A Neuroanatomy of Positive Affect Display - Subcortical Fiber Pathways Relevant for Initiation and Modulation of Smiling and Laughing

Abstract

Background: We here report two cases of stimulation induced pathological laughter (PL) under thalamic deep brain stimulation (DBS) for essential tremor and interpret the effects based on a modified neuroanatomy of positive affect display (PAD).

Objective/hypothesis: The hitherto existing neuroanatomy of PAD can be augmented with recently described parts of the motor medial forebrain bundle (motorMFB). We speculate that a co-stimulation of parts of this fiber structure might lead to a non-volitional modulation of PAD resulting in PL.

Methods: We describe the clinical and individual imaging workup and combine the interpretation with normative diffusion tensor imaging (DTI)-tractography descriptions of motor connections of the ventral tegmental area (VTA) (n = 200 subjects, HCP cohort), [[¹⁸F] fluorodeoxyglucose (¹⁸FDG)] positron emission tomography (PET), and volume of activated tissue simulations. We integrate these results with literature concerning PAD and the neuroanatomy of smiling and laughing.

Results: DBS electrodes bilaterally co-localized with the MB-pathway ("limiter pathway"). The FDG PET activation pattern allowed to explain pathological PAD. A conceptual revised neuroanatomy of PAD is described.

Conclusion: Eliciting pathological PAD through chronic thalamic DBS is a new finding and has previously not been reported. PAD is evolution driven, hard wired to the brain and realized over previously described branches of the motorMFB. A major relay region is the VTA/mammillary body complex. PAD physiologically undergoes conscious modulation mainly via the MB branch of the motorMFB (limiter). This limiter in our cases is bilaterally disturbed through DBS. The here described anatomy adds to a previously described framework of neuroanatomy of laughter and humor.

Keywords: deep brain stimulation; essential tremor; laughter; motorMFB; pathological laughter; pseudobulbar affect.

FIGURE 1

Case #1, FDG-PET activation pattern contrasting DBSon vs. DBSoff. Effects shown are related to initiation of DBS. Pattern description in text. (DLPFC, dorsolateral prefrontal cortex; ICa, anterior limb of internal capsule; NAC, nucleus accumbens; Vim, ventral intermediate nucleus of thalamus; VTG, ventral tegmental nucleus of Gudden; DTG, dorsal tegmental nucleus of Gudden.)

FIGURE 2

(A) Streamlines selected from global tractography based on the subject’s dMRI data (native space). (B) Same as a but in MNI space and normative dMRI data. Streamlines are constrained to visit the ICa/NAC and the Vim PET activation. MB pathway cannot be visualized in patient individual imaging but shows up on normative data. (MB, mamillary bundle of motorMFB; PFC, prefrontal cortex branch of motorMFB; Vim, ventral intermediate nucleus; VTA, ventral tegmental area; OFC, orbitofrontal cortex; ICa, internal capsule anterior limb; NAC, nucleus accumbens.)

FIGURE 3

Bilateral DBS electrodes perfectly hit MB bundles just medial to the DRT. The bilateral stimulation effectively reduces tremor (via DRT, not shown) while at the same time modulating the limiter pathway (MB); (A) view from anterior and upper left; (B) view from posterior and upper left. PET activation surrounding the left DBS electrode extends downward into the VTA and also encroaches on the PFC pathway (in PET imaging, Figure 1, leading to ICa/NAC activation). (C) View from right. To understand the relationship of the stimulation electrodes and the white matter geometry we show here bundle specific tractograms (based on normative connectome data from HCP) in the native space of the considered case. Additionally, deep GM structures are shown, which are partly taken from atlases, but were also manually drawn. DBS, deep brain stimulation electrode with volume of tissue activated in yellow; DRT, dentato-rubro-thalamic bundle; fx, fornix; hypoth., hypothalamus; lt, left; MB, mamillary body branch of motorMFB; mbb, mamillary body; OFC, orbitofrontal cortex; PET activ., PET activation, PFC, prefrontal cortex branch of motorMFB, RN, red nucleus; rt, right; STN, subthalamic nucleus; VTA, ventral tegmental area.

FIGURE 4

Case #1, unconstrained and constrained cortical projection patterns of the DRT and the regarded pathways relevant for PAD (HCP group level, MNI-space). Upper panel shows cortical projection patterns constrained to thalamic (Vim) PET activation. Lower panel shows a pattern constrained to the actual volume of activated tissue of the DBS. Note how PFC and MB focus on the facial region of the sensory-motor cortex. PFC branch cortical pattern shows central and lateral orbitofrontal involvement (inset). Lateral OFC is typically involved in response inhibition (Kringelbach, 2005). The lower right histogram shows a simulated percentage of tract activation. DRT, dentato-rubro-thalamic tract; PFC, MB and BC represent branches of motorMFB with distinct regions of origin: PFC, prefrontal cortex branch; MB, mamillary body branch; BC, brainstem cerebellum branch (see also Figure 7).

FIGURE 5

Case #2, bilateral stimulation in the MB tracts (limiter pathways) during thalamic DBS for tremor. See also the accompanying video. (A) DBS electrode positions with stimulation pattern as shown in (B). (B) Stimulation pattern used to evoke PAD response in postoperative phase (see also accompanying video). (C,D) Note initiation of PAD via bilateral stimulation (and inhibition) of limiter pathways (blue in A). (RN, red nucleus; STN, subthalamic nucleus; mbb, mammillary bodies; PFC, PFC bundle.)

FIGURE 6

Case #1, topographic presentation of three fiber tracts with respect to thalamic nuclei [following the atlas of Morel (2007)]. (A) Overview with DBS electrodes showing three principle fiber pathways: DRT, yellow; PFC, green; MB, blue. (B,C) Relation of the regarded fiber tracts to thalamic nuclei and DBS electrodes with simulated volumes of activated tissue (yellow spheres). All three fiber tracts have proximity with the ventro-lateral thalamic nuclei [for nuclei abbreviations refer to Morel (2007)].

FIGURE 7

Cartoonistic rendition of subcortical pathways for PAD. (A) The simplified wiring pattern of the different pathways involved: MB (blue), =limiter-pathway, M1 to VTA/mbb complex inhibiting PAD; PFC pathway (green), connects OFC via VTA to M1 and brainstem; red, BC pathway (connects dlPFC via VTA to brainstem and cerebellum). imMFB (purple); connects VTA to OFC and dlPFC (dopaminergic); slMFB (yellow), bidirectional between OFC/dlPFC and VTA. Selected stimulation effects with pathological or induced laughter out of the literature: (A) stimulation in the anterior limb of the internal capsule (Okun et al., 2010; Haq et al., 2011); (B) subthalamic nucleus (STN) DBS (Krack et al., 2001); (C) slMFB DBS in major depression (Schlaepfer et al., 2013; Coenen et al., 2018a); *, this contribution. (B) In the proposed concept the PFC branch (green arrows) of the motorMFB [OFC to M1 and facial nuclei (vii)] serves to immediately display (positive) affect (smiling, laughing). It is regulated, depending on environmental needs via the mamillary body branch (MB, blue arrow) as a “limiter pathway” which inhibits PAD (at the level of mbb/VTA complex). (C) Modulation of MB pathway via DBS leads to a dysfunctional control and thereby to (pathological) laughter (case #1) or simply enhanced PAD (case #2). (dlPFC, dorsolateral prefrontal cortex; OFC, orbitofrontal cortex; vmPFC, ventromedial prefrontal cortex; SMA, supplementary motor area; M1, primary motor cortex; ICa, anterior limb of the internal capsule; mbb, mammillary bodies; PAG, periaqueductal gray; STN, subthalamic nucleus; VTA, ventral tegmental area (of Tsai); SNr, substantia nigra; RN, red nucleus; NAC, nucleus accumbens; DN, dentate nucleus; CBT, cerebro-bulbar tract; VII, nucleus of the facial nerve; ANT, anterior nucleus of thalamus, PAG, periaqueductal gray.)

FIGURE A1

Implantation situation in both cases (upper panel, case 1, lower panel case 2). Ventral intermediate nucleus (Vim, pink) is traversed in both cases. Implantation occurred with the tips of the electrodes somewhat below the ACPC level (typical for Essential Tremor). (A–C) Axial–sagittal–coronal (respectively); (D) coronal with DRT reconstruction (yellow) from planning station (Elements, BrainLab, Munich, Germany). Other objects: red nucleus, red; subthalamic nucleus, green; substantia nigra, blue.