Cortico-Subcortico-Cortical Loops, Networks, High Frequency Stimulation: from Experimental Studies to Clinical Practice

A better understanding of the functional organization of the cortico-subcortico-(basal ganglia, BG)-cortical loops has furnished new insights about the pathophysiology of certain neurological and psychiatric diseases. It is the case for the motor loop and Parkinson’s disease (PD) and the limbic loop and obsessive compulsive disorder (OCD). For PD, the realization of a parkinsonian model in non-human primate, by using a dopaminergic neurotoxin, the MPTP, revealed the major role exerted by the subthalamic nucleus (STN), “a glutamatergic driving force”, in the network of BG. Thus, the dopamine (DA) depletion provokes an abnormal oscillatory hyperactivity of the subthalamic neurones. This oscillatory activity is mainly in the 15-30 Hz b range and less frequently in the 3-10 Hz q range. The elevated b activity is considered to be related to antikinetic motor activity. The oscillations in the low frequency q range are often in synchrony with the tremor. In Parkinsonism, these pathological rhythms invade the BG network and impede the build-up of coherent cortical motor messages. This situation is concomitant with a gabaergic inhibitory state in the GPi/SNr-thalamus-cortical pathways.The high frequency stimulation (HFS, DBS) of STN exerts a dual effect: (1) it suppresses the deleterious rythmes b and q and (2) it induces a new activity. The latter consists of bursts of 60-80 Hz spikes. Therefore it appears that the pathological disrupted activity, recorded in the STN, is totally replaced by an intermittent activity in the 60-80 Hz g range. Widespread to BG network the g oscillations are considered to be prokinetic and capable to thwart akinetic and hypertonic processes.Experimental approaches in non-human primates have also provided major clues concerning the relationship between the limbic loop, anterior cingulate cortex and OCD. Using a Stroop-like visuo-motor task in monkeys, we have studied unitary neuronal activity of the anterior cingulate cortex (ACC, CMAr: 24c) during error detection and conflict monitoring. Neuronal changes in discharge rates are always much more pronounced for an erroneous response than for a successful movement that induces reward delivery. Moreover, some neurons (so called “bimodal”) respond more markedly to the warning stimulus when a previous trial failed. In this case, the probability increases for a subsequent correct response. An abnormal hyperactivity of these neurons, which would take advantage from past errors, could contribute to the genesis of obsessive compulsive disorders (OCD). In OCD victime, functional magnetic resonance imagery (fMRI) demonstrates excessive activity in the ACC and in the limbic loop in which it is embedded. We proposed to counteract this hyperactivity by applying, in severe and resistant OCD, high frequency stimulation of the ventral striatum (nucleus accumbens), a major node of the limbic loop. Recordings of striatal neurons during electrodes implantation revealed an abnormal oscillatory activity in the 15-30 Hz b range. It can be assumed that this deleterious and antikinetic rhythm, occupying the limbic loop, is replaced by a prokinetic activity generated by HFS. This is supported by the fact that in two severe cases, OCD symptoms were markedly reduced by deep brain stimulation.These two examples argue for the concept of “network pathologies” where disrupted oscillatory activity can be thwarted by HFS of the appropriate target and replaced by a prokinetic rhythm.