Michele Lanotte

Overt versus covert treatment for pain, anxiety, and Parkinson's disease

The recent introduction of covert administration of treatment to biomedical research has produced some interesting results, with many clinical and ethical implications. Concealed treatment has been used in people with nervous system conditions including pain, anxiety, and Parkinsons disease. The main finding is that when the patient is completely unaware that a treatment is being given, the treatment is less effective than when it is given overtly in accordance with routine medical practice. The difference between open and hidden administrations is thought to represent the placebo component of the treatment, even though no placebo has been given. The decreased effectiveness of hidden treatments indicates that knowledge about a treatment affects outcome and highlights the importance of the patient-provider interaction. In addition, by use of covert administration, the efficacy of some treatments can be assessed without the use of a placebo and associated ethical issues.

WHEN WORDS ARE PAINFUL: UNRAVELING THE MECHANISMS OF THE NOCEBO EFFECT

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patients distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinsons disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus

Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here we show that placebo treatment caused reduced activity in single neurons in the subthalamic nucleus of placebo-responsive Parkinsonian patients. These changes in activity were tightly correlated with clinical improvement; no decrease in activity occurred when the clinical placebo response was absent.

Deep brain stimulation of the subthalamic nucleus: anatomical, neurophysiological, and outcome correlations with the effects of stimulation

Objectives: Bilateral chronic high frequency stimulation of the subthalamic nucleus (STN), through the stereotactical placement of stimulating electrodes, effectively improves the motor symptoms of severe Parkinsons disease. Intraoperative neurophysiological and clinical monitoring techniques (neuronal electrical activity recording and intraoperative stimulation) may improve and refine the localisation of the nucleus. The objective of this work was to compare the preoperative CT and MRI localisation with the intraoperative neurophysiological identification of STN. The relation between the localisation of the STN and the position of the most effective contact of the permanent quadripolar electrode at a 3 month and 1 year follow up was also studied. Methods: Fourteen consecutive parkinsonian patients were submitted to bilateral implant for STN stimulation. All the patients underwent a standard MRI and stereotactic CT to obtain, by image fusion and localisation software, the stereotactical coordinates of STN. The STN extension and boundaries were identified by a semimicrorecording of the neuronal electrical activity. The definitive quadripolar electrode was positioned to locate at least two contacts within the STN recording area. Intraoperative macrostimulation was performed to confirm the correct position of the electrode. Postoperative clinical evaluation of the effects of stimulation was checked for each contact of the quadripolar electrode testing the improvement on contralateral rigidity to select the best contact. This evaluation was repeated at 3 months and 1 year after surgery. Results: In 35.7% of the procedures it was necessary to perform more than one track to get a recording of neuronal activity consistent with STN. The mean position of the central point of all the 28 STN recording areas in respect of the AC-PC line midpoint was 2.7 mm posterior (SD 0.7), 3.8 mm inferior (SD 1.1), and 11.6 mm lateral (SD 0.9), and the mean distance between the anatomical target and the central point of the STN as defined by intraoperative recording was 0.5 mm (SD 0.5) on the anteroposterior plane, 0.7 mm (SD 0.7) on the lateral plane, and 0.9 mm (SD 0.6) on the vertical plane. At 1 year the mean position of the central point of the most effective contact of the electrode in respect of the AC-PC line midpoint was 1.7 mm posterior (SD 0.9), 1.7 mm inferior (SD 1.5), and 12.3 mm lateral (SD 0.9). Conclusion: The results highlight the role of the intraoperative recording to get a more accurate localisation of the STN in surgery for Parkinsons disease, allowing the identification of the boundaries and of the extension of the nucleus. The most effective contact of the quadripolar electrode was always in the upper part of the STN recording area or immediately above it, suggesting a role of this region in the clinical effectiveness of the STN electrical stimulation.

Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients.

Expectations about future events are known to trigger neural mechanisms that affect both perception and action. Here we report that different and opposite expectations of bad and good motor performance modulate the therapeutic effects of subthalamic nucleus stimulation in Parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation. By analyzing the effects of subthalamic stimulation on the velocity of movement of the right hand, we found hand movement to be faster when the patients expected a good motor performance. The expectation of good performance was induced through a placebo-like procedure, thus indicating that placebo-induced expectations have influence on the treatment outcome. All these effects occurred within minutes, suggesting that expectations induce neural changes very quickly.

Chronic Deep Brain Stimulation of the Subthalamic Nucleus for Parkinson’s Disease: Effects on Cognition, Mood, Anxiety and Personality Traits

Objective: To evaluate modifications occurring in cognitive functions and behavioural aspects in a group of 72 consecutive patients with Parkinson’s disease (PD) 15 months after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Methods: 72 consecutive PD patients bilaterally implanted for DBS of the STN were evaluated before and after surgery with a mean follow-up of 15 months. A neuropsychological assessment was performed to evaluate reasoning (Raven Colour Matrices), memory (Bisyllabic Word Repetition Test, Corsi’s Block-Tapping Test, Paired-Associate Learning) and frontal executive functions (Trail Making Test Part B, Nelson Modified Card Sorting Test, phonemic and category verbal fluency tasks). Mood and suicidal ideation were evaluated using the Beck Depression Inventory (BDI). Anxiety was measured by means of the State-Trait Anxiety Inventory and personality traits were evaluated with the Structured Clinical Interview for the DSM-III-R Axis II Disorders (SCID-II). Assessment of thought disorders and apathy was based on subitems of the Unified Parkinson’s Disease Rating Scale. Results: The comparisons between pre- and postoperative neuropsychological test scores showed a significant worsening only in phonemic and semantic verbal fluency tasks, while fewer errors were found in the Nelson Modified Card Sorting Test. Globally, behavioural assessment evidenced a small improvement in mood, as assessed by the BDI, in obsessive-compulsive and paranoid personality traits (SCID-II). Thought disorders worsened while suicidal ideation, anxiety and apathy showed no postoperative modifications. The analysis of individual outcomes (±1 SD criterion) evidenced a relevant postoperative cognitive decline in 3 patients out of 65 (4.5%). Moreover, following implantation, 1 patients exhibited psychosis (1.5%), 2 patients experienced a clinically relevant worsening of depressive symptoms (3%), 7 patients showed an increase in anxiety (12%) and 3 patients a worsening in depression and anxiety symptoms (3%). On the contrary, 12 patients (20%) showed a relevant improvement in mood and 14 patients (23%) a relevant reduction of anxiety symptoms after the surgery. Conclusions: The present study confirms that STN DBS is cognitively safe since the only relevant change observed was a mild decrease in verbal fluency tasks. Globally, a small postoperative improvement was found in the BDI, and in two SCID-II subscales concerning obsessive-compulsive and paranoid personality traits, even though postoperative behavioural disturbances can occur in individual patients.

One hundred and twenty-seven cases of acute subdural haematoma operated on. Correlation between CT scan findings and outcome.

SummaryTraumatic acute subdural haematoma is one of the most lethal of all head injuries: the mortality rate is reported to be between 50 and 90%. We reviewed the clinical records of 1688 head injured patients admitted to the Department of Neurosurgery at C.T.O. hospital between 1982 and 1992. In 127 cases (7,5%) CTscan on admission showed acute subdural haematoma requiring surgery because the midline shift was greater than 5 mm.The overall mortality rate was 57% and 23% had functional recovery.The following variables were assessed with regard to morbidity and mortality: mechanism of injury, age, neurological presentation, time delay from injury to intervention, CTscan finding on admission. GCS and CTscan findings were found to be the most important prognostic variable. Timing of operative intervention for clot removal with regard to outcome was not statistically significant. But no conclusions regarding the importance of early haematoma evacuation can be drawn from such an oversimplifying statement, because it does not take into account factors like rapidity of haematoma development and related brain decompensation as well as additional direct brain lesions.The results of this study suggest that the extent of primary brain injury underlying the subdural haematoma is the most important factor affecting outcome.

Effects of bilateral subthalamic stimulation on gait kinematics and kinetics in Parkinson’s disease

Abstract.Subthalamic nucleus (STN) stimulation, a recent surgical approach to Parkinson’s disease (PD), has been shown to be effective in relieving motor symptoms. The present study carried out a full body gait analysis, during overground walking, on ten PD patients with bilaterally implanted STN stimulation devices. Walking performance was analyzed on the same day, in four conditions (Stim Off–Med Off, Stim On–Med Off, Stim Off–Med On, Stim On–Med On). The results showed that, on average, STN stimulation alone (S+M−) and l -dopa alone (S-M+), significantly increased gait speed, stride length and the lower limb joint Range of Motion (ROM) with respect to the basal condition (S−M−); also cadence was found to play a role in velocity increase, particularly when l -dopa was administered. Both treatments improved pelvis and trunk kinematics, and power production at the ankle and hip joints. The combination of the two treatments (S+M+) produced an additional effect on gait speed, stride length, ROM of knee and ankle joints, pelvis obliquity and trunk inclination. Given the additive and synergistic effects, it can be hypothesized that the two treatments have different mechanisms of action. Our results confirm the findings of earlier studies that employed treadmill walking.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: comparison of pre- and postoperative neuropsychological evaluation

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of advanced Parkinsons disease (PD). The aim of this study was to assess the effect of the bilateral surgical procedure and STN DBS on the neuropsychological functions. Twenty Parkinsons disease patients underwent a neuropsychological assessment before and 6 months after surgery in four different conditions: medication on (with levodopa) and medication off (without levodopa) during the preoperative period, medication on/stimulation on (levodopa plus stimulators switched on) and medication off/stimulation on (stimulators switched on without levodopa) during the postoperative period. We did not find any significant difference in the four conditions for all the neuropsychological tests, confirming the lack of an overall cognitive decline after surgery. From a neuropsychological point of view, these results seem to indicate that bilateral STN DBS is a safe treatment for advanced PD.

Motor and Nonmotor Symptom Follow-Up in Parkinsonian Patients after Deep Brain Stimulation of the Subthalamic Nucleus

Objective: To evaluate motor and nonmotor symptoms in patients with Parkinson’s disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). Methods: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson’s Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. Results: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. Conclusions: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson’s disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.