Out with the Old and in with the New: the Contribution of Prefrontal and Cerebellar Areas to Backward Inhibition.

The inhibitory mechanism named backward inhibition (BI) counteracts interference of previous tasks supporting task switching. For instance, if task set A is inhibited when switching to task B, then it should take longer to immediately return to task set A (as occurring in an ABA sequence), as compared to a task set that has not been just inhibited (as occurring in a CBA sequence), because extra time will be needed to overcome the inhibition of task set A.The evidenced prefrontal and cerebellar role in inhibitory control suggests their involvement even in BI. Here, for the first time, we modulated the excitability of multiple brain sites (right presupplementary motor area (pre-SMA), left and right cerebellar hemispheres) through continuous theta burst stimulation (cTBS) in a valuable sham-controlled order-balanced within-subject experimental design in healthy individuals performing two domain-selective (verbal and spatial) task-switching paradigms. Verbal BI was abolished by prefrontal or cerebellar stimulations through opposite alterations of the basal pattern: cTBS on pre-SMA increased CBA reaction times, disclosing the current prefrontal inhibition of any interfering old task. Conversely, cerebellar cTBS decreased ABA reaction times, disclosing the current cerebellar recognition of sequences in which it is necessary to overcome previously inhibited events.

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy.

Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient's clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease.

Prismatic Adaptation Modulates Oscillatory EEG Correlates of Motor Preparation but Not Visual Attention in Healthy Participants.

Prismatic adaption (PA) has been proposed as a tool to induce neural plasticity and is used to help neglect rehabilitation. It leads to a recalibration of visuomotor coordination during pointing as well as to aftereffects on a number of sensorimotor and attention tasks, but whether these effects originate at a motor or attentional level remains a matter of debate. Our aim was to further characterize PA aftereffects by using an approach that allows distinguishing between effects on attentional and motor processes. We recorded EEG in healthy human participants (9 females and 7 males) while performing a new double step, anticipatory attention/motor preparation paradigm before and after adaptation to rightward-shifting prisms, with neutral lenses as a control. We then examined PA aftereffects through changes in known oscillatory EEG signatures of spatial attention orienting and motor preparation in the alpha and beta frequency bands. Our results were twofold. First, we found PA to rightward-shifting prisms to selectively affect EEG signatures of motor but not attentional processes. More specifically, PA modulated preparatory motor EEG activity over central electrodes in the right hemisphere, contralateral to the PA-induced, compensatory leftward shift in pointing movements. No effects were found on EEG signatures of spatial attention orienting over occipitoparietal sites. Second, we found the PA effect on preparatory motor EEG activity to dominate in the beta frequency band. We conclude that changes to intentional visuomotor, rather than attentional visuospatial, processes underlie the PA aftereffect of rightward-deviating prisms in healthy participants.SIGNIFICANCE STATEMENT Prismatic adaptation (PA) has been proposed as a tool to induce neural plasticity in both healthy participants and patients, due to its aftereffect impacting on a number of visuospatial and visuomotor functions. However, the neural mechanisms underlying PA aftereffects are poorly understood as only little neuroimaging evidence is available. Here, we examined, for the first time, the origin of PA aftereffects studying oscillatory brain activity. Our results show a selective modulation of preparatory motor activity following PA in healthy participants but no effect on attention-related activity. This provides novel insight into the PA aftereffect in the healthy brain and may help to inform interventions in neglect patients.

Early detection of memory impairments in older adults: standardization of a short version of the verbal and nonverbal Recognition Memory Test.

In several neurological conditions, in elderly and cognitively impaired subjects, memory functioning must be evaluated to early detect the cognitive deterioration processes. In particular, recognition memory assessment is an essential step in the clinical and neuropsychological evaluation of early memory impairments. The Recognition Memory Test (RMT) developed by Smirni et al. (G Ital Psicol XXXVII(1):325-343, 2010) is an effective instrument to assess verbal and nonverbal recognition memory in the Italian population. The current study provides a new, brief, and reliable RMT format to evaluate recognition memory on elderly subjects and it reports normative data in an older adult Italian population sample (including 100 participants well distributed across sex, education, and age categories). The shortened version of RMT keeps the administration procedures and materials of the original Italian RMT constant, i.e., words, faces, and buildings. Multiple regression analysis revealed significant effects of age and educational level on performance but no effect of sex. Inferential cutoffs have been determined and equivalent scores computed. The availability of equivalent scores for the Recognition Memory Test will prove useful in the clinical evaluation of patients' memory profiles.

Benton visual form discrimination test in healthy children: normative data and qualitative analysis.

The attention evaluation may be considered a crucial phase in neuropsychological assessment. It must take into account the systemic nature of the attentional functions and must use different reliable tests in relation to the neurological and attentional problems to be addressed. The aim of the study was to offer the clinician an effective tool for attention assessment and provide the normative data and performance analysis on the Benton Visual Form Discrimination Test on an Italian sample (number 323) of healthy school children, from ages 5 to 11. Performance on Visual Form Discrimination Test (VFDT) significantly increased with growing age. Performances were significantly different when the test was divided into four sets. All groups, especially the younger ones, showed some difficulty in maintenance and sustained attention. The correct answers were significantly more numerous when they were placed at the top quadrants. This effect was more marked in the younger groups. Sex was never a significantly influencing performance. Our data seem to indicate that the higher attentional frontoparietal network becomes more functionally organized around 9-10 years. VFDT appears as a discriminative task. In clinical practice, our normative data can be used both on complex visual attention skill evaluation in children and on the ability to maintain visual attention in time.

Standardization and validation of a parallel form of the verbal and non-verbal recognition memory test in an Italian population sample.

In the neuropsychological assessment of several neurological conditions, recognition memory evaluation is requested. Recognition seems to be more appropriate than recall to study verbal and non-verbal memory, because interferences of psychological and emotional disorders are less relevant in the recognition than they are in recall memory paradigms. In many neurological disorders, longitudinal repeated assessments are needed to monitor the effectiveness of rehabilitation programs or pharmacological treatments on the recovery of memory. In order to contain the practice effect in repeated neuropsychological evaluations, it is necessary the use of parallel forms of the tests. Having two parallel forms of the same test, that kept administration procedures and scoring constant, is a great advantage in both clinical practice, for the monitoring of memory disorder, and in experimental practice, to allow the repeated evaluation of memory on healthy and neurological subjects. First aim of the present study was to provide normative values in an Italian sample (n = 160) for a parallel form of a verbal and non-verbal recognition memory battery. Multiple regression analysis revealed significant effects of age and education on recognition memory performance, whereas sex did not reach a significant probability level. Inferential cutoffs have been determined and equivalent scores computed. Secondly, the study aimed to validate the equivalence of the two parallel forms of the Recognition Memory Test. The correlations analyses between the total scores of the two versions of the test and correlation between the three subtasks revealed that the two forms are parallel and the subtasks are equivalent for difficulty.

Processing past tense in the left cerebellum.

We report the case of a patient with ischemic lesion of the left cerebellum, who showed specific deficits in processing past versus future tense of action verbs. These findings confirm, in the presence of cerebellar damage, previous results obtained with transcranial magnetic stimulation in healthy subjects and suggest a specificity of the left cerebellum for preparation of responses to the past tense of action verbs. As part of the procedural brain, the cerebellum could play a role in applying the linguistic rules for selection of morphemes typical of past and future tense formation.

Left insular cortex and left SFG underlie prismatic adaptation effects on time perception: evidence from fMRI.

Prismatic adaptation (PA) has been shown to affect left-to-right spatial representations of temporal durations. A leftward aftereffect usually distorts time representation toward an underestimation, while rightward aftereffect usually results in an overestimation of temporal durations. Here, we used functional magnetic resonance imaging (fMRI) to study the neural mechanisms that underlie PA effects on time perception. Additionally, we investigated whether the effect of PA on time is transient or stable and, in the case of stability, which cortical areas are responsible of its maintenance. Functional brain images were acquired while participants (n=17) performed a time reproduction task and a control-task before, immediately after and 30 min after PA inducing a leftward aftereffect, administered outside the scanner. The leftward aftereffect induced an underestimation of time intervals that lasted for at least 30 min. The left anterior insula and the left superior frontal gyrus showed increased functional activation immediately after versus before PA in the time versus the control-task, suggesting these brain areas to be involved in the executive spatial manipulation of the representation of time. The left middle frontal gyrus showed an increase of activation after 30 min with respect to before PA. This suggests that this brain region may play a key role in the maintenance of the PA effect over time.

Exploring the reciprocal modulation of time and space in dancers and non-dancers.

We explored whether time and space representations modulate each other in subjects that are trained to integrate time and space dimensions, i.e., professional dancers. A group of dancers, and one of non-dancers, underwent two different tasks employing identical stimuli. A first static central line could last one of three possible durations and could have one of three possible lengths. A second growing line appeared from the left or right of the screen and grew up toward the opposite direction at constant velocity. In the Spatial task, subjects encoded the length of the static line and stopped the growing line when it had reached half the length of the static one, regardless of time travel. In the Temporal task, subjects encoded the duration of the static line and stopped the growing line when it had lasted half the duration of the static one, regardless of space traveled. Dancers, differently from non-dancers, anticipated time in the Temporal task. However, both dancers and non-dancers were biased by the stimulus length when performing the Temporal task, while they were not biased by the stimulus duration when performing the Spatial task. Concluding, this study underlines the plasticity of time dimension that can be influenced by spatial information and by sensorimotor training for the synchronization in space and time.

Prismatic adaptation coupled with cognitive training as novel treatment for developmental dyslexia: a randomized controlled trial.

Despite intense and costly treatments, developmental dyslexia (DD) often persists into adulthood. Several brain skills unrelated to speech sound processing (i.e., phonology), including the spatial distribution of visual attention, are abnormal in DD and may represent possible treatment targets. This study explores the efficacy in DD of rightward prismatic adaptation (rPA), a visuomotor adaptation technique that enables visuo-attentive recalibration through shifts in the visual field induced by prismatic goggles. A digital intervention of rPA plus cognitive training was delivered weekly over 10 weeks to adolescents with DD (aged 13-17) assigned either to treatment (N = 35) or waitlist (N = 35) group. Efficacy was evaluated by repeated measures MANOVA assessing changes in working memory index (WMI), processing speed index (PSI), text reading speed, and words/pseudowords reading accuracy. rPA treatment was significantly more effective than waitlist (p ≤ 0.001; ηp2 = 0.815). WMI, PSI, and reading speed increased in the intervention group only (p ≤ 0.001, ηp2 = 0.67; p ≤ 0.001, ηp2 = 0.58; p ≤ 0.001, ηp2 = 0.29, respectively). Although modest change was detected for words and pseudowords accuracy in the waitlist group only (words: p ≤ 0.001, d = 0.17, pseudowords: p = 0.028; d = 0.27), between-group differences were non-significant. rPA-coupled cognitive training enhances cognitive and reading abilities in adolescents with DD. This innovative approach could have implications for early remedial treatment.

Frontal and cerebellar contributions to pitch and rhythm processing: a TMS study.

Music represents a salient stimulus for the brain with two key features: pitch and rhythm. Few data are available on cognitive analysis of music listening in musically naïve healthy participants. Beyond auditory cortices, neuroimaging data showed the involvement of prefrontal cortex in pitch and of cerebellum in rhythm. The present study is aimed at investigating the role of prefrontal and cerebellar cortices in both pitch and rhythm processing. The performance of fifteen participants without musical expertise was investigated in a listening discrimination task. The task required to decide whether two eight-element melodic sequences were equal or different according to pitch or rhythm characteristics. Before the task, we applied a protocol of continuous theta burst transcranial magnetic stimulation interfering with the activity of the left cerebellar hemisphere (lCb), right inferior frontal gyrus (rIFG), or vertex (Cz-control site), in a within cross-over design. Our results showed that participants were more accurate in pitch than rhythm tasks. Importantly, the reaction times were slower following rIFG or lCb stimulations in both tasks. Notably, frontal and cerebellar stimulations did not induce any motor effect in right and left hand. The present findings point to the role of the fronto-cerebellar network in music processing with a single mechanism for both pitch and rhythm patterns.

Acute effects of prismatic adaptation on penalty kick accuracy and postural control in young soccer players: A pilot study.

Background: Prismatic adaptation (PA) is a visuomotor technique using prismatic glasses that are capable of moving the visual field and to affect the excitability of certain brain areas. The aim of this pilot study was to explore potential acute effects of PA on penalty kick accuracy and postural control in youth soccer players. Methods: In this randomized crossover study, seven young male soccer players performed three PA sessions (rightward PA, r-PA; leftward PA, l-PA; sham PA, s-PA) with a washout period of 1-week between them. Immediately before and after each PA session, penalty kick accuracy and postural control were assessed. Results: We detected an increase in penalty kick accuracy following PA, regardless of the deviation side of the prismatic glasses (F1,5 = 52.15; p = 0.08; ηp2 = 0.981). In detail, our results showed an increase in the penalty kick accuracy toward the right target of the football goal following r-PA and toward the left target of the football goal following l-PA. We detected a significant effect on the sway path length (F2,12 = 10.42; p = 0.002; ηp2 = 0.635) and the sway average speed (F2,12 = 9.17; p = 0.004; ηp2 = 0.605) parameters in the stabilometric test with open eyes following PA, regardless of the deviation side of the prismatic glasses. In detail, our results showed a significant difference in both the stabilometric parameters (p = 0.016 and p = 0.009, respectively) only following l-PA. Conclusion: The findings of this pilot study indicate that PA could positively affect penalty kick accuracy and postural control suggesting that PA could be used as a visual training technique in athletes.

Cerebellar contribution to mental rotation: a cTBS study.

A cerebellar role in spatial information processing has been advanced even in the absence of physical manipulation, as occurring in mental rotation. The present study was aimed at investigating the specific involvement of left and right cerebellar hemispheres in two tasks of mental rotation. We used continuous theta burst stimulation to downregulate cerebellar hemisphere excitability in healthy adult subjects performing two mental rotation tasks: an Embodied Mental Rotation (EMR) task, entailing an egocentric strategy, and an Abstract Mental Rotation (AMR) task entailing an allocentric strategy. Following downregulation of left cerebellar hemisphere, reaction times were slower in comparison to sham stimulation in both EMR and AMR tasks. Conversely, identical reaction times were obtained in both tasks following right cerebellar hemisphere and sham stimulations. No effect of cerebellar stimulation side was found on response accuracy. The present findings document a specialization of the left cerebellar hemisphere in mental rotation regardless of the kind of stimulus to be rotated.

Overestimation of Phonological Judgments on the Right Side of Space.

Spatial attentional biases can be observed during the processing of linguistic material. For example, we previously reported that healthy subjects overestimate the semantic distance between word stimuli in the right vs. left space. Here, we explored whether or not attentional biases are also observed in tasks requiring an evaluation of phonological distance between words in the right and left hemifield. Forty-one healthy subjects were presented with triplets of words arranged in space and were asked to indicate the side of the space in which the phonological distance between the middle word and an outer word was smaller. In Experiment 1, real words and pseudowords were used, while in Experiment 2, only pseudowords and consonant strings were used. Subjects overestimated the phonological distance between the middle and outer words in the right space. These findings were specific to word stimuli. These results are consistent with the idea that semantic and phonological information may be internally mapped onto spatial representations.

A novel digital approach for post-stroke cognitive deficits: a pilot study.

BACKGROUND: Cognitive dysfunctions after a brain stroke have a huge impact on patients' disability and activities of daily living. Prism adaptation (PA) is currently used in patients with right brain damage to improve lateralized spatial attentional deficits. Recent findings suggest that PA could also be useful for rehabilitation of other cognitive functions. OBJECTIVE: In the present study, we tested for the efficacy on cognitive rehabilitation of a novel device in which the procedure of prism adaptation is digitized and followed by cognitive training of attention and executive functions using serious games. METHODS: Thirty stroke patients were randomly assigned to two groups: an experimental group of 15 patients, which performed the experimental rehabilitation training using the novel device in 10 consecutive daily sessions; a control group of 15 patients, which performed the routine cognitive training in 10 consecutive daily sessions. Both groups were tested before and after the rehabilitation program on neuropsychological tests (digit and spatial span forward and backward, attentional matrices, Stroop task) and on functional scales (Barthel index and Beck Anxiety Index). RESULTS: The main results showed that only patients who received the experimental rehabilitation training improved their scores on tests of digit span forward, spatial span backward, attentional matrices and Stroop. Moreover, patients of the experimental but not of the control group showed a significant correlation between improvement on some tasks (mainly spatial span backward) and improvement on activities of daily living as well as with reduction of anxiety levels. CONCLUSIONS: These results suggest that combining digital PA with cognitive training using serious games may be added in clinical settings for cognitive rehabilitation of stroke patients, with beneficial effects extending in promoting independency in activities of daily living and reduction of psychiatric symptoms.

Keeping memory for intentions: a cTBS investigation of the frontopolar cortex.

The present study aimed to investigate the role of frontopolar cortex in prospective memory (PM) by means of inhibitory theta-burst stimulation (cTBS). "Experiment 1"-8 volunteers were evaluated after inhibitory cTBS over left Brodmann area (BA) 10, right BA10, and Cz. In the PM procedure, sequences of 4 words each were presented. During the intersequence delay, subjects had to repeat the sequence in the observed order (ongoing task forward) or in the reverse order (backward). At the occurrence of a target word, subjects had to press a key on the keyboard (PM task). Recall and recognition of the target words were also tested. PM accuracy was lower after cTBS over left BA10 compared with Cz (P = 0.012), whereas it was comparable in right BA10 and Cz conditions. No other significant differences between the 3 conditions were found. "Experiment 2"-8 subjects were administered the same experimental PM procedure as above after inhibitory cTBS over left BA46 and Cz. In this case, none of the tested effects were significant. Our findings corroborate the hypothesis that within the prefrontal cortex, the left BA10 is specifically involved in the mediation of processes related to the execution of delayed intentions.

Sensory Processing Disorders in Children and Adolescents: Taking Stock of Assessment and Novel Therapeutic Tools.

Sensory processing disorders (SPDs) can be described as difficulty detecting, modulating, interpreting, and/or responding to sensory experiences. Because SPDs occur in many individuals with autism spectrum disorder and in other populations with neurodevelopmental disorders, it is important to distinguish between typical and atypical functioning in sensory processes and to identify early phenotypic markers for developing SPDs. This review considers different methods for diagnosing SPDs to outline a multidisciplinary approach useful for developing valid diagnostic measures. In particular, the advantages and limitations of the most commonly used tools in assessment of SPDs, such as caregiver reports, clinical observation, and psychophysical and neuroimaging studies, will be reviewed. Innovative treatment methods such as neuromodulation techniques and virtual reality will also be suggested.

Changes in cerebello-motor connectivity during procedural learning by actual execution and observation.

The cerebellum is involved in motor learning of new procedures both during actual execution of a motor task and during observational training. These processes are thought to depend on the activity of a neural network that involves the lateral cerebellum and primary motor cortex (M1). In this study, we used a twin-coil TMS technique to investigate whether execution and observation of a visuomotor procedural learning task is related to modulation of cerebello-motor connectivity. We observed that, at rest, a magnetic conditioning pulse applied over the lateral cerebellum reduced the motor-evoked potentials obtained by stimulating the contralateral M1, indicating activation of a cerebello-motor connection. Furthermore, during procedural learning, cerebellar stimulation resulted in selective facilitation, not inhibition, of contralateral M1 excitability. The effects were evident when motor learning was obtained by actual execution of the task or by observation, but they disappeared if procedural learning had already been acquired by previous observational training. These results indicate that changes in cerebello-motor connectivity occur in relation to specific phases of procedural learning, demonstrating a complex pattern of excitatory and inhibitory drives modulated across time.

Transcranial Magnetic Stimulation Trains at 1 Hz Frequency of the Right Posterior Parietal Cortex Facilitate Recognition Memory.

Neuroimaging, neuropsychological, and brain stimulation studies have led to contrasting findings regarding the potential roles of the lateral parietal lobe in episodic memory. Studies using brain stimulation methods reported in the literature do not offer unequivocal findings on the interactions with stimulation location (left vs. right hemisphere) or timing of the stimulation (encoding vs. retrieval). To address these issues, active and sham 1 Hz repetitive transcranial magnetic stimulation (rTMS) trains of 600 stimuli were applied over the right or left posterior parietal cortex (PPC) before the encoding or before the retrieval phase of a recognition memory task of unknown faces in a group of 40 healthy subjects. Active rTMS over the right but not the left PPC significantly improved non-verbal recognition memory performance without any significant modulation of speed of response when applied before the retrieval phase. In contrast, rTMS over the right or the left PPC before the encoding phase did not modulate memory performance. Our results support the hypothesis that the PPC plays a role in episodic memory retrieval that appears to be dependent on both the hemispheric lateralization and the timing of the stimulation (encoding vs. retrieval).

Improvement of phonemic fluency following leftward prism adaptation.

Anatomo functional studies of prism adaptation (PA) have been shown to modulate a brain frontal-parieto-temporal network, increasing activation of this network in the hemisphere ipsilateral to the side of prism deviation. This effect raises the hypothesis that left prism adaptation, modulating frontal areas of the left hemisphere, could modify subjects' performance on linguistic tasks that map on those areas. To test this hypothesis, 51 healthy subjects participated in experiments in which leftward or rightward prism adaptation were applied before the execution of a phonemic fluency task, i.e., a task with strict left hemispheric lateralization onto frontal areas. Results showed that leftward PA significantly increased the number of words produced whereas rightward PA did not significantly modulate phonemic fluency. The present findings document modulation of a language ability following prism adaptation. The results could have a huge clinical impact in neurological populations, opening new strategies of intervention for language and executive dysfunctions.