The study was performed by Neurologists, Neuropsychiatrists, and Neuropsychologists from the CEMIC University Hospital Department of Medicine Neurology Section. Also, Neurosurgeons from CEMIC University Hospital, Department of Medicine, Neurosurgery Section participated in this work.

Researchers from CONICET and the Faculty of Social Sciences of Palermo University (UP), Argentina, collaborated in the development of this paper, and from Queen’s University. School of Medicine. Department of Psychiatry and Center for Neuroscience Studies, Canada.

We evaluated 48 patients of both sexes with a diagnosis of PD, over 40 years of age, who were candidates for DBS.

The study was conducted from 2017 to 2024 at the CEMIC University Hospital. The study was approved by the CEMIC ethics committee and the central ethics committee of the GCBA. All patients signed an informed consent.

Inclusion criteria[10]:

Patient with more than 5 years of PD evolution.Patients over 40 years of age.Patients with fluctuating phase* PD that PD medication adjustments could not manage.Patients with tremors that interfere with their quality of life.Levodopa test, which confirms the dopaminergic responsiveness of patients.

*A fluctuating phase refers to patients with end-of-dose deterioration, off-resistant periods, and problematic dyskinesias.

Exclusion criteria[10]:

Patients with atypical Parkinsonism.Patients with structural lesions observed in brain MRI scans.Patients are over 80 years of age.Patients with major depressive disorder.Patients with Dementia.Non-stabilized Psychiatric manifestations, such as acute psychotic symptoms.

The selection process for patients who qualify for STN-DBS neurosurgery consists of two distinct stages (Figure 1Figure 1).

In the first stage, patients were selected and evaluated by a neurology team specializing in PD. They completed the Unified Parkinson’s Disease Rating Scale (UPDRS) [12] for motor symptoms, and a brain MRI was performed. The dopaminergic responsiveness has been evaluated through a pharmacological test, the Levodopa Challenge Test. The test had to induce at least a 33% decrease in the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score, according to the Capsit PD program. The timed tests were performed for the motor evaluation: Arm movement between two points 30 cm apart, and a walking test with the patient walking as fast as possible 7 m back and forth, including turning. These tests were performed during the drug challenge in the “defined-off” and “defined-on conditions, according to the Capsit PD program. After this initial evaluation, patients were referred to the neurosurgery team, which determined their eligibility for neurosurgical intervention. The objective of this first stage was to determine whether the patients met the inclusion criteria.

Figure 1. Flow chart of the neurosurgical evaluation protocol.

In the second stage, the patients underwent a comprehensive neuropsychiatric and neuropsychological evaluation. They participated in a semi-structured neuropsychiatric interview, which included a structured assessment of their mood, neuropsychiatric symptoms, impulsivity, risk of suicide, and functional autonomy. Additionally, a complete neuropsychological evaluation was conducted using validated and standardized cognitive scales. The objective of this second stage was to evaluate whether the patient presented exclusion criteria.

After completing both stages of evaluation, the patient returned for further consultation with Neurosurgery and Neurology consultation to make a decision prior to DBS surgery.

Clinical classifications and operational criteria for “advanced PD”: the term APD remains poorly defined and a robust definition remains an unmet need in spite of consensus opinion. In this paper, advanced PD was defined as PD patients with a disease duration longer than 15 years who were experiencing a combination of motor (wheelchair-bound in the ON state) and non-motor symptoms, particularly dementia, that precluded consideration for device-aided therapies such as DBS [13].

Atypical Parkinsonism: the term was used to refer to those patients with neurodegenerative parkinsonian features who differed from idiopathic PD in their clinical course, clinical criteria and response to treatment, who also met diagnostic criteria for Multiple System Atrophy, Progressive Supranuclear Palsy or Corticobasal Degeneration.

Dementia: The Movement Disorder Society (MDS) defines Parkinson’s disease dementia (PDD) as a chronic cognitive decline in more than one cognitive domain—specifically affecting attention, executive function, visuospatial skills, and memory—that is severe enough to impair daily life (functional independence) and persists for at least 6 months [14].

Long disease duration: 5 patients were excluded for long disease duration (more than 15 years). These patients had also other motor and non motor limitations, such as being wheelchair-bound even in the ON state or having dementia.

1)Semi-Structured Neuropsychiatric Interview: This interview was performed by a neuropsychiatrist who evaluated the results of the complete psychiatric assessment and made the final diagnosis according to DSM V criteria.

The Semi-Structured Neuropsychiatric interview included demographic data, personal history, and family history, as well as a clinical neurological examination.

A complete psychiatric assessment was performed evaluating:

●The patient’s orientation: in time and space and person.

● Affectivity: hyperthymia, hypothymia, dysthymia, affective flattening, apathy.

●Will: normal, increased, decreased.

●Thought, evaluating its course: normal, accelerated, slowed, disintegrated, weakened; its content: the presence of depressive ideas, suicidal ideas, delusional ideas.

●Judgment: weakened, impaired, deviant, normal.

●Sensory perception to evaluate the presence or absence of hallucinations: visual, auditory, sensory-perceptual, olfactory, gustatory.

2) For the assessment of neuropsychiatric symptoms, the following scales are completed:

● Beck Depression Inventory is 21 self-administered items that determine the severity of depression (mild: score 10 to 15, moderate: 16 to 24, and severe: 25 to 63) [15].

●Patient Health Questionnaire (PHQ 9).The PHQ-9 is a nine-item self-report measure that assesses the presence of depressive symptoms based on the DSM-IV criteria for major depressive episodes [16][17]. In this case, the Spanish version of the scale was used [16][17]. The PHQ-9 was created as a screening tool, with recommended cut-off scores between 8 and 11 indicating a probable case of major depression. [16][17].

●Generalized Anxiety Disorder Scale (Generalized Anxiety Disorder GAD 7): This instrument has been created to serve as a screening instrument for generalized anxiety disorder [18][19]. There is no cut-off points established for the Spanish version [18]. In the original version, the authors propose a cut-off point of greater than or equal to 10 [19].

●Okasha Suicidality Scale [20]. Self-administered, Likert type, formed by four items, where the first three explore suicidal ideation, and the fourth one inquiry about suicide attempt: the answers of the suicidal ideation items are collected in a category frequency scale that is scored from 0 to 3 points for each item: never, rarely, sometimes, many times. The sum of these three items makes up the suicidal ideation sub score, which can range from 0 to 9 points. The cut-off points for suicidal ideation to determine the presence of a suicide attempt were 5 points, with a sensitivity of 90% and a specificity of 79% [21].

●Apathy Scale. This scale was developed by Marin RS et al. (1991) [22] to assess apathy symptoms in patients with depression. It was later validated in Spanish by Starkstein SE et al. 1992 for the detection of apathy symptoms in patients with PD [23].

●Barratt Impulsivity Scale: The Barratt Impulsivity Scale is one of the most widely used instruments for the assessment of impulsivity. It was designed by Barratt (1995) and in our setting, it has been adapted by Oquendo et al. (2001) [24][25]. It is a self-administered instrument consisting of 30 questions, grouped into three subscales: Items Cognitive Impulsivity, Motor Impulsivity, Unplanned Impulsivity. The total score is the sum of all the items. The total score is more valuable than the subscales. There are no cut-off points, although the median of the distribution has been proposed [22][23]. In the Spanish validation study, the median scores obtained in a sample of psychiatric patients were: Cognitive impulsivity: 9.5, Motor impulsivity: 9.5, Unplanned impulsivity: 14 Total score: 32.5 [24][25].

● Neuropsychiatric Inventory (NPI)[26] is completed by the patient’s family member regarding the frequency and severity of neuropsychiatric symptoms in the patient. It consists of 12 symptoms to be scored according to their severity, frequency of occurrence, and overload to the family member in charge. The symptoms are scored by multiplying the frequency by the severity [26].

For Neuropsychiatric evaluation, tests were self-completed by patients and their caregivers, and then they were checked during the consultation visit with the Neuropsychiatrist, who performed the semi structured interview and evaluated the diagnosis according to DSM-5 criteria. The time used by the patients and caregivers to complete the psychiatric scales was 20 to 30 minutes.

3) For the assessment of cognitive symptoms, a structured cognitive assessment battery was performed, consisting of different tests to evaluate each cognitive function:

●Tests to evaluate Semantic Memory: Rey’s Auditory Verbal Learning Test [27][28].

●Tests to assess language: Verbal Fluency [29], Boston Vocabulary Test [30][31].

●Tests to assess Executive Function: Trail making test part B [32], Phonological Fluency [29], Frontal Assessment Battery Scale [29].

●Tests to assess visuospatial: Rey’s complex figure (1997) [33].

●Tests to evaluate Attention: Trail making test part A [34], Digits Span [35].

All PD patients who received DBS, underwent structured and team-based follow-up to optimize outcomes and monitor for complications.

Initial postoperative visits were held one week after hospital discharge and focused on wound assessment and detection of surgical complications.

Typically, a few weeks after surgery, between 3 weeks to one month, the device was turned on, and a contact test through a monopolar review was done to systematically evaluate each electrode contact and determine the optimal stimulation settings. Following this, the initial parameters were set.

Subsequent visits, usually every three weeks were organized, to perform a gradual adjustment of stimulation parameters to achieve maximal symptom control while minimizing side effects, along with modification of antiparkinsonian medications.

Long-term follow-up included regular neurological evaluation of motor and non-motor symptoms, cognitive and psychiatric monitoring, assessment of speech and gait, and periodic review of device function and battery status, done in close collaboration among neurology, neurosurgery, psychiatry, and rehabilitation teams.

The results were entered into a computerized database, specifically prepared for this protocol, on a Microsoft Excel 2010 version program.

A descriptive analysis of the population was performed. For categorical variables, the frequency distribution was established, and the results were expressed as percentages. For continuous variables, the mean with its corresponding standard deviation was determined. When the distribution was nonparametric, the variable was described by the median and the 10th and 90th percentiles.

For the analysis of the neuropsychological tests, the Z score (z) was used, determined by the average value for the age and schooling of the patients evaluated using the following formula: Mean obtained from the score of the patients evaluated (x), Mean of the population for that age and schooling (µ) divided by the standard deviation (o).

Z score thresholds: z scores of −1.5; −2; −3, determine cognitive impairment in that domain (for example: memory, attention, executive functions, language, o visuospatial abilities).

If several (more than 1) domains have these scores, the patient will be diagnosed with a multidomian cognitive impairment. If only one domain is affected, for example memory, cognitive impairment will be determined by this domain and will be named in this case as follow: Amnestic cognitive impairment.

There are two typical kinds of cognitive profiles. 1) The cortical cognitive impairment profile: this profile is characterized by impairment in memory, language and visuospatial abilities. 2) The subcortical cognitive impairment profile in this profile attention and executive domains are the most affected. Patients with multidomain cognitive impairment have both cortical and subcortical impairments.

A correlation study of the different variables was carried out using Pearson’s test and Spearman’s Rho test. Correlation analyses were only exploratory and unadjusted.

A statistical measure that evaluates the linear relationship between two continuous variables. It is used to determine whether a linear association exists between two sets of data. This coefficient is denoted by “r” and ranges from −1 to 1.

●If r = 1, it indicates a perfect positive correlation, which means that as one variable increases, the other also increases in constant proportion.

●If r = −1, it indicates a perfect negative correlation, which means that as one variable increases, the other decreases in constant proportion.

●If r = 0, it indicates that there is no linear correlation between the two variables.

Bilateral Significance

A statistical approach in which the probability of observing an outcome at least as extreme as the one observed in either a positive or a negative direction is evaluated. In other words, it seeks to determine whether there are significant differences in both directions, either an increase or a decrease in the values of interest.

The information was processed using the SSPS 25 advanced statistical software.

All clinical work will be subject to the ICH Rules of Good Clinical Practice, the latest revisions of the Helsinki declarations (75th WMA General Assembly, Helsinki, Finland, October 2024), and the regulations of the Secretary of Health of the government of Buenos Aires city GCBA, according to Bill 3301.

Forty-eight patients with PD were evaluated. The mean age was 65.70 (SD 8.06), and the mean years of education was 12.27 (SD 4.285). Of the total number of patients, 26 (43.3%) were female, and 34 (56.7%) were male (see Table 1).

Table 1. Demographic data.

References: Values were expressed in Mean and SD: standard deviation.

We evaluated 48 patients of both sexes with a diagnosis of PD, over 40 years of age, who were candidates for DBS. The selection process for patients who qualify for STN-DBS neurosurgery consists of two distinct stages.

In the first stage, patients were selected and evaluated by a neurology team specializing in PD. In this first stage, five patients were excluded due to advanced PD and long disease duration, four patients were excluded due to atypical Parkinsonism.

In the second stage, the patients underwent a comprehensive neuropsychiatric and neuropsychological evaluation, after this, three patients were excluded due to dementia of multiple domains with a subcortical profile and impairment in daily life activities. Five of these patients were diagnosed with Severe Major Depression Episodes and exhibited more than two of the following conditions: 1) High scores on the Beck Depression Scale, 2) High Okasha suicididability score, 3) High total score on Barrat impulsivity scale, and/or 4) The presence of psychotic symptoms.

In summary of the 48 selected patients, seventeen of these patients were excluded as candidates for neurosurgery.

Neurological symptoms described in Table 2 were the results of the Unified Parkinson’s Disease Rating Scale depicted (UPDRS) [12].

After the Levodopa challenge test we observed an improvement in the UPDRS of 56.96% in Part 1, OF 49.16% in Part 2, and 49.37% in Part 3. Important inclusion criteria for the selection of patients for STN-DBS were an improvement of more than 33% of improvement in the results of UPDRS Part 3.

Neurological exclusion criteria are atypical Parkinsonism; four patients evaluated in our study were diagnosed as such and thus excluded for the STN-DBS surgery.

Patients had a mean of 15.67 (SD ± 7.3) years of illness. Five patients were excluded due to advanced PD and long disease duration.

The UPDRS [12] (Unified Parkinson’s Disease Rating Scale) is divided into four main parts that cover different aspects of Parkinson’s disease: Part I is for mentation, behavior, and mood; Part II is for activities of daily living (ADLs); Part III is the motor examination; and Part IV is for complications of therapy.

Important inclusion criteria for the selection of patients for STN-DBS were an improvement of more than 33% of improvement in the results of UPDRS Part 3.

Neurological exclusion criteria are atypical Parkinsonism, four patients evaluated in our study were diagnosed as such and thus excluded for the STN-DBS surgery.

Patients had a mean of 15.67 (SD ± 7.3) years of illness. Five patients were excluded due to advanced PD and long disease duration.

Medication context is important at the time of assessment. At baseline, all patients were receiving optimized medical therapy for PD and medication doses were recorded. Levodopa was prescribed in all patients, while approximately 30% of patients were also receiving dopamine agonists, 15% received MAOB inhibitors and 10% COMT inhibitors.

There were also patients receiving benzodiazepines, melatonin, antidepressants or quetiapine.

Adjustments to therapy were made postoperatively according to clinical response and DBS programming.

Generally neuropsychological and neuropsychiatric tests were performed with patients experiencing ON status.

Table 2. Unified Parkinson’s Disease Rating Scale (UPDRS) results.

Reference: Values were presented in Minimum, Maximum, Mean, and SD: standard deviation. UPDRS Part 1 patients in OFF status. UPDRS Part 1 patients in ON status. UPDRS Part 2 patients in OFF status. UPDRS Part II ON patients in ON status. UPDRS Part 3 patients in OFF status. UPDRS Part III ON patients in ON status. UPDRS Part 4 patients in OFF status.

In the scales assessing depressive symptoms (Beck Depression Inventory and PHQ-9), the average scores indicated a mild degree of depression. However, five patients exhibited scores suggesting moderate to severe depression (see Table 2).

Regarding the Anxiety Scales (GAD and Beck Anxiety Scale), mild to moderate anxiety symptoms were noted (see Table 3).

Intellectual performance was significantly affected according to the anosognosia scale (see Table 3).

In the impulsivity scale, patients scored above the cut-off points, with notable results in the total score (see Table 3).

Several patients also exhibited high scores on the apathy scale (see Table 3).

Table 3. Neuropsychiatric scales.

Reference: Values were presented in Minimum, Maximum, Mean, and SD: standard deviation.

Patients generally did not report dependence in instrumental activities of daily living (mean 1.63), in contrast to family members (mean 3.8) who did report a greater degree of dependence on these activities [36].

According to the Neuropsychiatric Inventory completed by the caregivers, nocturnal behaviors were the most prominent symptoms reported (mean 0.86) (SD 0.9), followed by Depression (mean 0.59) (SD 0.9), Anxiety (mean 0.48) (SD 0.8) and disinhibition (mean 0.43) (SD 0.8) [36].

The results of the complete neuropsychological evaluation showed a subcortical cognitive impairment pattern, with predominant executive dysfunction. The Frontal Assessment Battery (FAB) total score was significantly affected, with a z score of minus 2, showing a clear impairment in executive functions (see Table 4).

Table 4. Neuropsychological assessment.

Reference: Values were presented in Minimum, Maximum, Mean, SD: standard deviation, and Score Z (zeta).

Significant correlations (p < 0.005) were found between the suicidality scale and the Beck depression scale, and motor impulsivity scales (Table S1A). A direct relationship was also found between variables of the neuropsychiatric inventory (NPI) (such as apathy, euphoria, disinhibition, and depression) and the cognitive impulsivity scale (Table S1B). The Barratt impulsivity scale presented significant correlations (p < 0.005) between unplanned motor impulsivity and cognitive impulsivity, along with significant correlations with NPI variables: depression, nocturnal behaviors, and irritability (Table S1C).

Finally, the Beck Depression Scale, total FAB, and the Rey Complex Figure (ROCF) test were somewhat significant (p < 0.05) (Table S1D).

Correlations also indicated that with longer disease durations, there was a decrease in depression, disinhibition, nocturnal behaviors, and appetite scores (Table S1E).

Highly significant positive correlations (p < 0.005) were found between UPDRS part 1 (OFF) and Beck Depression Inventory and GAD 7 Anxiety scale, and positive significant (p < 0.05) correlations were found between UPDRS part 1 (OFF) and Suicidality scale (Table S1F).

Significant (p < 0.05) positive correlations were found between UPDRS part 1 (ON) and Beck Depression Inventory (Table S1F).

Significant (p < 0.05) positive correlations were found between UPDRS part 2 (OFF) and GAD 7 Anxiety scale, and between UPDRS part 3 (OFF) and GAD 7 Anxiety scale (Table S1F).

Out of all the patients evaluated, seventeen were excluded from DBS consideration.

Table 5. Excluded patients due to Neuropsychiatric symptoms.

References: The raw total score of the Beck Depression Scale, Beck Anxiety Scale, Suicidality Scale, and Barratt Impulsivity Scale with its subitems (total score, cognitive impulsivity, motor impulsivity, unplanned impulsivity) is described. The presence (YES) or absence (NO) of psychotic symptoms is described.

Five of these patients were excluded due to psychiatric symptoms of severe depression, as evaluated by the scales administered and in the semi-structured neuropsychiatric interview. Suicidal risk symptoms were also found through the Okasha suicidality scale. High levels of impulsivity and active psychotic symptoms (predominantly visual hallucinations and paranoid delusional ideation) were found in two patients (see Table 5).

Three patients were excluded due to dementia with multiple domains deficits and impairment of daily life activities (ADL score more than 2 points). The other 5 patients were excluded for long disease duration (more than 25 years). Four patients were excluded for an atypical Parkinsonism diagnosis.

As per post-DBS follow-up, thirty-one patients were followed up in the medical care setting. These patients had an improvement in motor-related symptoms (such as tremors and stiffness, on-off symptoms), verified in clinical evaluations. As for Neuropsychiatric evolution, most of them presented an improvement in Depression, Anxiety, and Impulsivity symptoms. Of the 31 patients who underwent surgery, only two experienced neuropsychiatric complications within the first three months’ post-surgery.

One of them experienced a psychiatric complication (a self-harm episode), despite having mild depression on both the Beck Depression Inventory and PHQ-9 during the pre-surgical assessment. This patient also had a history of isolated self-harm episodes in younger years, though no risk was indicated on the Okasha Scale (3 points). This self-harm episode was without suicidal thoughts and did not recur in other follow-up evaluations. The second patient demonstrated an increase in impulsivity in clinical settings and received psychopharmacological treatment indicated by the neuropsychiatrist, showing then improvement of depression and anxiety symptoms and a decrease in the level of impulsivity.