involved in attention. The cerebellum has been identified as a subcortical structure that interacts with cortical brain areas, thereby controlling attentional processes. The aim of this study was to investigate the role of the cerebellum in attentional processing of the stimulus using a P300 Novelty task. We studied the effects of transcranial Direct Current Stimulation (tDCS) delivered over the left cerebellar hemisphere in cathodal, anodal and sham sessions on the P300 components in healthy subjects. Only cathodal cerebellar tDCS significantly reduced the amplitude of the N1, N2 and P3 components for both the target and novel stimuli. Moreover, N1 latency for all the stimuli was shorter after the cathodal tDCS session than after the sham or anodal sessions. These results point to a role of the cerebellum in attentional processing of the stimulus. The cerebellum may act indirectly by regulating and managing the activation and inhibition levels of the cortical areas involved in attentional networks.

Prefrontocerebellar transcranial direct current stimulation increases amplitude and decreases latency of P3b component in patients with euthymic bipolar disorder.

INTRODUCTION: Neurocognitive impairments have been observed in patients with bipolar disorder (BD) even during the euthymic phase of the disease, potentially representing trait-associated rather than state-associated characteristics of the disorder. In the present study, we used transcranial direct current stimulation (tDCS) applied to cerebellar and prefrontal cortices to improve the neurophysiological performances of patients with euthymic BD. METHODS: Twenty-five outpatients with BD underwent open-label prefrontocerebellar tDCS for 3 consecutive weeks. Neurophysiological performances were assessed through the examination of the P3b and P3a subcomponents of P300 event-related potential at baseline and after stimulation. RESULTS: Compared to baseline, P3b component after tDCS showed significantly higher amplitude and shorter latency (latency: Fz P=0.02, Cz P=0.03, and Pz P=0.04; amplitude: Fz P=0.24, Cz P=0.02, and Pz P=0.35). CONCLUSION: In our sample of patients with euthymic BD, concomitant prefrontoexcitatory and cerebellar-inhibitory modulations led to improved brain information processing stream. This improvement may at least partially result from neuroplastic modulation of prefrontocerebellar circuitry activity.

Selective attentional deficit in essential tremor: Evidence from the attention network test.

INTRODUCTION: The traditional view of essential tremor (ET) as a monosymptomatic and benign disorder has been reconsidered after patients with ET have been shown to experience cognitive deficits that are also related to attention. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e. alerting, orienting and executive, by evaluating reaction times (RTs) in response to visual stimuli. The aim of this study was to investigate attentional functioning in ET patients by means of the ANT. METHODS: 21 non-demented patients with ET and 21 age- and sex-matched healthy controls performed the ANT. RESULTS: RT was significantly longer in ET patients than in controls (p < 0.001). Moreover, a significant difference in alerting and executive efficiency (p = 0.003 and p = 0.01 respectively) was found between groups, while the difference in the orienting efficiency only bordered on significance. CONCLUSION: Our results point to a difficulty in the alerting and executive domains of attention in ET patients, probably owing to a dysfunction in the cerebello-thalamo-cortical loop. These selective attentional deficits are not related to clinical motor symptoms, contributing to shed further light on the clinical picture of ET.

The Role of the Right Dorsolateral Prefrontal Cortex in Phasic Alertness: Evidence from a Contingent Negative Variation and Repetitive Transcranial Magnetic Stimulation Study.

Phasic alertness represents the ability to increase response readiness to a target following an external warning stimulus. Specific networks in the frontal and parietal regions appear to be involved in the alert state. In this study, we examined the role of the right dorsolateral prefrontal cortex (DLPFC) during the attentional processing of a stimulus using a cued double-choice reaction time task. The evaluation of these processes was conducted by means of Event-Related Potentials (ERPs), in particular by using the Contingent Negative Variation (CNV), and repetitive 1-Hz Transcranial Magnetic Stimulation (rTMS). Transient virtual inhibition of the right DLPFC induced by real 1-Hz rTMS stimulation led to a significant decrease in total CNV and W1-CNV areas if compared with the basal and post-sham rTMS conditions. Reaction times (RTs) did not decrease after inhibitory rTMS, but they did improve after sham stimulation. These results suggest that the right DLPFC plays a crucial role in the genesis and maintenance of the alerting state and learning processes.

P300 component in euthymic patients with bipolar disorder type I, bipolar disorder type II and healthy controls: a preliminary event-related potential study.

The aim of the present study was to investigate P300 event-related potential components in euthymic bipolar disorder type I (BDI) and bipolar disorder type II (BDII) patients and matched controls. A total of 10 BDI patients, 10 BDII patients and 10 healthy individuals were enrolled in the study. Event-related potential data were collected according to a standard auditory 'oddball' paradigm. A significant groups effect in both the peak amplitude (P<0.001) and the mean amplitude (P<0.001) was observed; post-hoc comparisons showed that the peak and mean amplitudes of BDI and BDII patients were significantly lower than the peak and mean amplitudes of the healthy controls. The neurophysiological patterns found in the present study might at least partially reflect the presence of a mild selective cognitive impairment in euthymic BDI and BDII patients. From a clinical point of view, these evidences support the potential role of cognitive interventions in the treatment of BD.

Insights from ERPs into attention during recovery after cerebellar stroke: a case report.

The role of the cerebellum in cognitive performance and attentional processes is a focus of research in recent years. We investigated the P300 component in a patient with a left posterior cerebellar ischemic stroke during both the acute phase and over 4 weeks of follow-up. After stroke, auditory event-related potentials showed a reduction in P3 amplitude, which appears to improve instead after 4 weeks of follow-up. These event-related potential findings could suggest a specific neural pattern of disruption in selective attention during the discrimination processes of the stimulus following a posterior cerebellar lesion. A recovery is observed in the long term.

Phasic alertness in a cued double-choice reaction time task: a Contingent Negative Variation (CNV) study.

A phasic change in alertness is produced every time that a warning stimulus precedes a target, and it enhances and maintains the response readiness to an impending stimulus. In the present study, we investigated the Contingent Negative Variation (CNV) phenomenon, as index of phasic alertness, during a S1-S2 paradigm in which the imperative stimulus was represented by a double-choice reaction time task, designed to increase the executive requests at S2. Subjects performed the task at three consecutive time points in order to explore the CNV activity over time. The repetition of a cued double-choice reaction time task reduced the reaction times (RTs), while CNV amplitude remained steady along the sessions. Our data suggest that the continuous recruitment of attentional resources does not undergo habituation when it is related to the brain activity required in the maintenance of working memory when the mental model of the stimulus environment is updated.