Modulation of memory by prism adaptation in healthy subjects.

Recent findings suggest that prism adaptation can extend its effects beyond spatial attention, modulating the performance of different cognitive tasks by acting on cerebellar, parietal and temporal-frontal networks. We tested groups of healthy subjects to investigate the effects of rightward vs. leftward prism adaptation vs. neutral lenses exposure in a series of memory tasks, probing either short-term (Digit span, Corsi span) or long-term memory (Supraspan verbal and spatial learning). In the short-term memory tasks, leftward prism adaptation selectively increased verbal span, while rightward prism adaptation increased spatial span. In the long-term memory tasks, leftward prism adaptation selectively increased verbal supraspan, i.e., increased the number of digits in the correct sequence reproduced and reduced the number of repetitions needed to learn the supraspan sequence. On the other hand, rightward prism adaptation selectively increased spatial supraspan, i.e. it increased the number of spatial positions in the correct sequence reproduced and reduced the number of repetitions needed to learn the supraspan sequence. Moreover, rightward, but not leftward, prism adaptation selectively increased supraspan recall after a delay interval, regardless of the stimulus material, i.e., it increased the number of digits or spatial positions recalled after a delay interval. Neutral lenses exposure did not influence any memory task. These findings suggest that prism adaptation can induce both modality/hemispheric-specific and process-specific effects on short-term and long-term explicit memory.

Reduction of drive for thinness and body dissatisfaction in people with self-reported dysregulated eating behaviors after intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex.

Aim: This study aimed to explore the effect of intermittent theta burst stimulation (iTBS) of the right and left dorsolateral prefrontal cortex (DLPFC) in people with self-reported dysregulated eating behaviors but without a diagnosis of eating disorders (EDs). Methods: Participants were randomly divided into two equivalent groups according to the side (right or left) of the hemisphere to be stimulated and they were tested before and after a single iTBS session. Outcome measurements were scores on self-report questionnaires assessing psychological dimensions related to eating behaviors (EDI-3), anxiety (STAI-Y), and tonic electrodermal activity. Results: The iTBS interfered with both psychological and neurophysiological measures. Significant variations of physiological arousal after iTBS of both the right and left DLPFC were witnessed by increased mean amplitude of non-specific skin conductance responses. With regard to the psychological measures, the iTBS on the left DLPFC significantly reduced the scores of the EDI-3 subscales drive for thinness and body dissatisfaction. Interestingly, these two scales are two of the three EDI-3 clinic scales (drive for thinness, body dissatisfaction, and bulimia) used as specific markers to assess the onset and/or maintenance of eating disorders. Conclusion: Our results show that the left DLPFC iTBS has an impact on the psychological dimensions that are risk factors for the onset of eating disorders, suggesting that an altered hemispheric asymmetry similar to that encountered in clinical populations is present in normal subjects even in the absence of clinical symptoms.

Commonalities and distinctions between two neurodevelopmental disorder subtypes associated with SCN2A and SCN8A variants and literature review.

This study was aimed to analyze the commonalities and distinctions of voltage-gated sodium channels, Nav1.2, Nav1.6, in neurodevelopmental disorders. An observational study was performed including two patients with neurodevelopmental disorders. The demographic, electroclinical, genetic, and neuropsychological characteristics were analyzed and compared with each other and then with the subjects carrying the same genetic variants reported in the literature. The clinical features of one of them argued for autism spectrum disorder and developmental delay, the other for intellectual disability, diagnoses confirmed by the neuropsychological assessment. The first patient was a carrier of SCN2A (p.R379H) variant while the second was carrier of SCN8A (p.E936K) variant, both involving the pore loop of the two channels. The results of this study suggest that the neurodevelopmental disorders without overt epilepsy of both patients can be the consequences of loss of function of Nav1.2/Nav1.6 channels. Notably, the SCN2A variant, with an earlier expression timing in brain development, resulted in a more severe phenotype as autism spectrum disorder and developmental delay, while the SCN8A variant, with a later expression timing, resulted in a less severe phenotype as intellectual disability.

De novo GRIN2A variants associated with epilepsy and autism and literature review.

N-methyl-D-aspartate receptors (NMDAR) are di- or tri-heterotetrameric ligand-gated ion channels composed of two obligate glycine-binding GluN1 subunits and two glutamate-binding GluN2 or GluN3 subunits, encoded by GRIN1, GRIN2A-D, and GRIN3A-B receptor genes respectively. Each NMDA receptor subtype has different temporal and spatial expression patterns in the brain and varies in the cell types and subcellular localization resulting in different functions. They play a crucial role in mediating the excitatory neurotransmission, but are also involved in neuronal development and synaptic plasticity, essential for learning, memory, and high cognitive functions. Among genes coding NMDAR subunits, GRIN2B is predominantly associated with neurodevelopmental disorders such as intellectual disability, developmental delay, autism, attention-deficit/hyperactivity disorder and, further, schizophrenia, Alzheimer's disease. The GRIN2A seems to be predominantly associated with a more definite phenotype including an epileptic spectrum ranging from Landau-Kleffner syndrome to benign childhood epilepsy with centrotemporal spikes, speech or language impairment, intellectual disability/developmental delay often in comorbidity. On the contrary, the occurrence of autism spectrum disorders, unlike GRIN2B-associated disorders, is questionable. To contribute to elucidate the latter issue and to better define the genotype/phenotype correlation, we report the clinical and neuropsychological profile of two patients featuring autism disorder, intellectual disability, language impairment, and focal epilepsy, associated with previously unreported heterozygous de novo GRIN2A pathogenic variants. We hypothesize that the unusual phenotype may be the result of interactions of tri-heterotetrameric 2GluN1/GluN2A-D/GluN3A-B subunits with mutated GluN2A subunit and/or the dysfunction may be influenced by other unknown modifier genes and/or environmental factors.

Recurrent missense variant in the nuclear export signal of FMR1 associated with FXS-like phenotype including intellectual disability, ASD, facial abnormalities.

Fragile X syndrome (FXS; MIM 300624) is an X-linked genetic disorder characterized by physical abnormalities associated with intellectual disability and a wide spectrum of neurological and psychiatric impairments. FXS occurs more frequently in males, 1 in 5000 males and 1 in 8000 females accounting for 1-2% of overall intellectual disability (ID). In more than 99% of patients, FXS results from expansions of a CGG triplet repeat (>200 in male) of the FMR1 gene. In the last years an increasing number, albeit still limited, of FXS subjects carrying FMR1 mutations including deletions, splicing errors, missense, and nonsense variants was reported. Nevertheless, the studies concerning the functional consequences of mutations in the FMR1 gene are rare so far and, therefore, we do not have sufficient knowledge regarding the genotype/phenotype correlation. We report a child carrying a hemizygous missense FMR1 (NM_002024.5:c.1325G > A p.Arg442Gln) variant, maternally inherited, associated with facial abnormalities, developmental delay, and social and communication deficits assessed with formal neuropsychological tests. The study contributes to highlighting the clinical differences between the CGG triplet repeat dependent phenotype and FMR1variant dependent phenotype and it also confirms the pathogenicity of the variant being reported for the second time in the literature.

Impact of Perceived Stress and Immune Status on Decision-Making Abilities during COVID-19 Pandemic Lockdown.

The ability to make risky decisions in stressful contexts has been largely investigated in experimental settings. We examined this ability during the first months of COVID-19 pandemic, when in Italy people were exposed to a prolonged stress condition, mainly caused by a rigid lockdown. Participants among the general population completed two cognitive tasks, an Iowa Gambling Task (IGT), which measures individual risk/reward decision-making tendencies, and a Go/No-Go task (GNG), to test impulsivity, together with two questionnaires, the Perceived Stress Scale and the Depression, Anxiety and Stress Scales. The Immune Status Questionnaire was additionally administered to explore the impact of the individual health status on decision making. The effect of the questionnaires scores on task performance was examined. The results showed that higher levels of perceived stress and a more self-reported vulnerable immune status were associated, separately, with less risky/more advantageous choices in the IGT in young male participants but with more risky/less advantageous choices in older male participants. These effects were not found in female participants. Impulsivity errors in the GNG were associated with more anxiety symptoms. These findings bring attention to the necessity of taking into account decision-making processes during stressful conditions, especially in the older and more physically vulnerable male population.

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.

Low-Frequency Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex Enhances Recognition Memory in Alzheimer's Disease.

BACKGROUND: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer's disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. OBJECTIVE: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. METHODS: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. RESULTS: Right real rTMS significantly improved memory performance compared to right sham rTMS (p = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p = 0.46). The two sham conditions did not differ between each other (p = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p = 0.0009), that persisted at 1-month follow-up (p = 0.002). CONCLUSION: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD.

Exploring the neural correlates of the reversed letter effect: Evidence from left and right parietal patients.

To investigate the hemispheric lateralization of attentional processes during visual search tasks depending on the stimulus material embedding the target, twelve patients with unilateral left (n = 7) or right (n = 5) parietal lesions and 20 age and education matched healthy controls (HC) were recruited. We used a visual search task for a uniquely tilted oblique bar embedded in an object shape 'N' or in its mirror reversal 'И'. The accuracy and the averaged reaction times (RTs) in each stimulus type ('N' or 'И') were analysed. HC presented significantly longer RTs when the target bar was embedded in 'N' among its mirror reversed 'И' (p < .05). This "reversed letter effect" was also found in the right parietal patients (p < .001), while no evidence of a reversed letter effect was found in the left parietal patients.

Modulating phonemic fluency performance in healthy subjects with transcranial magnetic stimulation over the left or right lateral frontal cortex.

A growing body of evidence have suggested that non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can improve the performance of aphasic patients in language tasks. For example, application of inhibitory rTMS or tDCs over the right frontal lobe of dysphasic patients resulted in improved naming abilities. Several studies have also reported that in healthy controls (HC) tDCS application over the left prefrontal cortex (PFC) improve performance in naming and semantic fluency tasks. The aim of this study was to investigate in HC, for the first time, the effects of inhibitory repetitive TMS (rTMS) over left and right lateral frontal cortex (BA 47) on two phonemic fluency tasks (FAS or FPL). 44 right-handed HCs were administered rTMS or sham over the left or right lateral frontal cortex in two separate testing sessions, with a 24h interval, followed by the two phonemic fluency tasks. To account for possible practice effects, an additional 22 HCs were tested on only the phonemic fluency task across two sessions with no stimulation. We found that rTMS-inhibition over the left lateral frontal cortex significantly worsened phonemic fluency performance when compared to sham. In contrast, rTMS-inhibition over the right lateral frontal cortex significantly improved phonemic fluency performance when compared to sham. These results were not accounted for practice effects. We speculated that rTMS over the right lateral frontal cortex may induce plastic neural changes to the left lateral frontal cortex by suppressing interhemispheric inhibitory interactions. This resulted in an increased excitability (disinhibition) of the contralateral unstimulated left lateral frontal cortex, consequently enhancing phonemic fluency performance. Conversely, application of rTMS over the left lateral frontal cortex may induce a temporary, virtual lesion, with effects similar to those reported in left frontal patients.

Combining tDCS with prismatic adaptation for non-invasive neuromodulation of the motor cortex.

BACKGROUND: Prismatic adaptation (PA) shifts visual field laterally and induces lateralized deviations of spatial attention. Recently, it has been suggested that prismatic goggles are also able to modulate brain excitability, with cognitive after-effects documented even in tasks not necessarily spatial in nature. OBJECTIVE: The aim of the present study was to test whether neuromodulatory effects obtained from tDCS and prismatic goggles could interact and induce homeostatic changes in corticospinal excitability. METHODS: Thirty-four subjects were submitted to single-pulse transcranial magnetic stimulation (TMS) over the right primary motor cortex to measure Input-Output (IO) curve as a measure of corticospinal excitability. Assessment was made in three experimental conditions: before and after rightward PA and anodal tDCS of the right motor cortex; before and after rightward PA; before and after anodal tDCS of the right motor cortex. RESULTS: A significant decrease of MEPs amplitude and of IO curve slope steepness was found after the combination of rightward PA and anodal tDCS; on the other hand, an increase of MEPs amplitude and of the steepness of IO curve slope on the right motor cortex was found following either rightward PA or anodal tDCS. CONCLUSION: These findings suggest that priming of motor cortex excitability using PA could be an additional tool to modulate cortical metaplasticity.

Modulating Memory Performance in Healthy Subjects with Transcranial Direct Current Stimulation Over the Right Dorsolateral Prefrontal Cortex.

OBJECTIVE: The role of the Dorsolateral Prefrontal Cortex (DLPFC) in recognition memory has been well documented in lesion, neuroimaging and repetitive Transcranial Magnetic Stimulation (rTMS) studies. The aim of the present study was to investigate the effects of transcranial Direct Current Stimulation (tDCS) over the left and the right DLPFC during the delay interval of a non-verbal recognition memory task. METHOD: 36 right-handed young healthy subjects participated in the study. The experimental task was an Italian version of Recognition Memory Test for unknown faces. Study included two experiments: in a first experiment, each subject underwent one session of sham tDCS and one session of left or right cathodal tDCS; in a second experiment each subject underwent one session of sham tDCS and one session of left or right anodal tDCS. RESULTS: Cathodal tDCS over the right DLPFC significantly improved non verbal recognition memory performance, while cathodal tDCS over the left DLPFC had no effect. Anodal tDCS of both the left and right DLPFC did not modify non verbal recognition memory performance. CONCLUSION: Complementing the majority of previous studies, reporting long term memory facilitations following left prefrontal anodal tDCS, the present findings show that cathodal tDCS of the right DLPFC can also improve recognition memory in healthy subjects.

Repetitive transcranial magnetic stimulation over the left parietal cortex facilitates visual search for a letter among its mirror images.

Interference by task irrelevant information is seen in visual search paradigms using letters. Thus, it is harder to find the letter 'N' among its mirror reversals 'И' than vice versa. This observation, termed the reversed letter effect, involves both a linguistic association and an interference of task irrelevant information­the shape of 'N' or 'И' is irrelevant, the search requires merely distinguishing the tilts of oblique bars. We adapted the repetitive transcranial magnetic stimulation (rTMS) methods that we previously used, and conducted three rTMS experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right posterior parietal cortex (PPC) on the search performance. The second experiment focused on the role of the left PPC. The third experiment explored whether another left posterior region, known to be involved in word reading (ventral occipito-temporal cortex, vOTC), plays a role. We found that rTMS on right PPC and left VOTC had no effect on the speed and accuracy of the visual search regardless of whether the target is 'N' or its mirror reversal. In contrast, rTMS on the left PPC speeded up the search on finding target 'N' among its mirror images. We suggest that left PPC is involved in letter recognition, and that rTMS on left PPC facilitated our visual search task by reducing task interference triggered by task irrelevant letter recognition.

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.

Impairments in top down attentional processes in right parietal patients: paradoxical functional facilitation in visual search.

It is well known that the right posterior parietal cortex (PPC) is involved in attentional processes, including binding features. It remains unclear whether PPC is implicated in top-down and/or bottom-up components of attention. We aim to clarify this by comparing performance of seven PPC patients and healthy controls (HC) in a visual search task involving a conflict between top-down and bottom-up processes. This task requires essentially a bottom-up feature search. However, top-down attention triggers feature binding for object recognition, designed to be irrelevant but interfering to the task. This results in top-down interference, prolonging the search reaction time. This interference was indeed found in our HCs but not in our PPC patients. In contrast to HC, the PPC patients showed no evidence of prolonged reactions times, even though they were slower than the HCs in search tasks without the conflict. This finding is an example of paradoxical functional facilitation (PFF) by brain damage. The PFF effect enhanced our patients' performance by reducing the top down interference. Our finding supports the idea that right PPC plays a crucial role in top-down attentional processes. In our search tasks, right PPC induces top-down interference either by directing spatial attention to achieve viewpoint invariance in shape recognition or by feature binding.

Benign nocturnal alternating hemiplegia of childhood: a new case with unusual findings.

It has been described a neuro developmental disorder labelled "Benign nocturnal alternating hemiplegia of childhood" (BNAHC) characterized by recurrent attacks of nocturnal hemiplegia without progression to neurological or intellectual impairment. We report a female patient who at 11months revealed a motionless left arm, unusual crying without impairment of consciousness and obvious precipitating factors. The attacks occur during sleep in the early morning with lack of ictal and interictal electroencephalographic abnormalities, progressive neurological deficit, and cognitive impairment. Unlike previous reports of BNAHC our patient come from a family with a history of both migraine, hemiplegic migraine, and sleep disorders. Our study remarks on the typical features described in previous studies and stresses the uncommon aspects that could help to identify the disorder which is likely to have been underestimated. Despite some clinical similarities between BNAHC and familiar hemiplegic migraine and alternating hemiplegia of childhood, the genetic analyses of our patient did not reveal genetic mutations found in both disorders.

The role of posterior parietal cortices on prismatic adaptation effects on the representation of time intervals.

Previous studies provided evidence of an ascending left-to-right spatial representation of time durations by using a technique affecting high levels of spatial cognition, i.e. prismatic adaptation (PA). Indeed, PA that induced a leftward aftereffect distorted time representation toward an underestimation, while PA that induced a rightward aftereffect distorted time representation toward an overestimation. The present study advances previous findings on the effects of PA on time by investigating the neural basis subtending these effects. We focused on the posterior parietal cortex (PPC) since it is involved in the PA procedure and also in the formulation of the spatial representation of time. We conducted two experiments where right-handed healthy adults were submitted to a time task, before and after PA, that could induce a leftward or rightward aftereffect. Repetitive TMS (rTMS) was used to inhibit the left or right PPC before PA administration. In a first experiment the time task consisted of reproducing an half duration (time bisection task) by pressing a key and the participants responded and adapted to prisms with their right hand. In a second experiment the time task consisted of reproducing a whole duration (time reproduction task) by pressing a key and the participants responded and adapted to prisms with their left hand. We found an abolition of the effects of PA on time when rTMS was delivered on the left and not on the right PPC, regardless of the task and moreover, when the participants responded and adapted with the right hand and also with the left hand. This result suggests a direct involvement of the left PPC in the interactive process, between spatial modulations induced by PA and the spatial representation of time, that does not depend on motor processes. This study provides useful results for future investigations on the neural mechanisms subtending the effects of PA on spatial representations.

West syndrome followed by juvenile myoclonic epilepsy: a coincidental occurrence?

BACKGROUND: West syndrome is an age-dependent epilepsy with onset peak in the first year of life whose aetiology may be symptomatic or cryptogenic. Long-term cognitive and neurological prognosis is usually poor and seizure outcome is also variable. Over the past two decades a few patients with favourable cognitive outcome and with total recovery from seizures were identified among the cryptogenic group suggesting an idiopathic aetiology. Recent research has described two children with idiopathic WS who later developed a childhood absence epilepsy. CASE PRESENTATION: We reviewed the medical records of patients with West syndrome admitted to the our Child Neuropsychiatry Unit in the last 15 years in order to know the clinical evolution of infantile spasms.We report a child with West syndrome with onset at 8 months of age followed by some clusters of bilateral, arrhythmic myoclonic jerks of the upper limbs, mainly on awakening, synchronous with the generalized discharges of 4 Hz spike-wave occurring at 12 years of age and by co-occurrence of a later generalized tonic-clonic seizure at 14 years and four months, both sensitive to Levetiracetam suggesting a juvenile myoclonic epilepsy. CONCLUSIONS: This unusual evolution, never previously reported, suggests that both electroclinical features mentioned above may share some pathophysiological processes genetically determined which produce a susceptibility to seizure and emphasizes that the transition between different age-related epileptic phenotypes may involve also the West syndrome.

Benign myoclonic epilepsy in infancy followed by childhood absence epilepsy.

Benign myoclonic epilepsy in infancy (BMEI) is a rare syndrome included among idiopathic generalized epilepsies (IGE) and syndromes with age-related onset. Recently, it has been shown that a few patients with BMEI later had other epilepsy types mainly IGE but never childhood absence epilepsy (CAE). We report a patient who at 11 months of age showed isolated myoclonic jerks occurring several times a day. The ictal video-EEG and polygraphic recording revealed generalized discharge of spike-wave (SW) lasting 1-2s associated with isolated bilateral synchronous jerk involving mainly the upper limbs controlled by valproic acid (VPA). At 6 years and 8 months the child developed a new electroclinical feature recognized as CAE. The ictal EEG disclosed a burst of rhythmic 3 Hz generalized SW. Our case is the first patient with BMEI reported in the literature who later developed a CAE. This finding suggests a common neurobiological and genetic link between different age-related epileptic phenotypes.