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• Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead
  Daniel Martinez-Ramirez, Erik H Middlebrooks, Leonardo Almeida and Michael S Okun
  Published on: 14 August 2020

• Published on: 14 August 2020

  Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead

  • Daniel Martinez-Ramirez, Phyician Scientist, Neurologist Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Ignacio Morones Prieto 3000, Monterrey, N.L., México,
  • Other Contributors:
    • Erik H Middlebrooks, Physican Scientist, Radiologist
    • Leonardo Almeida, Physician Scientist, Neurologist
    • Michael S Okun, Physician Scientist, Neurologist

  Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead

  To the Editor,

  We read the observational DBS cohort study by Kern DS et al with great interest. We agree that deep brain stimulation (DBS) implantation has been associated with brain atrophy. We previously published an experience that not cited in the present study and we wonder whether the authors accidentally cited one of our review articles rather than the primary source (2014). It is critical for the DBS field to be aware of the clinical implications of atrophy.

  Kern DS et al analyzed 32 Parkinson’s disease (PD) patients who completed bilateral staged DBS implant surgeries targeting the subthalamic nucleus (STN)(1). The patients had an average duration between the two DBS surgeries of 141 days and this duration offered an opportunity to compare pre-post atrophy measures. The authors observed a significant reduction in whole brain volumes of the ipsilateral or first implanted side. Also, the authors noted that all basal ganglia-thalamocortical brain regions (BGTC) ipsilateral to the DBS implantation had significantly reduced volumes, whereas non-BGTC structures seemed to be unaffected. The authors suggested the possibility that intracranial volumetric changes may occur following STN DBS electrode implantation as a direct result of the implantation itself.

  We believe it unlikely that DBS electrode implantation is a primary reason for volume loss. We...

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  Brain Atrophy is Inevitable Following Deep Brain Stimulation and Not Likely Caused by the Lead

  To the Editor,

  We read the observational DBS cohort study by Kern DS et al with great interest. We agree that deep brain stimulation (DBS) implantation has been associated with brain atrophy. We previously published an experience that not cited in the present study and we wonder whether the authors accidentally cited one of our review articles rather than the primary source (2014). It is critical for the DBS field to be aware of the clinical implications of atrophy.

  Kern DS et al analyzed 32 Parkinson’s disease (PD) patients who completed bilateral staged DBS implant surgeries targeting the subthalamic nucleus (STN)(1). The patients had an average duration between the two DBS surgeries of 141 days and this duration offered an opportunity to compare pre-post atrophy measures. The authors observed a significant reduction in whole brain volumes of the ipsilateral or first implanted side. Also, the authors noted that all basal ganglia-thalamocortical brain regions (BGTC) ipsilateral to the DBS implantation had significantly reduced volumes, whereas non-BGTC structures seemed to be unaffected. The authors suggested the possibility that intracranial volumetric changes may occur following STN DBS electrode implantation as a direct result of the implantation itself.

  We believe it unlikely that DBS electrode implantation is a primary reason for volume loss. We previously reported three DBS cases (2 Parkinson’s disease and 1 essential tremor) with unexpected loss of benefit following DBS. After undergoing our routine clinical DBS troubleshooting protocol, we observed a substantial change in brain atrophy indices including the 3rd ventricular width, the Evans index, the ventricular index, and the the cella media index. The measured DBS lead location comparisons revealed a more lateral position compared to earlier scans(2). We concluded that the most likely explanation for the changes in clinical outcome was loss of brain volume. The atrophy also likely underpinned the changes in thresholds for benefits and side effects when attempting device reprogramming.

  We also recently reported a postmortem analysis of a Huntington’s disease DBS case (2016) with similar atrophy occurring within basal ganglia structures.(3) Parkinson’s and Huntington’s disease both manifest expected atrophy. The volume loss in these cases will be faster and more severe than in control brains. The question that Kern asked is whether the DBS contributes to this atrophy in some unknown way. Though this study is interesting, there are a few concerning issues that must be considered.

  The first observation is that preoperative volumes of BGTC and non-BGTC were generally similar or larger on the ipsilateral side of the first implant (contralateral to symptom onset) as compared to the side contralateral to the implant. With the typical asymmetry of PD symptoms, one may expect that the BGTC structures contralateral to side of onset would have lower volumes; however, previous studies have illustrated that these expected asymmetries are more apparent with shape analysis when compared to absolute volumetrics, highlighting the apparent inaccuracy of pure basal ganglia volumetrics in detecting these changes (4).

  Second, a key claim regarding the authors’ hypothesis is that “the structures, susceptible to a change in volume were unique to the motoric network of the STN in PD and included the thalamus, caudate, putamen and pallidum.” Importantly, the regional volumetric changes reported were largely incompatible with this hypothesis as they did not manifest a strong predilection for the sensorimotor functional regions of the target nuclei (e.g., the sensorimotor posterior ventral pallidum and inferior lateral thalamus representing the ventral sensorimotor nuclei were less affected). In fact, it seems the regional volume changes may have more predilection for limbic portions of these nuclei, which is in line with the observation of progressive hippocampal atrophy noted by the authors and by others. The more anterior limbic portion of the STN and its respective subcortical connections (e.g. ansa subthalamica exiting the anterior pole of the STN) and limbic hyperdirect pathways that largely travel anteriorly into the anterior limb of the internal capsule would not be expected to be targeted either with lead implantation or with stimulation. Therefore, it would be difficult to attribute the atrophy directly to surgical implantation or to stimulation.

  It is also important to better understand the surgical procedure in their study, particularly the use of perioperative anesthesia. Although not specifically addressed, drugs such as propofol have been shown to have a sustained effect on cortico-subcortical connectivity and in local field potentials. The effects of non-brain surgery and anesthesia alone have also been shown to result in a subsequent cognitive decline in PD patients, which could explain the findings of atrophy in these limbic regions reported in this study (see above discussion) (4). Likewise, since the majority of patients had the first implant on the more affected side, it is possible that the volume changes reflect disease progression that would be expected to occur in a similar asymmetric fashion.

  The lack of a control group, given the strong selection bias in this cohort makes it challenging to prove these changes were simply a result of surgery or stimulation. Lastly, the sample size was small at only 32 patients. A much larger cohort taking into account errors introduced by imaging related methods and by lead artifacts should be performed to properly confirm or refute the author’s observation.

  In summary, brain atrophy is an issue which will occur after DBS surgery and it has potential implications in DBS management and outcomes. However, the exact mechanism of such atrophy is not well understood making it difficult to know if the phenomenon is expected or even preventable after DBS surgery. The introduction of novel DBS devices capable of current shaping and steering may provide an opportunity for enhanced management of DBS side effects which may emerge from expected progressive brain atrophy(5).

  Daniel Martinez-Ramirez, MD
  Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Ignacio Morones Prieto 3000, Monterrey, N.L., México, 64710.
  Email: daniel.martinez-ramirez@tec.mx

  Erik H. Middlebrooks, MD
  Departments of Radiology and Neurosurgery, Mayo Clinic, 4500 SW San Pablo Rd, Jacksonville, FL, USA, 32224.
  Email: Middlebrooks.erik@mayo.edu

  Leonardo Almeida, M.D.
  Norman Fixel Institute for Neurological Diseases, University of Florida Health, 3009 SW Williston Road, Gainesville, FL, USA, 32608.
  Email: leonardo.britoDEalmeida@neurology.ufl.edu

  Michael S. Okun, MD
  Norman Fixel Institute for Neurological Diseases, University of Florida Health, 3009 SW Williston Road, Gainesville, FL, USA, 32608.
  Email: okun@neurology.ufl.edu

  The authors have nothing to disclose.

  References
  1. Kern DS, Uy D, Rhoades R, et al. Discrete changes in brain volume after deep brain stimulation in patients with Parkinson's disease. Journal of neurology, neurosurgery, and psychiatry. 2020.
  2. Martinez-Ramirez D, Morishita T, Zeilman PR, et al. Atrophy and other potential factors affecting long term deep brain stimulation response: a case series. PLoS One. 2014;9(10):e111561.
  3. Vedam-Mai V, Martinez-Ramirez D, Hilliard JD, et al. Post-mortem Findings in Huntington's Deep Brain Stimulation: A Moving Target Due to Atrophy. Tremor Other Hyperkinet Mov (N Y). 2016;6:372.
  4. Tanner JJ, McFarland NR and Price CC (2017) Striatal and Hippocampal Atrophy in Idiopathic Parkinson’s Disease Patients without Dementia: A Morphometric Analysis. Front. Neurol. 8:139. doi: 10.3389/fneur.2017.00139
  5. Almeida L, Deeb W, Spears C, et al. Current Practice and the Future of Deep Brain Stimulation Therapy in Parkinson's Disease. Semin Neurol. 2017;37(2):205-14.

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  Conflict of Interest:
  None declared.

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