Yumei Jiang1, Bomin Sun2, Xiaoping Wang1, Weifeng Zhang1, Xinfeng Zhao1, Lassonde M○3

1Department of Neurology, First People’s Hospital Affiliated to Shanghai Jiao-Tong University, Shanghai  200080, China
2Department of Functional Neurosurgery, Ruijin Hospital Affiliated to Medical College, Shanghai Jiao-Tong University, Shanghai  200025, China
3Département de Psychologie and Centre de Recherche en Neuropsychologie et Cognition, Universite de Montreal, Quebec H3C 3J7, Canada

Yumei Jiang★, Master, Department of Neurology, First People’s Hospital Affiliated to Shanghai Jiao-Tong University, Shanghai  200080, China

Both Yumei Jiang and Bomin Sun contributed equally to this article.

Corresponding author: Xiaoping Wang, Doctor, Chief physician, Department of Neurology, First People’s Hospital Affiliated to Shanghai Jiao-Tong University, Shanghai  200080, China
x_p_wang@hotmail.com

Supported by: the Key Program of International Communication Foundation of Psychiatry and Neurology Department of Shanghai Jiao-Tong University, No. 200901*

www.crter.cn
www.nrronline.org

doi:10.3969/j.issn.1673-5374.2010.12.012

Abstract
BACKGROUND: Previous studies have shown that lesions in the anterior limb of the internal capsule contribute to obsessive-compulsive symptoms in patients with refractory obsessive-compulsive disorder (OCD). However, few reports have addressed the effects of lesions in the anterior limb of the internal capsule on cognition, learning, and memory functions in patients with refractory OCD.
OBJECTIVE: To investigate the degree of damage to memory tasks in refractory OCD patients following lesions to the anterior limb of the internal capsule.
DESIGN, TIME AND SETTING: A case-controlled, observational study was performed at the Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao-Tong University, China from May 2007 to March 2008.
PARTICIPANTS: A total of 10 refractory OCD patients were admitted to the Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao-Tong University, China from May 2007 to March 2008 and were recruited for this study. The OCD patients were of equal gender, with an average age of (25.1 ± 9.6) years. An additional 10 healthy volunteers were enrolled from a community of Shanghai City as controls; they were of equal gender and aged (25.1 ± 8.6) years.
METHODS: A total of 10 refractory OCD patients were subjected to lesions in the anterior limbs of the bilateral internal capsules. Wechsler Memory Scale–Chinese Revision (WMS-CR, as a task of explicit memory) and the Nissen Version (serial reaction time task) software (SRTT, as a task of implicit memory) were applied to determine memory functions and learning performance in pre- and post-operative OCD patients and controls.
MAIN OUTCOME MEASURES: WMS scores, reaction time in SRTT, and Yale-Brown obsessive compulsive scale scores were measured in pre- and post-operative OCD patients and controls.
RESULTS: Compared to controls, the pre-operative OCD patients exhibited reduced memory task scores (P = 0.005), whereas scores for reciting numbers of backwards digits were greater (P = 0.000). Figure recall and associative memory were less in OCD patients at 1 week following surgery than in the pre-operative OCD patients (P = 0.042, P = 0.002, respectively). Reaction time in implicit SRTT was significantly longer in pre-operative OCD patients compared with controls and post-operative OCD patients (P = 0.01, P = 0.03, respectively). These results suggested ameliorated SRTT following neurosurgery. Yale-Brown Obsessive Compulsive Scale results revealed significantly improved OCD following lesions in the internal capsule (P = 0.04). Some post-operative OCD patients suffered from deficits in short-term memory and implicit memory.
CONCLUSION: Lesions in anterior limbs of bilateral internal capsules improve obsessive- compulsive symptoms and implicit memory in OCD patients, but result in aggravated short-term memory deficits.
Key Words: obsessive-compulsive disorder; functional neurosurgery; basal ganglia; cognition; implicit memory

INTRODUCTION
   
Obsessive-compulsive disorder (OCD) is a frequent, chronic, costly, and disabling disorder. OCD patients exhibit deficits in prefrontal cortex function, as well as increased activity in the head of the bilateral or right caudate nucleus and thalamic functions. Drugs are commonly used to treat OCD. However, the positive effects of these drugs on OCD, especially refractory OCD, remain uncertain[1]. The treatment of lesions in the anterior limb of internal capsule, in particular the bilateral internal capsules, significantly improves obsessive-compulsive symptoms in refractory OCD, as well as maintains long-term improvements and improves patient’s quality of life[2].
Lesions in the anterior limbs of bilateral internal capsules are commonly used for refractory OCD[3]. However, few reports have addressed the effects of the lesions in anterior limbs of the bilateral internal capsule on cognition and memory functions, in particular implicit memory, such as procedural learning[4-6], in refractory OCD patients. The present study analyzed lesion outcomes in anterior limbs of the bilateral internal capsules for refractory OCD to determine changes in cognition, learning, and memory functions using Wechsler Memory Scale–Chinese Revision (WMS-CR, as a task of explicit memory) and the Nissen Version (serial reaction time task) software (SRTT, as a task of implicit memory).

SUBJECTS AND METHODS

Design
A case-controlled, observational study.
Time and setting
Experiments were performed at the Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao-Tong University, China from May 2007 to March 2008.
Subjects
A total of 10 refractory OCD patients (Table 1) were admitted to the Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao-Tong University, China from May 2007 to March 2008 and were recruited for this study. The OCD patients were of equal gender; the average age was (25.1 ± 9.6) years and ranged from 15 to 45 years. The groups consisted of four students and six employed individuals. Average disease course was (7.2 ± 7.23) years and ranged from 2 to 20 years. Average education course was (12.5 ± 3.1) years and ranged from 7 to 16 years. An additional 10 healthy volunteers, of equal gender, were enrolled from a community in Shanghai as controls. The average age was (25.1 ± 8.6) years and ranged from 16 to 42 years. Average education course was (15.4 ± 4.4) years and ranged from 10 to 20 years. The subjects were informed of the surgical methods, surgical outcomes, risks, and complications, and informed consents were obtained from patients and family members in accordance with item 33 of the Administrative Regulations on Medical Institution, formulated by State Council of the People’s Republic of China[7]. Protocols were approved by the Ethics Committee of Ruijin Hospital Affiliated to Medical College of Shanghai Jiao-Tong University in China.
OCD group
Inclusion criteria: the subjects were diagnosed with refractory OCD according to the diagnostic and statistical manual of mental disorders-IV, formulated by the American Psychiatric Association[8] prior to internal capsule lesions; treated with more than three types of drugs for longer than 6 weeks; and disease course was not less than 2 years. The drugs comprised tetracyclines, such as clomipramine, and selective serotonin reuptake inhibitors, such as fluoxetine.
Exclusion criteria: subjects with severe somatic disease, severe suicidal tendency, or epilepsy were excluded.
Control group
Inclusion criteria: no subjects exhibited a history of nervous or psychiatric system diseases. The subjects underwent examinations of nervous or psychiatric systems to eliminate cognitive deficits, anxiety or depression, psychiatric, and organic diseases.
 

Methods
Surgical methods
All OCD patients were subjected to magnetic resonance imaging (MRI) (GE, Tampa, FL, USA) prior to internal capsule lesions. MRI results revealed normal brains. MRI localization: under local anesthesia, a Leksell G stereotactic frame was fixed parallel to the AC-PC plane. Following GE 1.5T MRI, fast, spin-echo, inversion-recovery sequences were utilized, with 2 mm slice thickness and no interval. The anterior limb target points of the bilateral internal capsules were positioned by MRI (Figure 1) to calculate head-frame coordinates and needling angles. In accordance with the head-frame coordinates and needling angles, a 4-cm straight incision was made in the frontal region, and a hole was drilled into the skull. Subsequently, the radio frequency electrode was inserted into the target point, and the recording electrode was inserted under the surface of cerebrospinal fluid, gray matter, whiter matter, and internal capsule, and electric impedance was recorded. High-frequency (100 Hz) electrical stimulation was used to observe emotional changes, such as anxiety and fear. Radio frequency generator (Radionics, Massachusetts, USA) was employed to observe limb activity and speech in patients at 50 °C/60 seconds, followed by radio frequency at 80 Hz for 60 seconds[9].

Research tool
Patients in the OCD group underwent assessments using WMS-CR, SRTT, and the Yale-Brown obsessive-compulsive scale at 1 week before and after internal capsule lesions. Controls also underwent the above-mentioned assessments to eliminate abnormalities.
Explicit memory task
Explicit memory levels were measured utilizing WMS-CR (A/B)[10]. (1) The long-term memory test addressed personal experiences. (2) Short-term memory, visual recognition: two cards were utilized, which contained eight contents (pictures and symbols). The subject should remember contents from one card for 30 seconds and then recall what was observed on an additional card. Figure recall: the subject read a card with 20 pictures for 1.5 minutes, and then recalled the pictures on the card. Visual regeneration: the subject read three consecutive pictures for 10 seconds each. The subject was asked to draw identical pictures for each observed card. OCD patients were assessed using WMS-CR (A) prior to surgery, and WMS-CR (B) following surgery. Controls were evaluated utilizing WMS-CR (A).
Implicit memory task
The subjects were assessed by the SRTT[4, 10]. In accordance with the instructions, the subjects underwent training. There were four parallel-arranged symbols on the screen, and four corresponding parallel-arranged keys on the keyboard. When “*” appeared on the screen, the subject was asked to rapidly press the corresponding key. If the subject pressed the correct key, “*” disappeared. Every 100 keys represented a block, for a total of nine blocks. Among them, the fifth block was an irregular, randomized design. In accordance with tasks of the nine blocks, the subjects attempted to locate the internal rules. Reaction times and error/correct numbers were calculated by the computer software.
Yale-Brown obsessive compulsive scale
In accordance with a previous study[11], Yale-Brown obsessive compulsive scale reflects OCD severity – five items for obsession and five items for compulsion, with a score range of 0–4. Higher scores represent more severe OCD.
Main outcome measures
WMS scores, and reaction times from SRTT and Yale-Brown obsessive compulsive scale scores, were measured in pre- and post-operative OCD patients and controls.
Statistical analysis
Data were analyzed using analysis of variance and were expressed as Mean ± SD. The difference in both groups was compared utilizing independent t-test. A value of P < 0.05 was considered statistically significant.

RESULTS

Quantitative analysis of subjects
A total of 10 OCD patients and 10 healthy controls were included in the final analysis.
Baseline data of OCD patients and controls
Baseline data, such as gender, age, and education levels are shown in Table 2. No significant difference was detected in gender, age, and education level between OCD patients and controls.
Explicit memory results from OCD and control groups
As displayed in Table 3, total scores were significantly less in post-operative OCD patients compared with controls (P < 0.05). Scores of figure recall and association learning were significantly less in post-operative OCD patients than in pre-operative OCD patients (P < 0.05). The score of understanding memory was less in pre-operative OCD patients than in controls (P < 0.05), whereas scores of backwards digits were greater in pre-operative OCD patients than in controls (P < 0.05). Scores of figure recall, association learning, and understanding memory were less in the post-operative OCD patients compared with controls (P < 0.05), but the score of backwards digits was greater in the post- operative OCD patients compared with controls (P < 0.05).

Reaction time in SRTT
Average reaction time was (0.61 ± 0.24) seconds in pre-operative OCD patients, (0.47 ± 0.20) seconds in post-operative OCD patients, and (0.43 ± 0.08) seconds in controls. Reaction time was significantly longer in pre-operative OCD patients compared with controls (P = 0.01) and post-operative OCD patients (F = 6.88, P = 0.03). No significant difference was determined between post-operative OCD patients and controls (F = 4.76, P = 0.50). There were no significant differences in reaction times of each block between post-operative and pre-operative OCD patients (F = 6.70, P = 0.89; F = 1.06, P = 0.40). Significant differences in reaction times were detected between each block in the control group (F = 8.92, P < 0.01), and SRTT reaction time decreased over time in the control group (P < 0.05; Figure 2).
SRTT error rate
Error rates were 7.2% and 7.4% in pre-operative OCD patients and controls, respectively (t = 0.05, P = 0.96). The error rate in post-operative OCD patients was 10.1%, which was not significantly different from the pre-operative OCD patients (t = 0.76, P = 0.45).

Assessment results from the Yale-Brown obsessive-compulsive scale
The Yale-Brown obsessive-compulsive scale revealed significantly lower scores in post-operative OCD patients than in pre-operative OCD patients [(12.2 ± 8.0) points, vs. (18.80 ± 9.4) points, P < 0.05].

DISCUSSION

OCD is a common psychiatric disorder characterized by compulsion or obsession[1-2]. Interactions between the cortex-basal ganglia-thalamus are involved in OCD onset mechanisms and are derived from the orbitofrontal and anterior cingulate cortex, which projects to the caudate nucleus and ultimately the thalamus[10, 12-13]. A previous functional neuro-imaging study[14] suggested that functional activities are enhanced in prefrontal brain regions (orbitofrontal cortex, anterior cingulate cortex, and dorsal-lateral prefrontal cortex), as well as the ventral striatum (caudate nucleus) and thalamus. In addition, OCD patients exhibit abnormal functions in the dorsal-lateral prefrontal cortex, which is associated with working memory, together with the striatum and thalamus. Results from the present study demonstrated short-term memory deficits in pre-operative OCD patients, as well as increased backwards digits, compared with controls, which was consistent with previously published results[7].
The anterior limb of the internal capsule is a bridge that links the prefrontal cortex to basal ganglia[14-16], but lacks gray matter; it participates in cognitive functions, such as decision making, attention selection, behavioral transformation, temporal cognition, priming effect, working memory, and verbal memory[17-18]. A previous study[4] proposed a theory of multiple memory systems, in which explicit memory entails conscious recollection. This is comprised of working, episodic, and semantic memory. However, implicit memory is revealed when previous experiences facilitate performance on a task that does not require conscious or intentional recollection of those experiences. Implicit memory is composed of various types, such as procedural memory, implicit learning, habit formation, and priming effect. With the development of neuropsychology and neuroimaging, a dissociation between explicit and implicit memory has been verified in cognitive neuropsychological studies, and explicit and implicit memory depends on different memory systems that relate to various brain regions[19-20]. Therefore, implicit learning memory SRTT results demonstrated that OCD patients exhibited obvious procedural learning deficits, which could be a result of poor connections between basal ganglia and memory-related cortex or nuclei.
Lesions in the anterior limb of the internal capsule for refractory OCD are characterized by light trauma, high precision, remarkable symptom improvement, and few side effects. Internal capsule lesions rarely result in surgical complications, such as death, hemiplegia, or aphasia. Nevertheless, a small number of patients could develop poor posture, management difficulties and personality changes, which should be carefully monitored. The above-described symptoms could disappear over a period of several months or years in the majority of patients. Results from the present study confirmed significantly decreased obsessive-compulsive and memory scale scores in post-operative OCD patients, which suggested that anterior limb bilateral internal capsule lesions could dramatically improve obsessive-compulsive symptoms in OCD patients. Sun et al[9] demonstrated that obsessive-compulsive symptoms significantly improve in post-operative OCD patients. However, some patients exhibited transient memory disorder, and a minority of patients suffered from decreased volition, weak emotion, and childish behavior[9]. After a 1-week follow-up, the present study demonstrated significantly improved obsessive-compulsive symptoms in post-operative OCD patients, but short-term memory was not improved. Figure recall and association learning deficits were decreased in post-operative OCD patients, and short-term memory was significantly reduced following internal capsule lesions. SRTT test results revealed significantly improved procedural learning in post-operative OCD patients. Further investigations are needed to determine whether improvements in procedural learning are associated with ameliorated obsessive-compulsive symptoms.
Previous publications have reported internal capsule lesions to treat refractory OCD[21-23]. However, questions regarding surgical methods for refractory OCD remain[24-25], especially in patients younger than 18 years of age, as well as the potential effects on brain function and brain development. These risks should be clearly addressed with the patients and family members prior to the surgery.
In summary, the use of anterior limb bilateral internal capsule lesions significantly improved obsessive-compulsive symptoms and implicit memory function in refractory OCD patients, but aggravated short-term memory deficits. These memory changes were likely due to selective memory dissociation following lesion induction and could correlate with changes in frontal cortex and basal ganglia function[24-26].  

Acknowledgments
The authors wish to thank Yongbo Zhao from Department of Neurology, First People’s Hospital Affiliated to Shanghai Jiao-Tong University for assistance with completing the experiment.

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 (Edited by Qin YL/Qiu Y/Song LP)