Value and efficacy of transcranial direct current stimulation in the rehabilitation of neurocognitive disorders: A critical review since 2000.

open3siNon-invasive brain stimulation techniques, including transcranial direct current stimulation (t-DCS) have been used in the rehabilitation of cognitive function in a spectrum of neurological disorders. The present review outlines methodological communalities and differences of t-DCS procedures in neurocognitive rehabilitation. We consider the efficacy of tDCS for the management of specific cognitive deficits in four main neurological disorders by providing a critical analysis of recent studies that have used t-DCS to improve cognition in patients with Parkinson’s Disease, Alzheimer’s Disease, Hemi-spatial Neglect and Aphasia. The evidence from this innovative approach to cognitive rehabilitation suggests that tDCS can influence cognition. However, the results show a high variability between studies both on the methodological approach adopted and the cognitive functions aspects. The review also focuses both on methodological issues such as technical aspects of the stimulation ( electrodes position and dimension; current intensity; duration of protocol) and on the inclusion of appropriate assessment tools for cognition. A further aspect considered is the best timing to administer tDCS: before, during after cognitive rehabilitation. We conclude that more studies with shared methodology are needed to have a better understanding of the efficacy of tDCS as a new tool for rehabilitation of cognitive disorders in a range of neurological disordersopenCappon, D; Jahanshahi, M; Bisiacchi, PCappon, Davide; Jahanshahi, M; Bisiacchi, Patrizi

On the effects of transcranial alternating stimulation (tACS) on neuronal dynamics and cognition.

A few minutes at a busy square in London allow one to appreciate the wide array of actions that humans are capable of expressing— walking, reading a book, tapping touch screen of smartphone, eating, shaking hands and crossing the street. Response inhibition is an essential mechanism of action control and is one of the most studied processes. For example, crossing the street when a fast motorcycle is approaching might necessitate inhibition of stepping forward to avoid being hurt. This ability to quickly suppress a response in a dynamic environment has traditionally been associated with conscious control. Crucially, recent experimental evidence has challenged the view that inhibitory control is restricted to conditions where stimuli are accessible to conscious awareness. Such an unconscious and automatic activation of the motor response system does not necessarily require stimuli to be consciously perceived and is deemed essential to act in a constantly changing environment. This has been interpreted as a basic motor process allowing preparatory mechanisms to automatically suppress an activated movement without the need of conscious cognitive processes. Thus, while there may be differences between automatic and voluntary processes, they might not have entirely distinct neural representations. Indeed, automatic control appears to rely on the corticobasal ganglia network that has been associated with voluntary control. Contemporary research has shown that an up-regulation of neural beta oscillations in the cortico-basal ganglia dynamics can be functionally relevant for inhibition of movement. Consequently, beta oscillations have been proposed as an essential mechanism that allows the motor network to communicate in a dynamic and flexible manner. Present research has demonstrated that it is possible to interact with the neuronal activity by non invasive brain stimulation (NIBS) techniques such as transcranial Direct Current Stimulation (tDCS), transcranial Alternating Current Stimulation (tACS). Specifically, tACS allows delivery of alternating current at different frequencies and it has been used to manipulate ongoing brain oscillations in a controllable way. This concept is still in the very early stages of research, and much needs to be done in order to fully grasp the underlying mechanisms. Building upon these discoveries, the research presented in this thesis aimed to demonstrate a causal role of beta frequency oscillations on unconscious and automatic inhibition adopting tACS over the primary motor cortex and supplementary motor area. Furthermore combining tACS with TMS and EEG allowed me to characterise the underlying basic mechanisms of its action on corticospinal excitability and neuronal dynamics. Overall, this work contributes to our understanding of the human motor system while offering new insights into the combined approach of tACS and EEG in the characterization of a causal role of neuronal oscillatory dynamics on behaviour

Tele-supervised home-based transcranial alternating current stimulation (tACS) for Alzheimer’s disease: a pilot study

BackgroundOver 55 million people worldwide are currently diagnosed with Alzheimer’s disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activity. Here we investigate the feasibility, safety, and preliminary effects on episodic memory of an innovative protocol where tACS is administered within the homes of older adults with AD with the help of a study companion (HB-tACS).MethodsEight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14-week Acute Phase. Subsequently, participants completed a 2–3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2–3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD.ResultsAll participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus −0.64 ± 3.28 and Taper −2.56 ± 5.03 Phases.ConclusionThis pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04783350?term=NCT04783350&draw=2&rank=1, identifier NCT04783350

Tele-supervised home-based transcranial alternating current stimulation (tACS) for Alzheimer's disease : a pilot study

Over 55 million people worldwide are currently diagnosed with Alzheimer's disease (AD) and live with debilitating episodic memory deficits. Current pharmacological treatments have limited efficacy. Recently, transcranial alternating current stimulation (tACS) has shown memory improvement in AD by normalizing high-frequency neuronal activity. Here we investigate the feasibility, safety, and preliminary effects on episodic memory of an innovative protocol where tACS is administered within the homes of older adults with AD with the help of a study companion (HB-tACS). Eight participants diagnosed with AD underwent multiple consecutive sessions of high-definition HB-tACS (40 Hz, 20-min) targeting the left angular gyrus (AG), a key node of the memory network. The Acute Phase comprised 14-weeks of HB-tACS with at least five sessions per week. Three participants underwent resting state electroencephalography (EEG) before and after the 14-week Acute Phase. Subsequently, participants completed a 2-3-month Hiatus Phase not receiving HB-tACS. Finally, in the Taper phase, participants received 2-3 sessions per week over 3-months. Primary outcomes were safety, as determined by the reporting of side effects and adverse events, and feasibility, as determined by adherence and compliance with the study protocol. Primary clinical outcomes were memory and global cognition, measured with the Memory Index Score (MIS) and Montreal Cognitive Assessment (MoCA), respectively. Secondary outcome was EEG theta/gamma ratio. Results reported as mean ± SD. All participants completed the study, with an average of 97 HB-tACS sessions completed by each participant; reporting mild side effects during 25% of sessions, moderate during 5%, and severe during 1%. Acute Phase adherence was 98 ± 6.8% and Taper phase was 125 ± 22.3% (rates over 100% indicates participants completed more than the minimum of 2/week). After the Acute Phase, all participants showed memory improvement, MIS of 7.25 ± 3.77, sustained during Hiatus 7.00 ± 4.90 and Taper 4.63 ± 2.39 Phases compared to baseline. For the three participants that underwent EEG, a decreased theta/gamma ratio in AG was observed. Conversely, participants did not show improvement in the MoCA, 1.13 ± 3.80 after the Acute Phase, and there was a modest decrease during the Hiatus −0.64 ± 3.28 and Taper −2.56 ± 5.03 Phases. This pilot study shows that the home-based, remotely-supervised, study companion administered, multi-channel tACS protocol for older adults with AD was feasible and safe. Further, targeting the left AG, memory in this sample was improved. These are preliminary results that warrant larger more definite trials to further elucidate tolerability and efficacy of the HB-tACS intervention. NCT04783350. , identifier NCT04783350

On the effects of transcranial alternating stimulation (tACS) on neuronal dynamics and cognition.

A few minutes at a busy square in London allow one to appreciate the wide array of actions that humans are capable of expressing— walking, reading a book, tapping touch screen of smartphone, eating, shaking hands and crossing the street. Response inhibition is an essential mechanism of action control and is one of the most studied processes. For example, crossing the street when a fast motorcycle is approaching might necessitate inhibition of stepping forward to avoid being hurt. This ability to quickly suppress a response in a dynamic environment has traditionally been associated with conscious control. Crucially, recent experimental evidence has challenged the view that inhibitory control is restricted to conditions where stimuli are accessible to conscious awareness. Such an unconscious and automatic activation of the motor response system does not necessarily require stimuli to be consciously perceived and is deemed essential to act in a constantly changing environment. This has been interpreted as a basic motor process allowing preparatory mechanisms to automatically suppress an activated movement without the need of conscious cognitive processes. Thus, while there may be differences between automatic and voluntary processes, they might not have entirely distinct neural representations. Indeed, automatic control appears to rely on the corticobasal ganglia network that has been associated with voluntary control. Contemporary research has shown that an up-regulation of neural beta oscillations in the cortico-basal ganglia dynamics can be functionally relevant for inhibition of movement. Consequently, beta oscillations have been proposed as an essential mechanism that allows the motor network to communicate in a dynamic and flexible manner. Present research has demonstrated that it is possible to interact with the neuronal activity by non invasive brain stimulation (NIBS) techniques such as transcranial Direct Current Stimulation (tDCS), transcranial Alternating Current Stimulation (tACS). Specifically, tACS allows delivery of alternating current at different frequencies and it has been used to manipulate ongoing brain oscillations in a controllable way. This concept is still in the very early stages of research, and much needs to be done in order to fully grasp the underlying mechanisms. Building upon these discoveries, the research presented in this thesis aimed to demonstrate a causal role of beta frequency oscillations on unconscious and automatic inhibition adopting tACS over the primary motor cortex and supplementary motor area. Furthermore combining tACS with TMS and EEG allowed me to characterise the underlying basic mechanisms of its action on corticospinal excitability and neuronal dynamics. Overall, this work contributes to our understanding of the human motor system while offering new insights into the combined approach of tACS and EEG in the characterization of a causal role of neuronal oscillatory dynamics on behaviour.Alcuni minuti in una piazza affollata di Londra permettono di apprezzare l'ampia gamma di azioni che gli esseri umani sono capaci di esprimere— camminare, leggere un libro, toccare lo schermo dello smartphone, mangiare, stringere la mano e attraversare la strada. L'inibizione della risposta è un meccanismo essenziale del controllo motorio dell'azione e rappresenta uno dei processi più studiati. Ad esempio, attraversare la strada quando inavvertitamente si avvicina una motocicletta a grande velocità potrebbe richiedere l'inibizione di mettere i piedi giù per evitare di essere feriti. Questa capacità di sopprimere rapidamente una risposta in un ambiente dinamico è stata tradizionalmente associata al controllo cosciente. In modo cruciale, recenti prove sperimentali hanno sfidato la concezione che il controllo inibitorio è limitato alle condizioni in cui gli stimoli sono accessibili alla consapevolezza cosciente. Tale attivazione inconscia e automatica del sistema motorio non necessariamente richiede che gli stimoli siano consapevolmente percepiti e si ritiene essenziale per agire in un ambiente in costante evoluzione. Questa attivazione è stata interpretata come un processo motorio basale che permette a meccanismi preparatori di sopprimere automaticamente un movimento attivato senza la necessità di processi cognitivi coscienti. Così, sebbene ci siano delle differenze tra i processi automatici e quelli volontari, tali processi potrebbero non avere rappresentazioni neurali completamente distinte. Infatti, il controllo motorio automatico sembra avere come substrato neurale il circuito corticale-ganglio basale che è stato associato al controllo motorio volontario. La ricerca contemporanea ha inoltre dimostrato che l’incremento delle oscillazioni beta nelle dinamiche del sistema corticale-ganglio basale può essere funzionalmente rilevante per l'inibizione del movimento. Di conseguenza, le oscillazioni beta sono state proposte come un meccanismo essenziale che consente al network motorio di comunicare in modo dinamico e flessibile. Nel frattempo, la ricerca attuale ha dimostrato che è possibile interagire con l'attività neuronale mediante tecniche di stimolazione cerebrale non invasiva (NIBS) come la stimolazione transcranica a corrente diretta (tDCS), la stimolazione transcranica a corrente alternata (tACS). In particolare, tACS consente la diffusione di corrente alternata a diverse frequenze ed è stata utilizzata per manipolare le oscillazioni cerebrali in modo controllabile. Comunque, questo concetto è ancora nelle fasi iniziali della ricerca e molto deve essere fatto per comprendere appieno i meccanismi sottostanti. Basandosi su queste scoperte, la ricerca presentata in questa tesi ha lo scopo di dimostrare un ruolo causale delle oscillazioni neurali beta sull’ inibizione inconscia e automatica, adottando la tACS sulla corteccia motoria primaria e l'area motoria supplementare. Inoltre, la combinazione di tACS con TMS e EEG mi ha permesso di caratterizzare i meccanismi di base della sua azione attraverso la misurazione dell’eccitabilità corticospinale e delle dinamiche oscillatorie neuronali. Nel complesso, questo lavoro contribuisce alla nostra comprensione del sistema motorio umano, offrendo al tempo stesso nuove conoscenze sull'approccio combinato di tACS e EEG nella caratterizzazione di un ruolo causale delle dinamiche oscillatorie neuronali sul comportamento

Effects of 10Hz and 20Hz transcranial alternating current stimulation on automatic motor control

Background: Automatic motor inhibition is an important and adaptive process through which an activated motor plan is suppressed if the movement is not intended to be executed. Neuronal networks are characterized by oscillatory activity. In the brain, a large variety of rhythms have been described that differ in their frequency, origin and reactivity to changes in task demands. Recent studies have demonstrated that active cortical networks are susceptible to weak sinusoidal perturbations of exogenous electric fields. Objective/Hypothesis: The aim of this study was to investigate the frequency-specific effect of transcranial alternate current stimulation (tACS) over the automatic control of movement in healthy volunteers. We hypothesized that applying two different tACS frequencies during a visuo-motor task would result in different behavioural effects and in diverse modulation of cortical excitability. Methods: In this study we used tACS to interact non-invasively with the ongoing task-related oscillatory activity. Stimulation was delivered at alpha (10 Hz) and beta (20 Hz) frequency over the supplementary motor area and the primary motor cortex (SMA-M1) connections, which are part of the BG-cortical motor loop, during the execution of the subliminal masked prime task. We measured the effects on task performance and on motor cortex corticospinal excitability by means of motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS). Results: Results indicate a specific effect of 10 and 20-Hz tACS on functional inhibition in the SMA-M1 circuit. Behaviorally there is an interference in task-related automatic inhibition: 10 Hz tACS reduced the automatic inhibition. In contrast 20 Hz tACS increased the automatic inhibition. At a neurophysiological level there is a modulation in excitability of M1: 20 Hz tACS reduced MEP amplitudes, whereas there was no change after 10 Hz tACS. Conclusion(s): The current study provides novel evidence that automatic mechanisms of motor behaviour can be modulated by imposing synchronized electrical oscillatory activity upon motor cortical regions. Our study has important implications for cognitive neuroscience studies suggesting that the use tACS might offer the possibility to demonstrate a causal link between endogenous brain oscillations, specific exogenous alternate current frequencies and specific cognitive processes

Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson's Disease Dementia : A 36 Months Follow Up Study

Background: Degeneration of the nucleus basalis of Meynert (NBM) and cortical cholinergic dysfunction are hallmarks of Parkinson's disease dementia (PDD). There is no effective therapy for PDD. Deep brain stimulation of the NBM (NBM-DBS) has been trialed as a potential treatment. Objective: Our primary aim was to evaluate the sustained tolerability of NBM-DBS in PDD, and its impact on global cognition, behavioral symptoms, quality of life and caregiver burden and distress. Second, we aimed to determine whether baseline measures of arousal, alertness, and attention were predictive of the three year response to NBM-DBS in PDD patients. Methods: Five of the six PDD patients who completed the baseline assessment participated in a 3 year follow up assessment. We assessed the participants after three years of NBM-DBS on the Mini Mental State Examination, Dementia Rating Scale-2, Blessed Dementia Rating Scale, Neuropsychiatric Inventory, and the SF36. Results: The five patients showed varying trajectories of cognitive decline, with two showing a slower progression over the three-year follow-up period. A slower progression of decline on global cognition was associated with higher baseline accuracy on the Posner covert orienting of attention test, and less daytime sleepiness. Conclusions: Whether slower progression of cognitive decline in two patients was in any way related to individual variability in responsiveness to NBM-DBS requires confirmation in a larger series including an unoperated PDD control group. Higher accuracy in covertly orienting attention and better sleep quality at baseline were associated with better cognitive outcomes at 36 months assessment. These results require validation in future studies with larger samples

The sensitivity to change of the cluster headache quality of life scale assessed before and after deep brain stimulation of the ventral tegmental area

Abstract Background Cluster headache (CH) is a trigeminal autonomic cephalalgia (TAC) characterized by a highly disabling headache that negatively impacts quality of life and causes limitations in daily functioning as well as social functioning and family life. Since specific measures to assess the quality of life (QoL) in TACs are lacking, we recently developed and validated the cluster headache quality of life scale (CH-QoL). The sensitivity of CH-QoL to change after a medical intervention has not been evaluated yet. Methods This study aimed to test the sensitivity to change of the CH-QoL in CH. Specifically we aimed to (i) assess the sensitivity of CH-QoL to change before and following deep brain stimulation of the ventral tegmental area (VTA-DBS), (ii) evaluate the relationship of changes on CH-QoL with changes in other generic measures of quality of life, as well as indices of mood and pain. Ten consecutive CH patients completed the CH-QoL and underwent neuropsychological assessment before and after VTA-DBS. The patients were evaluated on headache frequency, severity, and load (HAL) as well as on tests of generic quality of life (Short Form-36 (SF-36)), mood (Beck Depression Inventory, Hospital Anxiety and Depression Rating Scale), and pain (McGill Pain Questionnaire, Headache Impact Test, Pain Behaviour Checklist). Results The CH-QoL total score was significantly reduced after compared to before VTA-DBS. Changes in the CH-QoL total score correlated significantly and negatively with changes in HAL, the SF-36, and positively and significantly with depression and the evaluative domain on the McGill Pain Questionnaire. Conclusions Our findings demonstrate that changes after VTA-DBS in CH-QoL total scores are associated with the reduction of frequency, duration, and severity of headache attacks after surgery. Moreover, post VTA-DBS improvement in CH-QoL scores is associated with an amelioration in quality of life assessed with generic measures, a reduction of depressive symptoms, and evaluative pain experience after VTA-DBS. These results support the sensitivity to change of the CH-QoL and further demonstrate the validity and applicability of CH-QoL as a disease specific measure of quality of life for CH