The Deep Brain Stimulation in Mesolimbic and Mesocortical Pathways

Acta Medica Mediterranea, 2020, 36: 1901

NEW THERAPEUTIC OPTION IN SEVERE AUTISM SPECTRUM DISORDERS: THE DEEP BRAIN STIMULATION IN MESOLIMBIC AND MESOCORTICAL PATHWAYS

Rosa Marotta Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro

ABSTRACT

Autistic spectrum disorder (ASD) is currently considered a complex neurodevelopmental disorder resulting in impaired social and language skills and behavioral disorders. Motor stereotypies and self-injurious behavior of low-functioning autism are often resistant to medical therapy. Deep brain stimulation in mesolimbic and mesocortical circuits seems to be significantly effective in controlling these symptoms but very few cases are treated with this approach. The targets proposed are globus pallidus internus (GPi), anterior limb of internal capsule (ALIC), basolateral amygdala (BLA) and nucleus accumbens (NAc). Studies conducted on greater number of patients are therefore necessary to verify the effectiveness of DBS in ASD and to explore other potential targets.

Keywords: Autistic spectrum disorder, self-injurious behavior, deep brain stimulation, globus pallidus internus, basolateral amygdala, nucleus accumbens.

DOI: 10.19193/0393-6384_2020_3_297

Received November 30, 2019; Accepted January 20, 2020

Introduction can be life threatening for patients themselves. In ad- dition, medical therapy of hyperkinetic movements Autistic spectrum disorder (ASD) is currently can often lead to the onset of tardive dystonia which considered a complex neuropsychiatric disorder, on- further complicates the clinical picture. set in developmental age, characterized by a clinical On the basis of the results of Deep Brain Stim- expression that varies between subject and subject ulation (DBS) in movement disorders and psychiat- and over time within the same subject. This disorder ric disease, such as obsessive-compulsive disorder results in impaired social and language skills and var- (OCD) and Tourette’s syndrome (TS), a potential ious behavioral disorders. Different manifestations therapeutic effect of DBS in autistic spectrum disor- of the autistic spectrum are divided into high-func- der symptoms, stereotyped movements and self-mu- tioning autism (subjects capable of communicating tilation symptoms has been hypothesized. verbally and endowed with normal or even superior ASD seems to have abnormalities of structural intelligence) and low-functioning autism (subjects and functional networks of the brain as its substrate with intellectual disability, impaired social commu- (connectivity disturbance affecting frontal, fron- nications or interactions, repetitive and stereotyped to-temporal, fronto-limbic, fronto-parietal and in- behaviour, lack of social or emotional reciprocity, ter-hemispheric connection)(1). A diminished neural aggressiveness and self-injurious behavior). Repet- response to social reward has been demonstrated in itive behavior with motor stereotypies and self-inju- children with ASD. The reward system is generally rious behavior are resistant to medical therapy in a considered to be composed of the major dopamine substantial percentage of cases and potentially they pathways that begin in the ventral tegmental area 1902 Rosa Marotta

(VTA) and connect the nucleus accumbens, amyg- bilaterally in order to obtain a simultaneous stimu- dala, hippocampus, and prefrontal cortex. When lation of GPi and ALIC which proved to be progres- exposed to a rewarding stimulus, brain responds by sively effective (improvement of 71.6%) in the first 3 increasing release of dopamine and thus the struc- months and then lost effectiveness in the following tures associated with the reward system are found months. Stimulation parameters used were for ALIC: along the major dopamine pathways in the brain, the bipolar configuration, 210 microseconds. pulse mesolimbic pathway and the mesocortical pathway. width, 100 Hz Frequency and 2.0 V amplitude, while Mesolimbic dopamine pathway connects the ventral for GPi: bipolar configuration, 120 microseconds tegmental area (VTA), one of the principal dopa- pulse width, 100 Hz Frequency and 2.5 V amplitude. mine-producing areas, with the nucleus accumbens, an area of the ventral striatum strongly associated Basolateral amygdala with motivation and reward, and it is a part of com- The “amygdala complex” is a small al- plex circuits involving the amygdala, anterior limb mond-shaped group of 13 nuclei in the medial tem- of internal capsula, hippocampus and the bed nu- poral lobe that is considered a center of integration of cleus of the stria terminalis. Mesocortical dopamine higher neurological processes regulating anxiety and pathway travels from the VTA to the ventromedial social interactions. Amygdala dysfunction has been prefrontal cortex (VMPFC). Mesolimbic pathway linked to many psychiatric disorders such as schiz- is considered important for mediating pleasure and ophrenia, bipolar disorder and depression and neu- rewarding experiences while mesocortical pathway rodevelopmental disorders including ASD. The nu- for a wide range of functions, such as motivation, clei of the “amygdala complex” do not have a specific emotion, and executive functions. name and they are generally referred to as lateral nu- With so many physiological and anatomical clei (L), basolateral nuclei (BL), centromedial nuclei sites implicated in the pathophysiology of ASD, (Ce) and corticalmedial nuclei (Co). The “extended more different targets for DBS have been proposed amygdala” or “dorsal amygdala” includes the centro- in treatment of symptoms of autism spectrum refrac- medial nuclei (CM), the sublenticular substantia in- tory to medical therapy, particularly for stereotypies nominate (SSI), the nucleus accumbens shell (NAcs) and self-injurious behavior. Few cases are report- and the bed nucleus of the stria terminalis (BNST). ed in literature with several stimulation targets ex- The BL nuclei are the main nuclear ‘receiving’ plored: globus pallidus internus (GPi), anterior limb group and receives inputs from the temporal cortex, of internal capsule (ALIC), basolateral amygdala the orbital and medial prefrontal cortex (OMPFC), (BLA) and nucleus accumbens (NAc). and the hippocampus. The Co nuclei receive olfac- tory and hippocampal inputs while the centromedial Globus pallidus internus (GPi), anterior limb nuclei have a connection function among the various of internal capsule (ALIC) nuclei of the amygdala complex. Sturm et al. report- Neuromodulation of cortico-basal circuits has ed a case of BLA DBS in a ASD 13 years-old patient been successfully proposed for treatment of invol- with refractory SIB, mental retardation and cerebral untary movements, such as tics, dystonic/dyskinetic palsy obtaining an improvement in SIB and in emo- syndromes and very disabling repetitive actions. On tional, social and cognitive symptoms on 24-month the basis of these findings, Stocco et al. used bilat - followup (3). The quadripolar electrode implant was eral stimulation of GPi and ALIC for the control of bilateral with contacts in lateral, basolateral and cen- self-injurious stereotypies in two patients with au- tromedial nuclei on one site and in extended amyg- tism and mental retardation, one of whom developed dala on the other site. Stimulation parameters were: tardive orolingual and cervical dystonia following 130 Hz frequency, 120 microsecond pulse width and treatment with risperidone (2). 2-6.5 V amplitude with monopolar configuration. In the first patient the electrodes were implant - Only stimulation of contacts in basolateral nuclei ed in GPi and stimulation was performed with bi- produced stable improvement while stimulation of polar configuration, 120 microseconds pulse width, contacts in paraliminar and central amygdaloid nu- 80 Hz Frequency and 3.3 V amplitude. Result was cleus and supra-amygdaloid efferents had no effect. impressive (improvement of 91.3%) starting from the first stimulation period remaining constant at the Nucleus accumbens 13-month followup, also affecting tardive dystonia. The Nucleus accumbens (NAc) can be divided In the second patient, the electrodes were implanted into a central “core” surrounded by a “shell”. Core is New therapeutic option in severe autism spectrum disorders: the deep brain stimulation in mesolimbic and... 1903 considered to be part of ventral striatum while shell this neuromodulation approach for OCD and for TS. is referred to as a part of dorsal amygdala. NAc is The number of patients treated is extremely small: the main input nucleus of the basal ganglia and it re- studies conducted on a greater number of patients ceives both indirect input via the mesolimbic dopa- are therefore necessary to verify its real short and minergic projections from the ventral tegmental area long term effectiveness and to explore other poten- (VTA) and substantia nigra as well as direct input tial targets. via the glutamatergic projections from the subiculum and amygdala, thalamus, hippocampus, prefrontal and prelimbic cortex. Efferent projections are fibers to the hypothalamus, the nuclei of the brainstem and the globus pallidus. Fibers to the Gpi are the connection point between the limbic system and the motor References system. The globus pallidus, in turn, sends output fibers to the medial dorsal nucleus of the thalamus 1) Zikopoulos B, Barbas H. Altered neural connectivity which then project to striatum as well as to the ven- in excitatory and inhibitory cortical circuits in autism. tromedial prefrontal cortex. The NAc plays an im- Front Hum Neurosci. 2013 27;7:609 doi: 10.3389/fn- hum.2013.00609. eCollection 2013. portant role in modulation of reward processes and 2) Stocco A., Baizabal-Carvallo J.F. Deep brain stimulation aversive behavior and consequently can be consid- for severe secondary stereotypies. Parkinsonism and Re- ered a target for DBS in the treatment of symptoms lated Disorders 2014; 20: 1035-1036 of the autistic spectrum. Park et al. performed a bi- 3) Sturm V., Fricke O., Buhrle C., Lenartz D., Maarouf M., Treuer H., Mai JK., Lehmkuhl G. DBS in the basolater- lateral DBS of NAc in a 14-year-old patient with ear- al amygdala improves symptoms of autism and related ly childhood autism, mental retardation, seizure and self-injurious behavior: a case report and hypothesis on SIB obtaining a progressive decrease in SIB with a the pathogenesis of the disorder. Frontiers in Human Neu- maximum of 40% and improvement in some items roscience 2013; 6, 341: 1-9 of social cognition at 24-month followup(4). Stimula - 4) Park HR, Kim IH, Kang H, Lee DS, Kim BN, Kim DG, Paek SH. Nucleus accumbens deep brain stimulation for tion parameters were 130 Hz frequency, 90 microsec a patient with self-injurious behavior and autism spec- pulse width, 3-5 V amplitude. After two years of trum disorder: functional and structural changes of the stimulation NAc DBS resulted in bilateral decrease brain, report of a case and review of literature. Acta Neu- of cortex matter density at MRI study in supplemen- rochir 2017; 159: 137-142 5) Baup N., Grabli D., Karachi C., Mounayar S., François tary motor cortex, pre and post central girus, pre- C., Yelnik J. High- frequency stimulation of the anteri- cuneus and lateral occipital cortex; furthermore the or subthalamic nucleus reduces stereotyped behaviors. J metabolism of frontal and occipital cortex reduced Neurosci. 2008; 28(35): 8785-8 bilaterally at the FDG-PET study. Another possible target in the treatment of SIB in ASD may be the subthalamic nucleus (STN) in its anterior limbic portion. There is no case treated with this target in humans while significant reductions in stereotypies induced by Bicuculline injections in limbic and associative part of Globus pallidus ex- ternus (GPe) have occurred in primate model(5). The choice of STN as the DBS target was based on the positive response of the obsessive compulsive symptoms in two parkinsonian patients with comorbidities for OCD who undergone to STN DBS.

Conclusion

In conclusion DBS of targets located in mesocortical and mesolimbic circuits seems to be signif- ––––––––– Corresponding Author: icantly effective in controlling SIB in patients with Rosa Marotta ADS. Support for its potential value and for its safety Email: [email protected] comes from the experience gained about the use of (Italy)