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Pharmacological treatment of deep brain stimulation-induced hypomania leads to clinical remission while preserving motor benefits

This article was downloaded by: [Leo Schilbach]On: 15 September 2011, At: 06:26Publisher: Psychology PressInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: MortimerHouse, 37-41 Mortimer Street, London W1T 3JH, UK Neurocase
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Pharmacological treatment of deep brain
stimulation-induced hypomania leads to clinical
remission while preserving motor benefits
L. Schilbach a , P. H. Weiss b c , J. Kuhn a , L. Timmermann c , J. Klosterköötter a &
W. Huff aa Department of Psychiatry, University of Cologne, Cologne, Germanyb Institute of Neuroscience and Medicine, Cognitive Neurology Section (INM-3),Research Center Juelich, Juelich, Germanyc Department of Neurology, University of Cologne, Cologne, Germany Available online: 15 Sep 2011 To cite this article: L. Schilbach, P. H. Weiss, J. Kuhn, L. Timmermann, J. Klosterköötter & W. Huff (2011):
Pharmacological treatment of deep brain stimulation-induced hypomania leads to clinical remission while preserving
motor benefits, Neurocase, DOI:10.1080/13554794.2011.568502
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NEUROCASE2011, iFirst, 1–8 Pharmacological treatment of deep brain
stimulation-induced hypomania leads to clinical
remission while preserving motor benefits
L. Schilbach1, P. H. Weiss2,3, J. Kuhn1, L. Timmermann3, J. Klosterkötter1, and W. Huff1
1Department of Psychiatry, University of Cologne, Cologne, Germany2Institute of Neuroscience and Medicine, Cognitive Neurology Section (INM-3), Research CenterJuelich, Juelich, Germany3Department of Neurology, University of Cologne, Cologne, Germany Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's dis-ease, but can lead to adverse effects including psychiatric disturbance. Little is known about the risk factorsand treatment options for such effects. Here, we describe a patient who reproducibly developed stimulation-in-duced hypomania when using ventrally located electrodes and responded well to pharmacological interventionwhile leaving the stimulation parameters unchanged to preserve motor benefits. In spite of clinical remission,[15O]-positron-emission-tomography (PET) demonstrated activation patterns similar to those reported duringmania. This case, therefore, highlights an important treatment option of adverse effects of DBS, but also pointstoward the need for investigations of its risk factors and their underlying neurobiological mechanisms.
Keywords: Subthalamic nucleus; Deep brain stimulation; Parkinson's disease; Stimulation-induced hypomania;
Pharmacological treatment; Positron-emission-tomography (PET).
Deep brain stimulation (DBS) of the subtha- of these effects, their underlying mechanisms and lamic nucleus (STN) is an effective treatment treatment options (e.g., Troster, 2009).
option for idiopathic Parkinson's disease (IPD) Here, we describe the case of a patient who and alleviates motor symptoms (Deuschl, Schade- reproducibly developed hypomanic episodes when Downloaded by [Leo Schilbach] at 06:26 15 September 2011 Brittinger, Krack, Volkmann, Schafer, Botzel, et al., switching STN-DBS from ‘dorsal' to ‘ventral' stim- 2006). Adverse effects of STN-DBS, however, are ulation sites (Figure 1a & b; ‘dorsal' stimula- also known and include severe psychiatric distur- tion shown in blue, ‘ventral' stimulation shown bance (Appleby, Duggan, Regenberg, & Rabins, in red). Due to significant motor impairment 2007; Soulas, Gurruchaga, Palfi, Cesaro, Nguyen, during the former, we opted for pharmacolog- & Fenelon, 2008; Voon, Krack, Lang, Lozano, ical treatment of the stimulation-induced hypo- Dujardin, Schupbach, et al., 2008). Relatively little mania. While the hypomanic syndrome could be is known about the risk factors for the occurrence well controlled pharmacologically, [15O]-positron- L.S. gratefully acknowledges Esther Florin's help in anatomically localizing the electrodes by means of image fusion. L.S. is also grateful to Carolin Urbach and Eun-Hae Kim for their involvement in patient care and to David Sharp for helpful comments on anearlier version of the manuscript. The authors thank the PET group of the Physics of Medical Imaging Section of the Institute ofNeuroscience and Medicine (INM-4, Research Centre Juelich), especially Professor Hans Herzog, for their expert assistance.
The authors have no conflicts of interests to declare.
Address correspondence to Leonhard Schilbach, M.D., Department of Psychiatry, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. (E-mail: [email protected]).
 2011 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business

SCHILBACH ET AL.
Downloaded by [Leo Schilbach] at 06:26 15 September 2011 Figure 1. (a) Quadripolar electrodes (Medtronic® model 3387) used for DBS in patient KS illustrating ‘ventral' (red) vs. ‘dorsal' (blue)
stimulation. Numbers denote the different contacts of each electrode that can be used for stimulation. (b) Localization of electrodes in KS
(right electrode shown in green, left electrode shown in red; electrode contacts shown in black) as assessed by postoperative stereotactic
X-ray imaging illustrated by means of overlays onto ascending axial slices (i–vii) of the preoperative T2 weighted MRI. The level of the
axial slices is shown schematically on the left hand side. RN: Red nucleus; STN: Subthalamic nucleus. (c) Neural correlates of ‘ventral' as
compared to ‘dorsal' stimulation of STN in KS (thresholded at p < .05 FWE corrected for multiple comparisons). Differential increase
of neural activity in (i) DLPFC (Right middle frontal gyrus∗; MNI: 30, 5, 6; k=164; T=23.64 & MNI: 46, 16, 40; k=20; T=15.54),
(ii) left MTG∗ (MNI: −48, −20, −14; k=117; T=21.48) and (iii) dACC (Left anterior cingulate cortex∗; MNI: −6, 22, 30; k=37;
T=15.54). Common activations for ‘dorsal' as compared to ‘ventral' stimulation were observed in left lingual gyrus∗ (not illustrated;
MNI: −22, −72, −2; k=42; T=19.63). ∗Anatomy assigned by using the SPM Anatomy Toolbox (Eickhoff et al., 2005).
HYPOMANIC EPISODES INDUCED BY DEEP BRAIN STIMULATION emission-tomography (PET) performed during (50 mg/12.5 mg/day), ropinirole (8 mg/day), aman- clinical remission several weeks later demonstrated tadine (2× 50 mg/day), valproate (450 mg/day) and stimulation-dependent neural activation differences clozapine (150 mg/day).
similar to those reported during clinically manifest The past medical history revealed a diagnosis of idiopathic Parkinson's disease (IPD) at the age of32 which had been made due to a typical clinicalpresentation and in spite of a history of paranoid CASE REPORT
psychosis. Psychosis had been diagnosed at the ageof 23 and led to three other acute episodes at the age Patient KS was a 48-year-old man referred for of 24, 28 and 41. First-generation antipsychotics admission to our inpatient psychiatric unit for were used briefly during the acute episodes that evaluation and management of a manic syndrome required hospitalization, while long-term treatment which had developed after the STN-DBS stimu- consisted of second-generation drugs. After the lation parameters had been changed from ‘dor- last episode requiring hospitalization clozapine was sal' to ‘ventral' stimulation several weeks before used continuously. After good response to L-DOPA (Figure 1a). Using a more symmetrical ventral stim- medication and a stable course of treatment of ulation (electrodes 1 & 5) had not been effective IPD for almost 10 years, the patient developed on- in alleviating motor impairment. After having been off fluctuations and pronounced dyskinesia. Three changed to the ‘ventral' stimulation (Figure 1a), years later, off-states comprised 30% of the day leav- the patient reported elation and developed symp- ing the patient immobile during these periods. In toms of grandiosity, insomnia, racing thoughts and light of the progressive worsening of Parkinsonian increased speed of speech. Reports by family mem- symptoms, a lack of benefit from medication and bers indicated conflicts resulting from the patient's no further psychotic episodes since 2002, the rec- aberrant behavior and lack of proper judgment with ommendation for DBS was given by a neurolo- respect to financial activities. Due to these difficul- gist outside our department in 2007. Thereupon ties KS was seen by a neurologist, who re-set the implantation of bilateral quadripolar electrodes DBS to the dorsally located electrodes (Figure 1) was performed. Upon preoperative neuropsycho- and had the patient transferred to the hospital.
logical assessment, executive function, attention Upon admission – a few hours after STN- and memory were normal. STN-DBS implantation DBS had been re-set from the ‘ventral' to ‘dor- resulted in an improvement of motor impairments.
sal' stimulation the mental status of the patient Several months after the implantation, the patient had changed significantly: All symptoms charac- developed a right-sided subdural hematoma, which teristic of mania had subsided and the patient required surgical intervention. After the operation, was found to be cooperative and calm during the the patient made a full recovery and lead loca- evaluation. His speech was found to be of nor- tion was controlled by means of neuroimaging.
mal speed and fluency. He described his mood Subsequently, bilateral stimulation of STN resulted Downloaded by [Leo Schilbach] at 06:26 15 September 2011 as ‘lower than in the past days' and did not in significant improvement of motor impairment appear irritable. His affect was euthymic and con- comparable to the benefit observed prior to the gruent with his mood. His thought processes were subdural hematoma. Over the next two years, how- somewhat circumstantial, but there was no loos- ever, the DBS had to be adjusted to rely more on ening of associations. His self-attitude was nor- the ventral contacts due to the progressive develop- mal, and he exhibited adequate judgment of the ment of significant motor impairment (Figure 1a).
current situation. He scored 30 of 30 on the Switching to these contacts, however, also lead to Mini-Mental State Examination. Abnormalities the development of two hypomanic episodes that upon neurological examination included significant required hospitalization. During each episode, volt- motor impairment manifest in a hypokinetic–rigid age applied to the ventral contacts was reduced syndrome including a resting tremor of the left to limit the hypomanic syndrome, but eventually hand and predominantly left-sided rigidity mak- STN-DBS had to be re-set to the dorsal contacts.
ing the patient wheelchair-bound. Routine blood Concomitantly, however, a significant worsening of work, a toxicology screening, EKG and EEG did motor symptoms was observed.
not show any significant abnormalities. Medication Due to the motor impairment apparent upon upon admission consisted of levodopa & car- admission and in agreement with the patient, bidopa (5 × 50 mg/day), levodopa & benserazide STN-DBS was again switched to the ‘ventral' SCHILBACH ET AL.
stimulation (Figure 1a) as this configuration had a cane, began to speak more quickly and appeared been most successful in treating motor symptoms more animated and expressive in mimic and ges- and in spite of the fact that this stimulation setting ture. He also described a sense of invigoration and had previously led to stimulation-induced hypoma- improvement in mood. Within days the changes in nia. Within minutes, a significant improvement of cognition and behavior became more pronounced, motor functions and change in mental status could finally resulting in a hypomanic syndrome (as mea- be observed. KS was able to walk with the help of sured by the Young Mania Rating Scale; Figure 2a).
Downloaded by [Leo Schilbach] at 06:26 15 September 2011 Figure 2. (a) Observed change in motor function (as assessed by the UPDRS-III; higher scores indicating more pronounced motor
impairment) and mental status (as assessed by the YMRS; <5: Clinical remission, >12: Hypomania, >20: Mania) during the first two
weeks of treatment after the change of stimulation (flash) from dorsal to ventral electrodes on the day of admission. (b) Daily dosages
of anti-manic medication (VPT: Valproate; CLZ: Clozapine) used to treat stimulation-induced change of mental status during the first
two weeks of treatment. (c) Blood serum levels of anti-manic and antipsychotic drugs (VPT: Valproate; CLZ: Clozapine) measured at
different time points. Therapeutic range of VPT: 50–100 mg/l. Therapeutic range of CLZ: 350–600 µg/l.
HYPOMANIC EPISODES INDUCED BY DEEP BRAIN STIMULATION In order to preserve the motor benefits (as mea- LEFTcontact6: −11.2, −0.5, −1.7; LEFTcontact7: sured by the Unified Parkinson Disease Rating −11.8, 0.9, −0.2).
Scale-III; Figure 2a), we decided to leave the stimu-lation parameters unchanged this time and optedfor pharmacological treatment. The dosage of PET scanning
valproate and clozapine were increased while leav-ing the anti-parkinsonian medication unchanged The patient was accompanied to the scanning site (Figure 2b & c). This adjustment resulted in a by the first author (LS). Upon arrival at about remission of the hypomanic syndrome within the 08.00 h the patient was familiarized with the details next week while preserving most of the motor ben- of the scanning procedure by the second author efits (Figure 2a).
(PW), YMRS and UPDRS ratings were carried In spite of the clinical remission, psychopatho- out (YMRS: 5 UPDRS-III: 14) and informed con- logical differences in KS continued to be observ- sent was obtained. Approval for the procedure had able depending upon the stimulation site: This was been obtained from the University ethics commit- assessed eight weeks later and reproducibly demon- tee and the regulatory authorities (Bundesamt fuer strated ‘dorsal' stimulation to result in a decrease Strahlenschutz) gave permission to administer the of psychomotor function and lowering of his mood, radioactive substances. The first six PET measure- while switching back to ‘ventral' stimulation would ments were carried out starting at 09.00 h during increase his rate of speech and his subjective sense which DBS continued making use of the ventral of well-being immediately. Based upon this clin- stimulation settings. At 12:30 h, the stimulation ical insight and in light of studies, which have parameters were changed to the dorsal settings. At demonstrated wide-spread activation differences 14:30 h, YMRS and UPDRS ratings were again as a result of STN stimulation during clinically carried out (YMRS: 0 UPDRS-III: 25). The second manifest mania (e.g., Mallet, Schupbach, N'Diaye, six PET measurements were carried out starting Remy, Bardinet, Czernecki, et al., 2007), we utilized at 15:00 h. rCBF was measured by recording the PET to investigate regional cerebral blood flow regional distribution of cerebral radioactivity after (rCBF) during ventral vs. dorsal STN-DBS. This the intravenous injection of [15O]-water. The PET study demonstrated a differential increase of rCBF measurements were carried out using an ECAT in right dorsolateral prefrontal cortex (DLPFC), EXACT HR+ scanner (CTI Siemens, Knoxville, right middle temporal gyrus (MTG) and dorsal TN), with a total axial field of view of 155 mm anterior cingulate cortex (dACC) (Figure 1c).
covering the whole brain. Data were acquired inthree-dimensional mode with interdetector colli-mating septa removed and a Neuro-Insert installed to limit the acceptance of events originating fromout-of-field-of-view activity (i.e., the whole body).
Anatomical localization of electrodes
For each measurement of rCBF, 555 MBq of [15O]- Downloaded by [Leo Schilbach] at 06:26 15 September 2011 and stimulation sites
water were given intravenously as a bolus injection.
The patient was subjected to a radiation dose of In order to assess the precise anatomical local- 7.7 mSv (effective dose) during the entire course ization of the different stimulation sites, i.e., the of the PET measurement. Twelve PET scans were location of the quadripolar electrodes within STN collected, each beginning when the brain activity bilaterally, the stereotactic coordinates of the elec- exceeded a threshold of 5 kilo counts per second trodes as assessed by post-operative imaging were (kcps) above the background level. Emission data used to generate an overlay onto the individual were thereafter collected sequentially over 40 s.
preoperative MRI scan that had been coregistered This process was repeated for each emission scan, to the stereotactic cerebral computed tomography with 10 min between scans to allow for the ade- (CCT) (Figure 1b). Schaltenbrand–Wahren atlas quate decay of radioactivity. All emission scan data (SWA) coordinates (x,y,z) were determined for all were corrected for scattered events and for radiation 4 contact sites of the left and right electrode attenuation by means of a transmission scan taken (RIGHTcontact0: 11.0 −1.4 −2.9; RIGHTcontact1: prior to the first emission measurement. The cor- 11.7, −0.2, −1.5; RIGHTcontact2: 12.3, 1.0, 0.0; rected data were FORE rebinned and reconstructed RIGHTcontact3: 13.1, 2.2, 1.5; LEFTcontact4: −10.0, into 63 transverse images (separation 2.4 mm) of −3.2, −4.6; LEFTcontact5: −10.5, −1.9, −3.1; 128 × 128 pixels (size 2.0 × 2.0 mm2) by SCHILBACH ET AL.
two-dimensional filtered back projection (DIFT) resulting from other etiologies. Likewise, the using a Shepp filter with a width of 6 mm. The syndrome in KS did respond well to pharmaco- reconstructed PET images had a resolution of 7 mm logical intervention. We opted for pharmacolog- and were regarded to represent rCBF qualitatively.
ical treatment to control the symptoms in orderto preserve the motor benefit that resulted from‘ventral' stimulation. Even during clinical remis- sion occurring as a result of pharmacological treat-ment, however, differential stimulation effects on All calculations and image manipulations were psychopathology continued to be noticeable. In performed on a Transtec Linux cluster using accordance with these observations, PET imaging MATLAB version 6.5 (The Mathworks Inc., performed months later demonstrated a differen- Natick, MA). Statistical parametric mapping tial increase of neural activity in DLPFC, MTG and dACC for ‘ventral' as compared to ‘dorsal' Imaging Neuroscience, London, UK; http://www.
STN-DBS. This pattern of activation serves as evi- fil.ion.ucl.ac.uk/spm/software/spm5) was used for dence for widespread changes of brain metabolism image realignment, normalization, and smooth- as a result of targeting what has been described ing (low-pass Gaussian filter of 12 mm) and to as the ‘limbic' subregion of the STN and is highly create statistical maps of significant relative rCBF consistent with findings observed during clini- changes. The resulting voxel size in stereotactic cally manifest mania (Mallet et al., 2007; Ulla, space was 2 × 2 × 2 mm. The stereotactic coor- Thobois, Lemaire, Schmitt, Derost, Broussolle, dinates of the voxels of local maximum significant et al., 2006). Here, it has been described as changes in relative rCBF within areas of significant an activation of a subcortico-cortical limbic net- relative rCBF change associated with the different work whose modulation can alter mood, atten- factors were determined. The anatomical localiza- tional and emotional processes (Mayberg, Lozano, tion of these local maxima was assessed by refer- Voon, McNeely, Seminowicz, Hamani, et al., 2005), ence to MNI space as well as by making use of the but could also reflect compensatory processing of SPM Anatomy toolbox. Additional validation of abnormal behavior (Ulla et al., 2006). More specif- this method of localization was obtained by super- ically, our findings seem to be in line with evidence, imposition of the SPMs maps on the single subject which suggests that the STN forms part of a net- MRI template (in MNI space) provided by SPM5.
work, which includes medial and lateral frontalcortex and contributes to cognitive control (e.g., Aron, Behrens, Smith, Frank, & Poldrack, 2007).
Alterations of this network could, therefore, possi- This case report adds to the growing body of evi- bly contribute to mania-related cognitive changes.
dence suggesting that a considerable number of Recent evidence, indeed, suggests that STN-DBS patients treated with STN-DBS experiences signif- may significantly impact impulse control (Frank, Downloaded by [Leo Schilbach] at 06:26 15 September 2011 icant psychiatric disturbance (e.g. Appleby et al., Samanta, Moustafa, & Sherman, 2007; Halbig, Tse, 2007; Soulas et al., 2008; Voon et al., 2008).
Frisina, Baker, Hollander, Shapiro, et al., 2009), Furthermore, our case demonstrates that pharma- which could relate to neurofunctional alterations cological intervention can be an important treat- of the above described neurocircuits (Ballanger, ment option for stimulation-induced hypomania.
van Eimeren, Moro, Lozano, Hamani, Boulinguez, Even though the risk factors for ‘psychiatric' et al., 2009). In light of the suggestion of a possi- adverse effects of STN-DBS are not well under- ble link between a higher risk of suicide attempts stood, it has been demonstrated that their occur- after STN-DBS and stimulation-induced changes rence may depend upon the exact location with in impulsivity (Rodrigues, Rosas, Gago, Sousa, anterior and ventrally located contacts being more Fonseca, Linhares, et al., 2010), systematic inves- likely to produce them (e.g., Mallet et al., 2007; tigations thereof and the underlying neural mech- Okun, Fernandez, Wu, Kirsch-Darrow, Bowers, anisms as well as interdisciplinary approaches to Bova, et al., 2009). Accordingly, we found evi- postoperative patient care seem to be warranted.
dence that ‘ventral' as compared to ‘dorsal' stim- With respect to the exact localization of the ulation of the STN reproducibly resulted in hypo- electrodes in the case of our patient, intra- manic episodes in our patient. Clinically, the operative recordings and post-operative anatomical psychopathological features of hypomania induced localization are consistent with placement of the by STN-DBS did not differ from manic syndromes contacts within the STN. In light of the behavioral HYPOMANIC EPISODES INDUCED BY DEEP BRAIN STIMULATION responses to the different stimulation settings and and ventral stimulation vs OFF states would have their neural correlates as assessed by PET imag- been helpful to investigate this issue further.
ing, it seems likely that the most ventral con- With respect to the putative neural mechanisms tacts target the anterior-medial or ‘limbic' sub- that underlie mania-associated change in cogni- region of the STN (Mallet et al., 2007). It is tion, it is tempting to speculate that STN-DBS- noteworthy, however, that the ‘ventral' stimula- induced differences in cognitive function could be tion included relatively high voltage on the left- related to changes in dopaminergic neurotransmis- sided contact, which is closest to the substantia sion (Hershey, Revilla, Wernle, Gibson, Dowling, nigra (SN). In light of recent reports by Ulla & Perlmutter, 2004). Recently, it has been demon- and colleagues (Ulla et al., 2006; Ulla, Thobois, strated that DBS can lead to increased levels of Llorca, Derost, Lemaire, & Chereau-Boudet, 2010), dopamine in parts of the subcortico-cortical loops the possibility must, therefore, be raised that the that are targeted. Furthermore, this increase of observed effects of ‘ventral' stimulation could also dopamine may be accompanied by an increase be due to current spread to neighbouring regions of impulsive behavior (Sesia, Bulthuis, Tan, Lim, such as the SN. In this respect, the resemblance Vlamings, Blokland, et al., 2010). Here again, the of the activation pattern resulting from bilateral previous history of a paranoid psychosis – known stimulation of the SN described by Ulla et al.
to be associated with alterations of the mesolim- (2006) and our activation results is informative.
bic dopamine system – appears to be of crucial Additional neuroimaging data (e.g., high-resolution importance. In light of this diagnosis, it makes sense contrast-based and diffusion-based magnetic res- to assume that KS may have been even more vul- onance images) could have been helpful to relate nerable than other Parkinsonian patients to the individual contact location to the differential stim- modulatory effects of STN-DBS on dopaminer- ulation effects observed in other brain regions (e.g., gic neurotransmission. Consistent with the view Gutman, Holtzheimer, Behrens, Johansen-Berg, & of DBS-induced alterations of dopaminergic trans- Mayberg, 2009). However, such data was not avail- mission possibly contributing to mania-related cog- able in our patient.
nitive changes, effective pharmacological treatment In the case of KS, it is interesting to note that of our patient included the dopamine receptor- the PET activation differences were observed even binding agent clozapine.
though he was in clinical remission. In the case Taken together, this case report demonstrates of KS, we speculate that this might be related to that hypomanic episodes induced by STN-DBS his previous psychiatric history (cf. Bejjani, Damier, can depend upon the exact stimulation site and Arnulf, Thivard, Bonnet, Dormont, et al., 1999; that the resulting states can be controlled phar- Lilleeng & Dietrichs, 2008). In light of this, it macologically. The latter may be clinically rele- might seem plausible that KS has a neurobiolog- vant when motor improvement and hypomanic side ical predisposition to show an activation pattern effect result from stimulation of the same elec- that is also observed in bipolar disorder (Blumberg, trode contacts. Given that therapeutic adjustments Downloaded by [Leo Schilbach] at 06:26 15 September 2011 Stern, Martinez, Ricketts, de Asis, White, et al., to adverse effects of DBS conventionally involve 2000) and stimulation-induced, clinically manifest changes of stimulation sites and parameters, our mania (Ulla et al., 2006), but longitudinal inves- finding suggests a clear benefit of pharmacologi- tigations would be necessary to investigate this.
cal intervention. Furthermore, the here-described Furthermore it must be noted that relatively little case demonstrates that stimulation-dependent acti- evidence appears to exist about the neural cor- vation differences, previously reported as the neural relates of differential STN stimulation and their correlate of mania-related behavioral alterations, impact on cognition (Kalbe, Voges, Weber, Haarer, can be observed after clinical remission. We suggest Baudrexel, Klein, et al. 2009; Hirano, Eckert, that this highlights the need for investigations into Flanagan, & Eidelberg, 2009). Additionally, similar the risk factors of adverse effects of DBS and their activation patterns as those observed in the case of underlying neurobiological mechanisms.
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