Conceived and designed the experiments: TFM MH. Performed the experiments: MH G. Berding G. Baillot. Analyzed the data: MH G. Berding. Wrote the paper: TFM MH JV HJH G. Berding.
The authors have declared that no competing interests exist.
The influence of bilateral deep brain stimulation (DBS) of the nucleus nucleus (NAcc) on the processing of reward in a gambling paradigm was investigated using H2[15O]-PET (positron emission tomography) in a 38-year-old man treated for severe alcohol addiction. Behavioral data analysis revealed a less risky, more careful choice behavior under active DBS compared to DBS switched off. PET showed win- and loss-related activations in the paracingulate cortex, temporal poles, precuneus and hippocampus under active DBS, brain areas that have been implicated in action monitoring and behavioral control. Except for the temporal pole these activations were not seen when DBS was deactivated. These findings suggest that DBS of the NAcc may act partially by improving behavioral control.
Positive and negative reinforcement are assumed to be key mechanisms in the acquisition and maintenance of drug addiction
DBS treatment was conducted as part of an off-label study protocol approved by the ethical review board of the University of Magdeburg. PET scanning was performed with approval of the ethical review board of the Medical School Hannover. The patient gave written informed consent before the beginning of the first scanning session. Consent to publication was obtained from the patient as well.
The patient, a 38 year old man, had started to drink alcohol at age 11. By the age of 18 he fulfilled the DSM-IV criteria for alcohol dependence. His first detoxification treatment was at age 15. Multiple detoxification and prolonged withdrawal therapies as well as anti-craving therapy with acamprosate had been unsuccessful. Before surgery the longest period of abstinence lasted 3 months. During these drug-free intervals the patient reported massive craving and high sensitivity to alcohol-related cues. Pre- and post-surgical assessment included Symptom Check list 90 (SCL), psychopathology, obsessive-compulsive drinking scale (OCDS), alcohol urge questionnaire (AUQ). The alcohol dependence scale (ADS) was only assessed before surgery. In addition, the patient had also been examined with a comprehensive neuropsychological test battery, which had revealed neither marked neuropsychological difficulties nor dementia. One week after implantation of the DBS electrodes (13 January, 2008) the stimulation was switched on. The patient experienced a short period of hypomania, which stopped upon changing stimulation parameters. Since then up to the submission of this report the patient has been alcohol abstinent and reports a virtually complete reduction of his sensitivity to alcohol related cues.
Bilateral stereotactically guided implantation of quadripolar brain electrodes (model 3387, Medtronic, Minneapolis, MI, USA) was performed in general anesthesia as described by Heinze et al.
In order to investigate the impact of DBS on reward-processing and risk-taking we used an adapted version of a gambling task
The PET scanning was carried out 18 month after DBS implantation. Two sessions comprising 12 runs/tracer-injections each were performed. After the first session during which the stimulator was active, the generator was switched off and 90 min later the second session was started. At the end of the second session DBS was reactivated. The patient was blind to the generator status.
An ECAT EXACT 922/47 PET-Scanner (Siemens, Erlangen, Germany) with a total axial field of view of 162 mm and a spatial resolution of 7–8 mm (full width at half maximum) in reconstructed tomograms was used for data acquisition. At the beginning of the session a transmission scan of 10 min was performed using Ge-68 rod sources. Thereafter the regional distribution of cerebral radioactivity was recorded always after bolus injection of 740 MBq O-15 water (H2[15O]) per run). Each injection started after the first 12 trials of a run, i.e. when the winning chance turned to either 75∶25 or 25∶75. The 3D-acquisition of a 90s PET-frame started 15 seconds after tracer injection.
After iterative reconstruction statistical calculations and image processing was performed with Matlab 7.2 (The Mathworks Inc., Natick, MA). For realignment, image normalization and statistical mapping we used the PET-module of SPM2
Crosshair position indicates the location of the nucleus accumbens according to MNI standard coordinates. Activations are corrected for multiple comparisons (FWE = 0.05; cluster threshold 50 voxel). See
on>off | hemis-phere | Z-values | MNI coordinates |
medial globus pallidus | left | 6.88 | −10 6 −6 |
thalamus, ventral posterior medial nucleus | right | 6.78 | 16 −18 −2 |
frontal lobe (white matter) | right | 6.42 | 22 0 28 |
middle temporal gyrus | left | 6.80 | −56 −54 −8 |
superior temporal gyrus | left | 6.50 | −44 −26 6 |
temporal lobe (white matter) | left | 6.49 | −36 −48 16 |
occipital lobe | left | 6.76 | −40 −86 40 |
inferior frontal gyrus | left | 6.51 | −38 18 −20 |
middle frontal gyrus | left | 5.84 | −46 26 −30 |
inferior frontal gyrus | left | 5.51 | −56 34 −6 |
Cerebellum | right | 5.82 | 6 −60 −20 |
lateral occipital cortex | right | 5.73 | 60 −62 42 |
inferior frontal gyrus | right | 5.48 | 38 32 −20 |
parietal lobe, postcentral gyrus | right | 5.45 | 62 −20 24 |
lateral occipital cortex, cuneus | right | 5.39 | 26 −74 36 |
Cerebellum | left | 5.39 | −22 −82 −26 |
occipital fusiform gyrus | left | 5.09 | −22 −86 −16 |
middle occipital gyrus | left | 5.33 | −40 −82 12 |
inferior occipital gyrus | left | 4.77 | −42 −88 2 |
Cerebellum | left | 5.27 | −36 −48 −48 |
inferior frontal gyrus | left | 5.14 | −50 24 22 |
middle frontal gyrus | left | 5.13 | −30 2 52 |
frontal lobe (white matter) | left | 4.94 | −24 8 40 |
DBS status had a marked effect on choice behavior and response speed. Since in the present paradigm selecting 25 instead of 5 results in an overall 50%/50% chance in winning/losing 25 Eurocent, choosing 25 is considered as the riskier choice
Upper panel: Reaction times for the “5” and “25”-selections for each condition. Lower panel: percent choices for the “25”-selection for each condition.
Contrasting active against inactive DBS conditions resulted in prominent activations in the left medial globus pallidus, the left temporal and frontal lobe as well as in the right ventral posterior medial nucleus of the thalamus (see
With active DBS the win condition (relative to losses) caused pronounced activations in the paracingulate cortex (BA32) and the temporal poles bilaterally, whereas losses showed significantly more activity in the precentral gyrus, the frontal pole, the hippocampus and the precuneus (see
Contrast images for the comparisons win>loss (color scale red/yellow) and loss>win (color scale blue/green) with active (left panel) and inactive (right panel) DBS in the target area. First level statistical analysis was performed with p<0.005 (uncorrected) and 50 voxel cluster threshold. Except for activation at the temporal pole no activation shown for the DBS on condition remained statistically significant when DBS was off.
hemis-phere | Z-values | MNI coordinates | |
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temporal fusiform cortex, anterior division | right | 4.45 | 34 0 −36 |
temporal pole, superior temporal gyrus | left | 4.40 | −50 14 −32 |
fusiform cortex | left | 4.14 | −26 0 −46 |
inferior frontal gyrus | left | 3.40 | −54 22 −2 |
paracingulate cortex | right | 4.10 | 8 50 8 |
superior frontal gyrus | right | 3.00 | 2 34 56 |
lingual gyrus | left | 3.00 | −16 −58 −8 |
frontal pole | right | 2.96 | 0 64 −18 |
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middle frontal gyrus | left | 4.10 | −42 28 50 |
precentral gyrus | left | 3.60 | −18 −20 78 |
precentral gyrus | right | 3.60 | 12 −28 78 |
frontal pole | left | 3.46 | −36 62 −10 |
superior frontal gyrus | left | 3.21 | −26 48 −26 |
frontal pole | left | 2.94 | −34 58 −18 |
parietal lobe | left | 3.26 | −20 −40 42 |
superior occipital gyrus | right | 3.18 | −34 80 34 |
parahippocampal gyrus | right | 3.00 | 32 −20 −16 |
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parahippocampal gyrus, temporal pole | left | 3.39 | −22 2 −34 |
hippocampal gyrus | left | 3.14 | −28 −6 −24 |
nucleus caudatus | right | 3.29 | 18 6 10 |
white matter | left | 3.05 | −24 14 22 |
occipital pole | left | 2.89 | −12 −98 4 |
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middle frontal gyrus | left | 3.75 | −42 24 26 |
posterior cingulated gyrus | right | 3.57 | 2 −28 26 |
superior frontal gyrus | right | 3.43 | 8 26 62 |
frontal pole | right | 3.36 | 2 64 −8 |
frontal pole | right | 2.78 | 24 70 −4 |
superior temporal gyrus | left | 3.27 | −62 −4 6 |
frontal lobe (white matter) | right | 3.13 | 24 8 30 |
parietal lobe (white matter) | right | 3.13 | 16 −46 14 |
inferior parietal lobe | right | 3.04 | 54 −38 54 |
postcentral gyrus | right | 2.85 | 40 −30 72 |
middle occipital gyrus | left | 2.83 | −52 −78 2 |
middle occipital gyrus | left | 2.64 | −58 −76 10 |
With stimulator turned off, the win-associated activation in the paracingulate cortex disappeared and that of the temporal poles decreased remarkably. Likewise, the loss-related activations of the hippocampus and the precuneus were no longer seen.
This case study provides evidence, that DBS affecting the NAcc/BSTM/VP region has an impact on reward processing. Behaviorally, the patient showed a tendency towards more risky behavior when the stimulator was turned off. A similar behavioral pattern is known from Parkinson patients treated with drugs affecting dopaminergic D2/D3 receptors
Importantly, robust and statistically significant changes in the PET activation maps were observed that were more pronounced with stimulators turned on. Specifically, monetary rewards (compared to losses) led to an activation of the paracingulate cortex and the temporal poles. The paracingulate cortex integrates affective and motor information in behavioral control and adaptation
Interestingly, no blood flow changes were observed in the DBS target area. This might be caused by the partial volume effect in PET imaging, which results in an underestimation of the activity in small structures like the NAcc or BSTM
To sum up, under stimulator on conditions, brain areas were seen activated under active DBS that have been previously linked to aspects of behavioral control and decision making. Importantly, under deactivated DBS most of these activations were no longer seen with the exception of the right temporal pole. This said, it has to stressed that the present PET and behavioral data are coming from a single case and thus have to be interpreted with caution. Due to ethical reasons it was not practicable to examine the patient a second time and accordingly potential order effects cannot be ruled out. However, the reported results fit well to the literature and provide a first glimpse at the impact of DBS on the neural underpinnings of decision making and cognitive control. Together with the behavioral effect towards more risky behavior this suggests that behavioral control is impaired with the stimulator turned off. Future investigations have to examine the hypothesis that enhanced behavioral control is likely to contribute to the clinical effect of DBS in the NAcc.
Despite the known limitations of single case reports we conclude that DBS in the NAcc improves behavioral control in decision making processes by activating areas related to processing of self-referential information, integration of emotional information and updating of contextual information. While further investigations are needed to substantiate this finding, this mechanism might contribute to the efficacy of DBS in addiction.
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