Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept

doi:10.21203/rs.3.rs-2071346/v1

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Research Article

Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept

https://doi.org/10.21203/rs.3.rs-2071346/v1

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Purpose

Deficits in neuro-cognitive function is not uncommon for patients who have undergone surgical removal of brain tumors. Our goal is to evaluate the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a non-invasive tool for the treatment of neuro-cognitive dysfunction following craniotomy.

Methods

We present a retrospective review of individualized rTMS in twelve patients from Cingulum Health from December 2019 to July 2021 who presented with new onset neuro-cognitive deficits following craniotomy. Multiple cortical targets were selected based on the patient’s neurological disorder, associated networks, and anomalies in the functional connectivity of the brain as determined by machine-learning. TMS treatment was performed for 5 consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient’s deficit were assessed prior to, after, and during two-month follow-up of rTMS treatment.

Results

Nine patients had unilateral functional deficits in either upper, lower, or both limbs. One patient reported post-operative depression, another experienced short term memory difficulties, and a third reported hypobulia. All twelve patients reported significantly improved EQ5D after rTMS treatment and during follow-up. More than half of the patients with lower and upper functional deficits had a 9-point improvement during follow-up. In the patient who developed depression, an 88% reduction in depressive symptoms based on the Beck’s Depression Inventory (BDI) was observed during follow-up. No adverse events, such as seizures, occurred.

Conclusion

The personalized functional connectivity approach to rTMS treatment may be effective and safe for patients with post-craniotomy neuro-cognitive dysfunction.

Intra-axial cerebral surgeries are associated with neurocognitive deficits. The Glioma Outcomes Project (GOP), a database of 800 patients who had undergone glioma surgery across 60 surgical sites in the United States, found that of patients who underwent their first craniotomy, 32% of patients reported motor deficits, 35% patients endorsed memory loss, and 16% endorsed altered levels of consciousness [1]. Ninety-three percent of patients reported new onset of depression-like symptoms following surgery [2]. A meta-analysis found that new long-term motor deficits were observed in 2–14% of patients following glioma surgery [3]. Another study found that 36.2% patients reported treatment-related symptoms that prevented them from returning to work, citing neurological deficits and neuropsychological impairments as the second and third major causes [4].

There have been few quality-of-life (QoL) interventions to treat the myriad of symptoms developed by patients with brain tumors. Only two interventions have been shown to be successful in improving clinical outcomes following surgery: a 6-week cognitive rehabilitation program for cognition impairment and fatigue and Donepezil to improve memory [3, 5, 6]. The numerous symptoms experienced by post-surgical patients and the lack of a one-size-fits all therapy for such diverse symptoms warrants a more personalized approach to post-craniotomy treatment to improve QoL.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive tool approved by the FDA for the treatment of neuropsychological impairments, including major depressive disorder (MDD), MDD with anxiety, obsessive compulsive disorder (OCD), and migraines, and smoking cessation [7]. rTMS has been previously shown to improve motor function and language in patients following post-glioma craniotomy [8]. However, much less information has been studied on the improvement of psycho-cognitive deficits, and most importantly, QoL.

Using a personal, parcel-guided approach to rTMS, which we have coined the Agile Method, we could target multiple symptoms at multiple anatomical locations. We hypothesized that personalized rTMS could be used to address various neurocognitive and motor deficits and would be associated with improvements in QoL as assessed by the EuroQol (EQ-5D).

Subjects

A retrospective analysis was conducted of twelve patients who were treated at Cingulum Health from December 2019 to July 2021 for post-operative neurological and psycho-cognitive symptoms following craniotomy. Patients provided informed consent on the off-label nature of the rTMS treatment and its potential risks. This study was approved by the Human Research Ethics Committee of the South Eastern Sydney Local Health District (2022/ETH00139).

Evaluations

Twelve patients submitted a EuroQol (EQ-5D) prior to rTMS treatment, directly after treatment, and during their follow-up from 1 to 4 months after treatment. One patient who reported post-surgery depressive symptoms and was administered the Beck’s Depression Inventory (BDI). For patients with functional deficits, lower extremity functional scales (LEFS) and upper extremity functional scales (UEFS) were administered either together or individually.

Personalized target selection based on brain atlas

A Phillips 3T Achieva was used to collect DTI, rsfRMI, and non-contrast T1-weighted images as described previously (8, 9). DTI was performed based on the following acquisition parameters: 2 mm x 2 mm x 2 mm voxels, FOV = 25.6 cm, matrix = 128 mm x 128 mm, slice thickness = 2.0 mm, one non-zero b-value of b = 1000, 40 directions, gap = 0.0 mm. A T2-star EPI sequence with used for rsfMRI based on the following parameters: 3 x 3 x 3-mm voxels, 128 volumes/run, a TE = 27ms, a TR = 2.8s, a field of view – 256mm, a flip angle = 90° and an 8-minute total run time.

The machine learning-based parcellation software Infinitome was utilized on the obtained DTI and rsfMRI as previously described (8, 9). Known as the Agile Method, anomaly detection matrices (Fig. 1) were produced for each patient to determine abnormal functional connectivity. No subjective, conscious guidance was provided in the creation of anomaly detection matrices. Connectivity anomalies greater than 3 sigmas from the normal range (as determined by the rsfMRI of 200 healthy individuals) were detected. From the anomaly detection matrices, a hypothesis-driven target selection approach was utilized to identify areas of target within connectivity networks that have been verified by literature to be implicated in the presenting symptoms.

rTMS treatment

Accelerated Theta burst stimulation (aTBS) sessions were completed with a Magventure MagPro X100 TMS machine with a butterfly cool coil (Alfaretta, USA). Patients were administered aTBS for five sessions per day for five days in a maximum period of 2 weeks with an hour gap between sessions (10).

Target areas that were hyperconnected were selected for cTBS to induce cortical depression whereas iTBS was selected for hypo-connected areas (11, 12). cTBS was performed at one train of 600 stimuli applied at 3 pulses of 500 Hz bursts every 200 ms at a total of 1800 pulses. iTBS was performed at 3 pulses of 50 Hz bursts given every 200 ms for 40 trains with an inter-train interval of 6.3 seconds for a total of 1200 pulses.

Safety and Tolerability

Scalp discomfort was mediated by allowing patients to adjust to intensity by gradually increasing from low levels to its full percentage. To minimize seizure risk, patients received the minimum effective dosage, referred to as the resting motor threshold (RMT), to provoke an observed response as a muscle twitch in their left or right hand. Prior to every treatment day, patients were assessed for changes in risk factors that could increase the likelihood of seizures, including the consumption of caffeine or alcohol, changes to medications, or inadequate sleep. If such risk factors were screened, the RMT was retaken.

Statistical methods

Wilcoxon matched pair signed rank tests and Mann-Whitney tests were performed as applicable using GraphPad Prism 9. A p-value of < 0.05 was considered significant.

Patient demographics

Twelve patients met criteria for our study (Table 1). The average age of patients was 50.2 ± 11.1 years. The average follow-up time was 2.5 ± 1.1 months after rTMS treatment. Patient 8 was lost to follow up, and patient 9 passed away before follow-up could be conducted.

Table 1

Patient Demographics
Characteristics		Patients (% out of 12 patients)
Age (yrs)		50.2 ± 11.1
Sex	Male – no (%)	7 (58.3)
	Female – no (%)	5 (41.7)
Average time from surgery to TMS treatment	Acute Phase (2–4 weeks)	5 (41.7)
	Sub-acute Phase (up to 3 months)	3 (25.0)
	Chronic Phase (more than 3 months)	4 (33.3)
Hemisphere	Left – no (%)	5 (41.7)
	Right – no (%)	7 (58.3)
Tumor Location	Frontal Lobe – no (%) Temporal Lobe – no (%) Brainstem Lob – no (%) Thalamus Lobe – no (%) Insular Lobe – no (%)	6 (50.0) 3 (25) 1 (8.3) 1 (8.3) 1 (8.3)
Functional Deficits Cognitive and Psychological Deficits Tumor Type WHO Grade	Left Upper Extremity – no (%) Left Lower Extremity – no (%) Whole Left Side – no (%) Right Upper Extremity – no (%) Whole Right Side – no (%) Depression – no (%) Hypobulia – no (%) Short Term Memory – no (%) Glioblastoma – no (%) Ganglioglioma – no (%) Oligodendroglioma – no (%) Astrocytoma – no (%) Grade I – no (%) Grade II – no (%) Grade III – no (%) Grade IV – no (%)	1 (8.3) 1 (8.3) 4 (33.3) 1 (8.3) 2 (16.7) 1 (8.3) 1 (8.3) 1 (8.3) 5 (51.7) 1 (8.3) 4 (33.3) 2 (16.7) 1 (8.3) 2 (16.7) 4 (33.3) 5 (51.7)

Quality of life, motor, and psycho-cognitive assessments following rTMS

EQ-5D scores as an assessment of QoL were increased for patients after rTMS (p = 0.0024, Wilcoxon test, N = 12) and during follow-up (p = 0.0039 Wilcoxon test, N = 10) compared to baseline (Fig. 2A). There was no difference in the magnitude of change in EQ-5D scores between males and females after treatment (p = 0.8409, Mann-Whitney test, N = 5–7) and during follow-up (p = 0.7143, Mann-Whitney test, N = 4–7). There was no difference in EQ-5D magnitude changes between younger (below age 48) and older (age 48 and above) patients after treatment (p > 0.9004, Mann-Whitney test, N = 6) and during follow-up (p > 0.3889, Mann-Whitney test, N = 5). Patients who underwent rTMS treatment within 1 year of surgery had greater magnitudes of change in EQ-5D scores between baseline and post-treatment rTMS (p = 0.0303, Mann-Whitney test, N = 2–10) and during follow-up (p = 0.0222, Mann-Whitney test, N = 2–8) compared to patients who underwent rTMS treatment after more than 1 year following surgery (Fig. 2B and C).

Nine patients were administered the LEFS (Fig. 2D) after treatment (mean ± SD, 4.6 ± 4.7), and seven individuals were administered the LEFS during follow-up (9.9 ± 10.2). The minimal detectable change is 9 points on the LEFS scale. Three (33%) individuals had at least a 9-point improvement between post-treatment and baseline. Four (57%) individuals had a 9-point increase between follow-up and baseline.

Eight patients were administered the UEFS (Fig. 2E) after treatment (7.4 ± 10.1), and six patients were administered the UEFS during follow-up (10.7 ± 12.0). A minimal of a 9-point change is required to detect a change on the UEFS scale. Four (50%) individuals had at least a 9-point improvement between post-treatment and baseline. Four (67%) individuals had at least a 9-point improvement between follow-up and baseline, and one (17%) patient had at least a 9-point decrease between follow-up and baseline.

Patient 10 was treated for post-surgical depression and administered the BDI (Fig. 2F). She had a 47% and 88% reduction in depressive symptoms after rTMS and follow-up, respectively, compared to baseline.

Area of resection and rTMS targets

Table 2 lists the target regions for rTMS in each patient. No patient has the same three or four target regions as another patient. For patients with motor deficits, the sensorimotor network was a common network shared by all nine patients. Six of the nine patients had additional rTMS targets within networks outside of the sensorimotor network. For patients with psycho-cognitive deficits (patients 10–12), there was not one target network that was shared for all three patients. All twelve patients had at least one rTMS target outside of the immediate region of surgical resection. An example of this is seen in patient 12 who developed hypobulia after tumor resection of the right frontal lobe, removing significant regions of the salience network (Fig. 3A-C). His hypobulia resolved following rTMS. Patients 1 (Fig. 3D-F) and 3 had targets that were directly contralateral to the resection site. Patients 4, 6, and 10 had infratentorial resection sites which are difficult to target with rTMS, but their anomaly matrices identified supratentorial targets for rTMS. Patient 4 had a left thalamic resection with rTMS targets in the cortex (Fig. 3G-I). Patient 6 had a resection in the cerebellum with rTMS targets in the ventral premotor cortex (L6v) and the primary somatosensory cortex (L4). Patient 10 had a resection of the insular and had targets in the frontal lobe (L46), parietal lobe (LPFm), and posterior cingulate cortex (L7m).

Table 2

Patient Clinical Details
Patient	Tumor Type	Surgical Site	Time from surgery to TMS	Symptoms	Targets
1	GBM	R Temporal Lobe	3 years	Paralysis and weakness of L side of body due to craniotomy	1. L1 cTBS† 2. R6d iTBS†
2	Astrocytoma Grade 2	Frontal craniotomy w excision of the portion in the superior frontal gyrus	2 years	L arm deficit	1. L6Mp cTBS† (80–100%) 2. R3a iTBS† (80–100%) 3. LPFm iTBS‡ (80–100%)
3	GBM	Debulking of right frontal parasagittal lesion	1 week	L side paralysis	1. R55b iTBS§ (100%) 2. L8Av cTBS‡ (100%) 3. R6Mp iTBS† (100%) 4. L6Mp iTBS† (100%)
4	High grade glioma	Left posterior thalamic contrast enhancing lesion w evidence of necrosis	1 week	R side paralysis	1. L4 iTBS† (120%) 2. L6v cTBS† 3. R6v cTBS†
5	Right temporal tumor	Right pterional craniotomy	2.5 months	L sided weakness and vertigo	1. RA5 cTBS 2. LTE1m cTBS‡ 3. R1 iTBS† (100%) 4. L6a cTBS†
6	Ganglioglioma Grade 1	Suboccipital craniectomy and surgical changes within L posterioinferior cerebellum	5 months	L sided mobility problems	1. L6v cTBS† 2. R4 iTBS† (100%)
7	GBM	Debulking of multifocal enhancing lesions in the L frontal supraventricular white matter extending down to pericallosal white matter	1 month	R sided weakness and language deficits	1. L55b iTBS¶ 2. R6Ma cTBS† 3. LSCEF iTBS 26 Sessions
8	Oligodendroglioma Grade 2	Brain tumor in right temporal lobe (dx 2011) operated on 10 years later followed by immediate post- op stroke leading to ischemic changes in the right striatocapsular region	1.5 months	Lack of movement in L arm following stroke – all L side affected	1. L3A cTBS† 2. R4 iTBS† 100% 3. L8Av cTBS‡
9	GBM	Left frontal	3 days	R side hemiparesis and limited R side facial movement	1. R6Mp cTBS (100%) 2. L6v iTBS† (120%) 3. L6a iTBS† (120%) 4. LPHT cTBS¶ (100%)
10	Astrocytoma Grade 3	L craniotomy of insula glioma	5 weeks	Mild word finding difficulty (not deemed troublesome for patient and was not treated), extreme mood swings, suicidal thoughts and aggression	1. L46 iTBS§ 2. LPFm iTBS‡ 3. L7m iTBS
11	Oligodendroglioma Grade 3	R frontal	2.5 months	Confusion and short- term memory deficits	1. R6Ma iTBS† 2. RTE1p iTBS 3. LTE1m cTBS‡
12	Oligodendroglioma Grade 3	R frontal	2 days	Severe hypobulia	1. R6Ma cTBS† 2. RPGi iTBS 3. RTGd iTBS
GBM = glioblastoma. R = right. L = left. Targets were stimulated at 80% of RMT unless otherwise specified in the column. rTMS treatment was 25 sessions for each target unless otherwise specified. Targets indicated in † are within the sensorimotor network. Targets indicated in ‡ are within the Central Executive Network. Targets with § are within the Salience Network. Targets with ¶ are within the Language Network. Targets in bold are within the Default Mode Network. The target in italics is within the Multiple Demand Network. The target underlined is within the Limbic and Paralimbic Network.

Safety and Tolerability

No patients reported any seizures following rTMS treatment. Four patients reported no noticeable side effects from treatment (33.3%), seven reported noticeable fatigue (58.3%), three reported headache (25%) four reported scalp discomfort at the stimulation site (33.3%), and one reported facial twitching due to stimulation (8.3%).

QoL encompasses functional outcomes as well as psycho-cognitive wellbeing. In this retrospective case series, we present personalized rTMS treatment for persistent neurological and psycho-cognitive symptoms following surgical resections of brain tumors in twelve patients. QoL as assessed by the EQ-5D was significantly improved after treatment and during follow-up.

Personalized, multi-network rTMS treatment

A transdiagnostic approach goes beyond diagnosis and categorization of diseases to better understand an individual’s affliction and its underlying cause. Gaining steam in the mental health community for anxiety, eating disorders, and posttraumatic stress disorder, its benefits are realized for multi-faceted disorders where individuals face a myriad of symptoms and disease presentations [9]. For patients with brain tumors, a transdiagnostic approach allows physicians to treat the symptoms by addressing the underlying issue, namely the problem with brain circuitry following the growth and resection of a tumor. When tumor location and symptom manifestations are so variable, a personalized, targeted approach is the ideal approach to treatment. The theory is that once the underlying cause is addressed, the motor and neuropsychiatric symptoms would resolve, significantly improving QoL.

We now have the technology to utilize a transdiagnostic approach to obtain a sophisticated hypothesis-driven target selection of areas that go awry following the development and resection of a malignant tumor. This is the first parcel-guided, personalized rTMS treatment that targets multiple regions and treats several symptoms at once. Targets are selected by a machine learning algorithm based on the connectome of the individual patient, and a hypothesis-driven approach is utilized to confirm literature-backed targets implicated in the symptoms of interest.

Our ability to target numerous symptoms and anomalous regions at once takes advantage of the idea that networks are sensitive to influences from remote cortical areas [10]. Even if a brain region is resected, changing remote cortical regions may ameliorate the effects of resection. Patients with infratentorial brain resections, regions that are often difficult to target with rTMS, were able to improve QoL after rTMS in supratentorial regions of the brain. This was observed in patients 4, 6, and 10 who had tumors in thalamus, cerebellum, and insula respectively. We have also shown the potential for inter-network modulation in patient 12 who developed severe hypobulia following a craniotomy that resected areas of the right salience network. Previous reports have shown that abulia after brain tumor resection can be prevented by sparing the cingulum tract of the prefrontal cognitive initiation “axis,” a network of connections between the DMN, salience network, and the SMA via the cingulum and frontal aslant tract [11, 12]. Two of the three rTMS targets for this patient were within this “axis”. R6Ma (of the sensorimotor network) is proximal to the tumor resection site, and RPGi (of DMN) lies outside of the immediate region of the resection site. These examples support the notion of remote cortical regions inter-communication and show how targeting regions away from the immediate resection site can improve post-craniotomy motor and psychiatric deficits caused by the resection.

The rTMS targets and use of cTBS and iTBS are supported by literature in the treatment of motor deficits with rTMS. The contralateral side of an injured motor cortex exhibits hyperconnectivity and increased transcallosal interhemispheric inhibition to the side of injury, which leads to the worsening of the motor deficit [13]. Therefore, rTMS studies for motor deficits usually utilize high frequency rTMS to increase cortical excitability to the motor cortex of the lesion hemisphere and low frequency rTMS to decrease cortical excitability in the contra-lesion hemisphere [14–16]. In our nine patients with motor deficits, the target choices and use of inhibitory or excitatory rTMS selected by the machine-learning algorithm corroborates with the use of cTBS in the contra-lesion hemisphere and iTBS in the ipsi-lesional hemisphere. Patients 1 and 3 had rTMS targets that were directly contralateral to the site of tumor resection. In those regions, cTBS was administered directly contralateral to the site of resection, thereby depressing the hyperconnectivity of the contralateral region following tumor resection. Therefore, in addition to the rTMS treatment regimen being personalized to the brain of the individual, the targets and use of TBS modality identified by this machine-learning algorithm is supported by evidence in the literature.

Quality-of-Life and Neuropsychiatric disorders Following rTMS

In this study, we have shown that personalized, parcel-guided rTMS may improve physical and psychiatric symptoms experienced post-craniotomy. The magnitude of improvement in QoL was not affected by gender or age. However, patients who received rTMS therapy within 1 year of brain resection had significantly greater increase in quality of improvement than those who received rTMS after 1 year of surgery. In addition to increased QoL, lower motor function was significantly improved after rTMS treatment. In the patient who experienced post-surgical depression, BDI was reduced by 88% during follow-up after rTMS.

We have previously reported improvements in language and motor deficits using the Agile Method for rTMS in post-surgical glioma patients [8]. Here, we go beyond measuring motor outcomes by including QoL measurements. The EQ-5D has been used in other studies, such as in the investigation of QoL for patients with glioblastoma [17, 18]. A deterioration in QoL scores have been found to be correlated with shorter survival for patients with glioblastoma following craniotomy [17].

The presence of neuropsychiatric disorders may worsen QoL as much as motor deficits. Depression has been reported by the GOP to be significantly increased in patients following craniotomy [1, 2]. MDD may be treated with an FDA- approved rTMS to the dlPFC [7]. There have also been numerous studies on the use of personalized treatment using parcel-guided and fRMI-guided rTMS [19, 20]. Furthermore, finding treatment for depression as a secondary result of another disorder is not uncommon. rTMS have been successfully used to treat depression as a post-concussive symptom for patients with TBI [21–23]. To our knowledge, there has not been any studies focused on rTMS interventions to improve psychiatric symptoms that arise following craniotomy. The results in this present study suggest that the personalized, parcel-guided approach to rTMS treatment may help in decreasing depressive symptoms following craniotomy. Further studies must be done to show whether this preliminary finding holds true in a larger group of patients as well as for the potential that other neuropsychiatric symptoms can also be treated with this same method.

Safety

To mitigate the scalp discomfort experienced by some patient’s, stimulation intensity was ramped up from low percentages to the patient’s full percentage to allow the patient to adjust to the intensity. All patients were encouraged to maintain constant hydration during their treatment to reduce likelihood of headaches due to dehydration. All patients had the option of chewing gum or cotton buds to help control any facial movement due to muscular twitching from stimulation. All patients were also offered earplugs and were encouraged to use them if their stimulation intensity was higher than average.

No seizures or adverse side effects were reported by patients following rTMS. Some patient reported minor side effects of fatigue, headaches, and scalp discomfort which were consistent with our previous use of rTMS treatment in patients with psycho-cognitive symptoms following strokes [24]. Therefore, the parcel-guided approach to multi-region rTMS targeting appears safe for patients following glioma resection.

Study Limitations

Our study is limited by its retrospective nature. The placebo effect has been shown to be very strong for motor function, as was described by a study on perceived treatment on individuals with Parkinson’s disease [25]. The treatment of depression with rTMS specifically has also shown to have a high the placebo effect [21]. However, one study on the use of rTMS for depression found that the placebo effect diminishes 11 weeks following therapy [26, 27]. The patient in our study with depression were followed up with 2 months after rTMS. Therefore, subsequent follow-up is warranted to identity whether the decrease in BDI scores is sustained three months following treatment. Moreover, additional studies with a larger sample size are warranted before a conclusion can be made on its efficacy in treating post-craniotomy depression. Subsequent follow-ups would also be beneficial for the eight patients with motor deficits.

The personalized, parcel-guided rTMS approach is shown to be safe and may be effective in treating motor deficits and neuropsychiatric symptoms for patients following craniotomy.

Conflicts of Interest Statement

Charles Teo and Michael Sughrue are founders and employees of Omniscient Neurotechnology. Jonas Holle is an employee of Cingulum Health. Jacky Yeung and Olivia Lesslar are consultants of Cingulum Health but are not employees. Si Jie Tang does not report any conflicts of interest.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Competing interest reported. Charles Teo and Michael Sughrue are founders and employees of Omniscient Neurotechnology. Jonas Holle is an employee of Cingulum Health. Jacky Yeung and Olivia Lesslar are consultants of Cingulum Health but are not employees. Si Jie Tang does not report any conflicts of interest.

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Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept

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Abstract

Figures

Introduction

Method

Subjects

Evaluations

Personalized target selection based on brain atlas

rTMS treatment

Safety and Tolerability

Statistical methods

Results

Patient demographics

Area of resection and rTMS targets

Discussion

Personalized, multi-network rTMS treatment

Quality-of-Life and Neuropsychiatric disorders Following rTMS

Safety

Study Limitations

Conclusion

Declarations

References

Additional Declarations

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