Cognitive Rehabilitation and Modulating Neuroplasticity with Brain Stimulation: Promises and Challenges

Abstract

A substantial proportion of the severe functional disability observed in patients with schizophrenia is attributable to their persistent negative symptoms and cognitive deficits [1, 2]. Identifying these determinants of functional disability becomes even more crucial when patients remit from their florid hallucinations and delusions [3]. Indeed, there are very few evidence-guided interventions (e.g., cognitive remediation) that specifically target the neural systems underlying the persistent cognitive and volitional impairments. Despite showing promising results, the magnitude of benefits from cognitive remediation strategies could at best be described as modest [4]. It is therefore critical to explore and empirically examine alternative strategies to ameliorate cognitive deficits and improve functional outcome. The core deficits in schizophrenia are increasingly being viewed as resulting from aberrant neuroplasticity, operating at multiple mechanistic levels of brain functioning— such as synapses, axons, glia and network plasticity. This maladaptive ‘‘dysplasticity’’ may involve both hypoplastic changes in strategic brain networks supporting cognitive functions and goal-directed behavior or volition, and hyperplastic changes in neural systems governing salience detection, emotion regulation as well as default mode systems [5]. A range of neurophysiological investigations probing plasticity at multiple levels supports these conclusions. For example, synchronous neural oscillations during spindle sleep, which have been considered, as markers of learningrelated synaptic plasticity are reduced in schizophrenia. Moreover, they also predict deficits in attention, motor learning and executive functions [6, 7]. Similarly, pairing median nerve stimulation with transcranial magnetic stimulation (TMS) over the motor cortex produces lesser plasticity-dependent facilitation of motor potentials in schizophrenia when compared with healthy subjects; these plasticity-impairments were also significantly associated with the motor learning deficits observed in these patients [8]. One strategy that has promising therapeutic potential to adaptively modulate neuroplasticity is the use of non-invasive brain stimulation using TMS or transcranial direct current stimulation (tDCS). TMS is a non-convulsive method of modulating focal brain activity via induced electrical currents that result in neuronal depolarization. Repeated pulses (rTMS) administered at low (B1 Hz) and high frequencies (C5 Hz) can either inhibit or enhance the underlying cortical activity respectively [9]. The application of TMS in treating cognitive deficits, supported by advancing neurobiological evidence is only recently gaining momentum [10]. For instance, 4-weeks of 20-Hz rTMS delivered to bilateral dorsolateral prefrontal cortices resulted in significant improvement on working memory performance in schizophrenia patients, when compared to sham TMS [11]. Potentiation of task-evoked frontal gamma oscillatory activity may mediate this response [12]. However, another study using unilateral (left) 10-Hz rTMS to the dorsolateral prefrontal cortex did not find similar benefits [13]. Initial evidence suggests that social cognition deficits may also benefit from high frequency rTMS to the & Urvakhsh Meherwan Mehta urvakhsh@gmail.com