Prehabilitation, Rehabilitation and Comprehensive Approach to the Sequelae of Brain Tumors

The goal of the present pilot single-cohort feasibility trial is to investigate the feasibility and understand potential mechanisms of efficacy for Neuromodulation-Induced Cortical Prehabilitation (NICP) in adults with brain tumours and eligible for neurosurgery.

The main questions it aims to answer are:

* is the intervention feasible, in terms of adherence, retention, safety and patient's satisfaction;
* what are the mechanisms of neuroplasticity primed by NICP

Participants will undergo a prehabilitation protocol, consisting of daily sessions (total: 10-20 sessions) structured as follows:

* Intervention 1: non-invasive neuromodulation (TMS/tDCS).
* Intervention 2: motor and/or cognitive training, during or immediately after non-invasive neuromodulation, for about 60 minutes.

The timeline is structured as follows:

T1: baseline (before NICP) T2-T3: NICP period T4: after NICP T5: surgery T6: after surgery

Clinical, neuroimaging and neurophysiology assessments will be performed before NICP (T1), after NICP (T4), and after neurosurgery (T6). Feasibility outcomes will be determined during NICP protocol (T2-T3).

The objective of the proposed intervention is to progressively reduce the functional relevance of eloquent areas, which are healthy brain areas close with the tumour and thus exposed to the risk of being lesioned during surgery. In fact, previous studies have shown that temporary inhibition of eloquent areas (by neuromodulation) coupled with intensive motor/cognitive training promoted the activation of alternative brain resources, with a shift of functional activity from eloquent areas to areas functionally related, but anatomically distant from the tumour.

By moving the activation of key motor/cognitive functions away from the tumour, the risk of postoperative functional sequelae will be reduced; which in turn will falicitate a more radical tumour excision by the neurosurgeon.

Neuromodulation-Induced Cortical Prehabilitation (NICP) is a relatively new approach in the neurosurgical field. It consists of priming neuroplastic changes before neurosurgery for brain tumours, in order to improve surgical outcomes and, hopefully, long-term survival and quality of life. The intervention comprises two elements:

1. Neuromodulation (like transcranial magnetic stimulation, TMS, and transcranial direct current stimulation, tDCS). The goal of neuromodulation is to inhibit the eloquent areas, defined as brain areas functionally active and close to the tumour.
2. Behavioural training (like motor training, cognitive training, or a combination). The function trained corresponds with the function of the eloquent area targeted by neuromodulation.

The two interventions are provided on a daily basis, and repeated over 10-20 consecutive weekdays. Notably, after the inhibition of the eloquent area there is a temporal window of about one hour, where intensive training of the same function requires the activation of alternative areas/pathways. By consolidating this alternative activation over multiple sessions, the outcome is a reduction in the functional relevance of eloquent areas, in favour of alternative resources anatomically distant from the tumour.

Only few case reports have been published so far, with very positive results obtained by means of invasive neuromodulation; the term 'invasive' means that a first neurosurgery was required to implant electrodes over eloquent areas for intracranial electrical stimulation, followed after few days/weeks by a second surgery for tumour removal. Despite relevant neuroplastic changes, the problem with this approach has been the high rate of adverse events occurred (infections, edema, pain, seizure) due to the invasiveness of the procedures. Therefore, by using a non-invasive neuromodulation approach, the goal of the present trial is to promote neuroplastic changes beneficial for neurosurgery, while at the same time ensuring no serious adverse events.

Further details on neuromodulation. Investigators will apply the most appropriate neuromodulation protocol, personalized based on whether to perform TMS and/or tDCS, individual resting motor threshold (for TMS), and target determination (related to eloquent areas).

Protocol for low frequency rTMS:

* intensity: 90% RMT;
* frequency: 1 Hertz;
* total number of pulses: 1600.

Protocol for tDCS:

* cathode: over eloquent areas
* anode: typically over areas that should be activated, as opposed to eloquent areas

Further details on upper limb prehabilitation training.

Within the 60 minutes immediately after neuromodulation, patients will perform an intensive training of the same function of the eloquent area, which is now temporarily inhibited. Intensity of the training will be continuously adjusted in terms of type, difficulty and variability:

* Type: exercises specific for finger individuation (play the piano, typewriting), finger coordination (dexterity, manipulation), arm reaching. In order to integrate upper limb function with other motor-cognitive functions, dual task training will be performed, both motor-cognitive (decision making, stroop task, motor sequence learning etc.) and motor-motor (bimanual activites, arm and balance tasks, etc.);
* Difficulty: the intensity of the exercise will be set as to result 'difficult, yet achievable' by the patient. This way it is ensured that the brain is under a stress condition which, together with concurrent eloquent area inhibition, will promote and consolidate the activation of alternative resources.
* Variability: varying systematically the type and difficulty of the training is useful to keep the patient engaged and ensure that the end result will be a global motor-cognitive training, instead of a monotonic improvement in a specific performance.

Further details on Prehabilitation for language and cognitive training. Language-cognitive training will follow the same rationale illustrated for motor training. Soon after neuromodulation the patient will perform a computerized cognitive training on a dedicated platform ("Guttmann NeuroPersonalTrainer"® (GNPT). Exercises will be customized based on specific patient's deficits, and/or functions at risk of being compromised after surgery. For instance, the neuropsychologist may vary settings such as presentation speed, latency time or number of images, thus finely tuning several difficulty levels. Regarding language, tasks will be planned and supervised in a personalized way by a neuropsychologist, readjusting their planning if necessary.

Discontinuation, adherence, and permission for concomitant care.

The intervention will be discontinued in the following cases:

* participant's request;
* serious adverse events attributable to the intervention. Patients will be allowed to continue any ongoing treatment. Formal training of motor-cognitive functions outside the protocol will be discourage, as it may affect neuroplastic changes in an unpredictable way.

Eligibility Criteria:
Inclusion Criteria:

* diagnosis of brain tumour requiring neurosurgery
* ability to undertake at least 10 sessions of prehabilitation protocol
* tumour location posing the patient at risk of developing post-operative neurological deficits, for instance at the level of upper limb motor function and speech production
* ability to understand the general purpose of the prehabilitation program and understand simple instructions
* being willing to participate and sign the informed consent
* being able to sit unassisted for one hour.

Exclusion Criteria:

* any contraindication for magnetic resonance imaging or transcranial magnetic stimulation
* unstable medical conditions
* musculoskeletal disorders that may significantly affect functional training
* pain, depression, fatigue that may significantly affect functional training
* history of alcohol/drug abuse