Dopamine and Brain Computer Interface

The use of Brain-Computer Interface system (BCI system) allows for the detection of neurophysiological signals on the surface of the head and provides feedback to subjects or patients. For patients with neurological disorders who have severe motor deficits, self-generated brain signals can be translated, for example, into orthosis-supported movement of the paralyzed limb. Another possibility is to translate the brain signal into peripheral electrostimulation (functional electrical stimulation, FES), which generates muscle contraction and thus movement.

Fundamentally, BCI technology can be used as a replacement therapy when no recovery of motor function is expected. Another important application lies in improving motor training, relearning, and initiating movements. In the latter case, it is hoped that BCI training will stimulate neuroplastic mechanisms that lead to functional improvement.

Problems on the translational path to clinical application are:

* The high interindividual variability between different people regarding learning to control the BCI system;
* The extent of learning and motor improvement is often limited For this reason, the present study aims to investigate whether dopaminergic influence on the brain affects the effectiveness of using a BCI system in healthy subjects.

Aims of the present research project are to assess the effect of dopaminergic modulation on BCI performance in healthy elderly subjects to understand the underlying neurophysiological mechanisms. The perspective lies in the application of this approach for improved motor recovery after stroke.

Stroke is one of the most common causes of motor function impairment, and its prevalence is expected to rise due to an aging population. Stroke survivors often experience some level of spontaneous recovery of motor function during the acute stage and reach a functional plateau after which the recovery is generally slow or stagnant. Interestingly, there is emerging evidence indicating that brain-computer interface (BCI) based therapies can induce recovery beyond this plateau.

Pharmacological MRI (phMRI) is a new and promising method to study the effects of substances on brain function that can ultimately be used to unravel underlying neurobiological mechanisms behind drug action. Like most of the imaging methods it represents a progress in the investigation of brain disorders and the related function of neurotransmitter pathways in a non-invasive way with respect of the overall neuronal connectivity.

Moreover, it provides an ideal tool for translation to clinical investigations. MRI, while still behind in molecular imaging strategies compared to PET and SPECT, has the advantage to have a high spatial resolution and no need for the injection of a contrast-agent or radio-labeled molecules, thereby avoiding the repetitive exposure to ionising radiations. Functional MRI (fMRI) is extensively used in research and clinical setting, where it is generally combined with a psycho-motor task. phMRI is an adaptation of fMRI enabling the investigation of a specific neurotransmitter system, such as dopamine, under physiological or pathological conditions following activation via administration of a specific challenging drug.

The importance of the neurotransmitter dopamine (DA) for motor processes has long been known. In patients suffering from the Parkinson's disease the dopamine deficiency in the basal ganglia is known to cause strong movement-related deficits.

Recent studies suggest that DA stimulates neuronal structures, which in turn affect extensive brain regions, and thus contributes to various processes of behavioural control: both motor processes of movement control and cognitive processes in the context of perceptual categorisation, reward, motivation, and executive control. For this reason, DA is also referred to as a "teaching signal".

There's emerging evidence, that DA can be effective also for forming new stroke rehabilitation strategies. For a rehabilitation strategy to be effective, it should result in formation of new motor memories, which is anatomically mediated by networks that connect the dorsolateral prefrontal cortex, primary motor cortex, striatum, and the cerebellum. New motor memories are formed and pruned by the processes of synaptic plasticity such as LTP and LTD, which require dopaminergic signaling between the substantia nigra pars compacta and striatal medium spiny neurons in the putamen. Within the motor loops of the basal ganglia, dopaminergic binding to D1Rs facilitate desired movements, whereas binding to D2Rs inhibit undesired movements.

In addition to its role in motor drive within the basal ganglia, the dopaminergic system also potentiates visuomotor integration, which is the coordination of perceptual and action-related information. At the receptor level, D1Rs are critical for proper visuomotor integration. This system is important for relating visualized environmental information with body position, thus enabling optimal movement planning and correction. Therefore, potentiating the coordination of motor drive and visuomotor integration through dopaminergic therapy may enhance recovery after stroke.

Drugs that increase the availability of central nervous system neurotransmitters (dopamine, noradrenaline, serotonin, and acetylcholine) have been shown to exert a facilitatory effect on neuroplasticity. With this in mind, investigators have studied the effects of amphetamines, selective serotonin reuptake inhibitors, donepezil, psychostimulants such as methylphenidate, and dopaminergic agents on motor recovery after stroke. Of the aforementioned drugs, only levodopa has been shown to enhance the induction of LTP-like plasticity, practice-dependent plasticity, and motor recovery after stroke in human subjects. In addition, levodopa has a safe side effect profile and is not a controlled substance.

The most common side effect of levodopa is dyskinesia, followed by nausea, then hallucinations and dizziness. Also, there is some risk of levodopa induced dyskinesia in patients with Parkinson's disease. However, these severe side-effects generally enroll after long-term (i.e., years) intake of the drug. In addition, the risk in patients with other conditions, such as stroke, is estimated to be much lower. In fact, levodopa has been used in numerous studies that focus on motor recovery in stroke survivors without any reports of dyskinesia nor other minor or major side effects. "The literature" concludes that treating stroke survivors with levodopa is unlikely to cause levodopa-induced dyskinesia, unless there is comorbid basal ganglia damage or Parkinson's disease.

The basis of BCIs functioning is the translation of neural activity directly recorded from the subject into real-time feedback in order to train consistent brain activation patterns associated with specific mental states. Neural activity can be detected through invasive (ECoG/iEEG), or non-invasive (EEG, MEG, real-time fMRI, or NIRS) methods. The majority of studies deploy EEG based non-invasive BCIs, as they are relatively easy and fast to operate, and have good temporal and spatial characteristics, thus can be used safely and effectively to elicit functional gains in stroke survivors with persistent motor deficits and may enhance the efficacy of concurrent or associated therapies, even after individuals reach a functional plateau using traditional therapies.

Currently, the majority of BCIs that target restoration of motor function are based on motor imagery (MI). Such systems are not reliant on actual movements, but rather use the mental process of imagination of a movement. The main reason is that MI leads to the activation of the same brain areas as actual movement. Problems that arise with the motor imagery without any feedback are the lack of control of the activity as well as the lack of motivation. Using a BCI, motor imagery can be measured in real-time, thus making it possible to provide real-time feedback to the subject. Furthermore, the coupling of BCI devices with MI triggered functional electrical stimulation (FES) allows for resynchronisation of cortical activation, peripheral activation, and sensory feedback. In addition to this, some studies have argued for inclusion of virtual reality for immediate visual feedback. Combination of virtual reality based action observation and FES feedback may potentiate the motor function improvement as subjects interact with the real-time on-screen avatar. Thus, it is possible to close the circuit: the motor imagery is detected by the system, and FES is applied to the targeted muscle to help the participant carry out the movement. At the same time, an avatar performs the exact same movement (in synchrony with FES), which is displayed on the participant screen in real-time. Hence, in addition to performing the physical movement which contributes to the success of the therapy, the areas of the sensory cortex are also activated synchronously with the motor imagery via the afferent nerve impulses. This leads to the stimulation of the Hebbian plasticity, which states that neurones which are repeatedly stimulated together create common connections. This is thought to induce use-dependent plasticity and facilitate functional recovery. Such strengthening of central-peripheral connections via complimentary technologies has the potential to enhance motor function recovery through induced use-dependent plasticity and facilitate post-stroke functional recovery.

There is evidence of changes in brain activation and functional connectivity (FC) in stroke patients receiving BCI based rehabilitation therapies. They can potentially result in an increase of FC between the inferior parietal lobe and the supplementary motor area (SMA), as well as between the anterior cingulate cortex and the SMA, positively correlated with gains in Fugl-Meyer scores. Moreover, FC increases were observed between the ipsilesional thalamus and the contralesional cingulate, contralateral paracentral lobule, and the bilateral precuneus.

Eligibility Criteria:
Inclusion Criteria:

* Age: between 18 and 80 years old at the time of signing the consent form
* BCI naïve
* MRI compatible
* Participation in a detailed discussion on the explanation of the experiment
* Signing of consent to participate in each experiment

Exclusion Criteria:

* Sensory deficits (visual and auditory)
* Wernicke's or global aphasia
* Strong spasticity
* Neurological and/or psychiatric diseases
* Severe pre-existing lung or heart diseases; Gastrointestinal diseases; Malignant disease
* Thyroid diseases
* Taking other medications
* Narrow angle glaucoma
* Non-age-related otological diseases
* Stimulators (cardiac, neuro, etc.)
* Participation in a similar study
* Fractures or lesions in the upper extremities
* Preceding neurosurgical procedures
* Inability to perform the experimental tasks
* Inability to give consent
* Have contraindication for magnetic resonance tomography (MRI) (e.g. braces, cardiac pacemakers, metallic implants that might interfere with the MR signal, claustrophobia)
* Severe attention and drive disorders
* Alcohol or drug abuse
* Pregnancy
* Women in breastfeeding period