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Intracranial Neuromodulation
As early as the 1950s temporary deep brain stimulation (DBS) electrodes were implanted into the septal region. The procedure was performed for pain control and was reported to have beneficial effects ( ). There were various attempts at DBS, with most documented experiences revealing its usefulness in test stimulation prior to ablative brain lesions ( ). In 1987, when Alim-Louis Benabid was operating on a chronic pain patient, he noticed that the patient’s tremor improved during test stimulation and decided to chronically stimulate this patient. Over the ensuing decades, multiple DBS placements into several brain regions for a variety of clinical indications have been attempted ( ).
High-frequency stimulation (HFS) has been thought to affect the basal ganglia network and has been previously described to operate as an informational lesion, though this explanation continues to be modified and refined ( ). HFS has been hypothesized to result in a decoupling of the cellular and the axonal output within a thalamocortical relay circuit. The firing rates and patterns of the cell body may be suppressed, while fibers of passage may be excited. DBS may, ultimately, affect a cortico-striatopallido-thalamo-cortical (CSPTC) network and result in upstream, as well as downstream, changes within this complex basal ganglia network ( ). The specific effects of an electrical field are thought to reflect changes relative to the position and orientation of the axon to the actual DBS lead and to exert trans-synaptic influences ( ).
The clinical benefits of DBS have been hypothesized to be due to more than just local neurotransmitter release ( ); however, several authors have argued that there is a collective effect and that transmitter release may be very important to the mechanism of action ( ). Animal models of DBS have revealed increased extracellular concentrations of glutamate, γ-aminobutyric acid (GABA), adenosine, and dopamine ( ). Depolarization blockade, synaptic inhibition, and synaptic depression ( ) have also been proposed to play a role in the potential mechanisms of action of DBS. The mechanisms underpinning the therapeutic effects of DBS remain unknown; however, neurophysiological, neurochemical, neurovascular, neurogenic, and neuro-oscillations all play a role.
DBS technology involves placement of a lead with four to eight contacts into a specific and predetermined brain target ( Fig. 38.1 ). Selective placement of the DBS leads within different anatomical regions. Somatotopies may affect the neuronal network and, in the best possible cases, lead to improvement in clinical symptoms. The lead is usually connected to a neurostimulator placed subcutaneously under the clavicle, although the battery can be placed in a multitude of regions. The neurostimulator can then be programmed or adjusted in order to tailor a setting to an individual patient. There are thousands of different combinations that may be chosen. The amplitude, frequency, pulse width, and electrode configuration may all be changed. The optimal settings are patient- and symptom-specific, and generally require that patients be reprogrammed frequently for the first 4–6 months. Additionally, medications as well as stimulation settings must be monitored ( ).
A, Deep brain stimulation (DBS) consists of a lead connected to an internal pulse generator placed subcutaneously, usually under the clavicle. B, This lead has four contacts that can be activated through a programmer. In this case, the lead is placed in the subthalamic nucleus.
Each disorder or symptom considered for treatment with DBS should be carefully evaluated. Only a fraction of the patients with a given neurological or neuropsychiatric disorder may be eligible for this type of therapy. Most patients receiving DBS should be medication-resistant and should undergo a complete multidisciplinary screening by a neurologist, psychiatrist, neuropsychologist, neurosurgeon, and by physical, occupational, and speech/swallowing therapists. Following screening there should be a detailed interdisciplinary discussion about the goals of therapy including symptoms targeted, symptoms that will likely respond, symptoms that are not likely to respond, and an individual patient’s expectations.
In cases of Parkinson disease (PD), patients should undergo an “off/on” levodopa medication challenge to determine which symptoms respond best to medication. The symptoms that respond best to medication usually are those that respond best to stimulation (with the exceptions of tremor and dyskinesia). Risks and benefits of a potential DBS surgery, as well as the potential brain target(s), and unilateral versus bilateral DBS should all be carefully addressed in preoperative conversations with patients and families ( ). There are many potential adverse events that may occur as a result of DBS, some of which may constitute emergencies ( ).
Depending on the region of the world and the preference of individual surgical teams, leads and batteries may be placed in a single setting or may be staged (separate operating room procedures). Additionally, one lead, two leads, or, in exceptional circumstances more than two leads, may be implanted in a single session. One review of DBS hardware-related complications cited lead migration, lead fracture, lead erosion/infection, and lead malfunctions as not uncommon occurrences ( ). Surgically related and stimulation-related complications can occur; they may include but are not limited to hemorrhage, infection, stroke, seizures, paresthesias, dysarthria, hypophonia, dystonia, mood worsening, suicide, apathy, and worsening of comorbidities. Difficulty with verbal fluency and anger seem to be common sequelae in PD patients ( ; ; ; ; ). DBS teams must differentiate between lesion effects, stimulation-induced effects, and transient versus permanent neurological dysfunction.
Parkinson Disease
PD is a complex disorder thought to be the result of extensive loss of neurons and their projections within motor and nonmotor basal ganglia circuitry ( ). A rationale for neuromodulatory therapy has been developed as a result of models of basal ganglia physiology. Perhaps the most famous model reveals loss of dopaminergic neurons in the substantia nigra pars compacta with a resultant abnormal neuronal activity in both the direct and indirect basal ganglia circuitry. These changes are thought to result in the genesis of many of the motor symptoms of PD.
Initial treatment of PD is usually with dopaminergic therapy, although disease progression may lead to limitations in medical therapy including such symptoms as wearing “off” between doses, “on-off” fluctuations, and medication-related dyskinesia ( 
). The subthalamic nucleus (STN) and the globus pallidus internus (GPi) DBS have been used to modulate basal ganglia pathways and to restore important functions in select patients, as can be seen in 
( ). To date, STN and GPi DBS have shown similar motor outcomes and the potential benefits between these targets have been shown to manifest differences. STN DBS may have a slightly larger benefit in the medication off state, and may allow for larger dopaminergic medication reductions, though STN DBS may have an equal or higher risk of neuropsychiatric changes as compared with GPi DBS. GPi DBS may provide better dyskinesia suppression, better long-term flexibility, and a relatively safer risk–benefit profile ( ). GPi is also a better target for dyskinesia that tends to occur at very low medication doses, often referred to as “brittle” dyskinesia.
“Off” Stimulation Evaluation in Parkinson Disease.
“On” Stimulation Evaluation in Parkinson Disease.
Clinical Evidence: Randomized Controlled Trials
There have been multiple smaller studies to determine the efficacy of STN and/or GPi DBS in the treatment of PD symptoms. The best supporting evidence for the use of DBS in PD patients comes from several randomized clinical trials that compare these targets with the best medical treatment ( Table 38.1 ).
TABLE 38.1
Deep Brain Stimulation—A Few Selected Deep Brain Stimulation Studies from the Literature
| Author | Site/No. | Follow-up | Outcomes/Author Conclusions |
|---|---|---|---|
| Parkinson Disease | |||
| ( ) VANTAGE |
STN (B/L): 40 | 12–52 weeks | Constant current, 8-contact DBS device was safe and effective. |
| ( ) NSTAPS | GPi: 65 STN:63 |
1 year | STN stimulation showed greater improvement in UPDRS while off-medication and greater medication reduction, while there were no differences in cognition, mood, and behavior. |
| ( ) EARLYSTIM | STN (B/L) | 2 years | Early stimulation ( N = 124) was superior to medical therapy alone ( N = 127) in terms of motor disability, ADL, levodopa-induced complications, and time with good mobility. |
| ( ) | STN (B/L): 136 | 1 year | Constant-current device DBS had better outcomes in terms of good quality on time and improved UPDRS motor score. |
| ( ) | GPi (B/L): 152 STN (B/L):147 |
2 years | Similar improvement in motor function with stimulation of either target. STN group has lesser medication requirement and more decline in visuomotor skills and level of depression compared with GPi group. |
| ( ) COMPARE | STN (U/L): 22 GPi (U/L): 23 |
7 months | UPDRS motor scores improved in STN and GPi; worsened mood with ventral DBS of both sites; worsened letter fluency more with STN; anger in both targets. |
| ( ) | STN (B/L): 49 | 5 years | Improved motor function, dyskinesia, and ADLs off-medication. Worsened on medication akinesia, speech, postural instability, freezing, and cognitive problems. |
| Tremor | |||
| ( ) | VIM (B/L): 47 (ET) VIM (U/L): 80 |
6 months | Constant-current device showed improved upper extremity tremor, ADLs, quality of life and depression. |
| ( ) | VIM (B/L): 11 (ET) VIM (U/L): 23 |
3–128 months | Overall 80.4% improvement in tremor with average follow-up of 56.9 months. |
| ( ) | VIM: 38 (PD) | 6 years | Tremor effectively controlled by DBS with stable appendicular rigidity and akinesia. Axial scores worsened. Improvement in ADLs disappeared despite tremor control. |
| ( ) | VIM: 19 (ET) | 7 years | Effective treatment for ET but improvement diminishes over time. |
| Dystonia | |||
| ( ) | STN (B/L): 20 | 3 years | BFMDRS motor scores improved 70.4%, TWSTRS scores improved 66.6%. Improvement at 36 months equivalent to 6 months. |
| ( ) | GPi (B/L): 40 | 5 years | There is sustained improvement in dystonia and rating and disability at 5 years with B/L GPi in primary generalized or segmental dystonia. |
| Pain | |||
| ( ) | VTA: 21 (CH) | 4–60 months | Sixty percent improvement in headache frequency, 30% improvement in severity. Abortive medication usage dropped by 57%. QoL, disability and mood scales improved. |
| ( ) | PH: 16 (CH) 1 (SUNCT) 3 (AFP) |
18 months | 10/16 CH patients completely pain-free, the SUNCT patient responded, no benefit in AFP. |
| Epilepsy | |||
| ( ) | RNS device at seizure focus: 111 | 2–6 years | Median seizure reduction of 70%. 29% of patients had at least one seizure-free period of ≥6 months, 15% with ≥1 year. |
| ( ) | RNS device at seizure focus: 126 | 2–6 years | Seventy percent median seizure reduction with frontal and parietal seizure onsets, 58% with temporal onsets, 51% with multilobar. No deficits seen in stim over eloquent cortex. |
| Neuropsychiatry | |||
| ( ) | GPi: 15 | 8–36 months | 15.3% improvement in YGTSS scores at end of blinded stimulation period; 40.1% improvement in YGTSS after open-label phase. |
| ( ) | CMN, substantia periventricularis, VO: 6 (TS) | 1 year | Stimulation effect persisted after a year with a 49% improvement in YGTSS. |
| ( ) | ALIC/BNST area: 24 | 4–16 years | Significant improvement in obsessions, compulsions, anxiety, depression and function. |
| ( ) | VC/VS: 26 (OCD) | 24–36 months | Two-thirds of patients improved; patients with more posterior target had more effective treatment. |
| ( ) | VC/VS: 6 (OCD) | 1 year | 4/6 patient responders, sham stimulation period for half the patients. |
This table is a summary of some of the major neuromodulatory studies, but for space considerations not all studies could be listed. We apologize to any authors who were excluded.
ADLs, Activities of daily living; AFP, atypical facial pain; ALIC, anterior limb of the internal capsule; BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; B/L, bilateral; BNST, bed nucleus of the stria terminalis; CH, cluster headache; CMN, centromedian thalamic nucleus; DBS, deep brain stimulation; ET, essential tremor; GPi, globus pallidus internus; OCD, obsessive-compulsive disorder; PD, Parkinson’s disease; PH, posterior hypothalamus; QoL, quality of life; STN, subthalamic nucleus; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; TS, Tourette syndrome; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; U/L, unilateral; UPDRS, United Parkinson Disease Rating Scale; VC/VS, ventral capsule/ventral striatum; VIM, ventral intermediate thalamic nucleus; VO, nucleus ventralis oralis of the thalamus; VTA, ventral tegmental area; YGTSS, Yale Global Tic Severity Scale.
In 2006, the German Parkinson Study Group published a comparison between bilateral STN stimulation and medication versus medical management alone ( ). In this study, 156 patients with advanced PD younger than 75 years of age were enrolled and randomized into both groups. The primary outcome of the study was to assess changes in the quality of life per the Parkinson Disease Questionnaire (PDQ-39) and the severity of motor symptoms per the Unified Parkinson Disease Rating Scale motor score (UPDRS-III) between the stimulation-and-medication versus the medication-alone group. The stimulation group had a significant improvement in the PDQ-39 and UPDRS-III scores. One of the drawbacks of the German Parkinson Study Group trial was that the population studied was relatively young.
The Veterans Administration CSP 468 Study Group published a second randomized clinical trial 3 years later ( ). The objective of the study was to compare the outcomes of bilateral DBS implanted in either the STN ( N = 60) or GPi ( N = 61) versus best medical management ( N = 134) stratified by site and age less than 70 years and more than 70 years. This trial demonstrated an improvement in quality of life and motor symptoms. The improvements persisted, despite the inclusion of an older population. However, the differences between targets were not analyzed. In 2012, the same group reported sustained benefits of stimulation of either the STN ( N = 70) or the GPi ( N = 89) on motor function after a 36-month follow-up ( ). The findings of the CSP 468 trial have been largely confirmed by a Dutch trial, the NSTAPS study, which also revealed similar outcomes for STN and GPi DBS ( ). A 3-year follow-up, which included 90 of the 128 patients originally enrolled in the NSTAPS study, observed slightly more improvement in off-medication motor symptoms favoring STN and greater medication reduction, also favoring STN. There were similar risks of cognitive, mood, and behavioral outcomes though this study used some outcome variables that were not comparable to many other studies ( ).
DBS plus best medical therapy versus best medical therapy alone for advanced PD, better known as the PD SURG trial, provided further evidence of the efficacy of DBS in the treatment of PD ( ). In this study, 366 patients were randomized to surgical intervention with DBS and best medical treatment or best medical treatment alone. Again, the DBS group had better quality of life as assessed by the PDQ-39 a year after randomization. Long-term efficacy of DBS in PD has been excellent. Symptoms that respond to levodopa seem to continue to respond to DBS, with the exceptions of tremor and dyskinesia that may have persistent benefits despite waning levodopa responses ). We know that as disease progresses, nonmotor complications emerge and these are often not responsive to levodopa or to DBS.
There has been much interest in delivering DBS earlier in the disease course. The EARLYSTIM trial studied 251 subjects between the ages of 18 and 60 years, disease duration of 4 years or more, with a severity rating below stage 3 on the Hoehn and Yahr scale, and presence of fluctuations or dyskinesia for 3 years or less ( ). Bilateral STN DBS devices were implanted on 124 subjects. When compared with the best medical treatment ( N = 127), again the DBS group had better quality of life and motor scores per the PDQ-39 and UPDRS-III. All secondary outcome variables improved in this study. It has been suggested that the patient’s expectation of a negative outcome (the patient was aware of randomization to the nonsurgical group) led to a placebo effect that may have positively biased the outcome. The behavioral effects of DBS were recently evaluated in a secondary analysis of the 251 patients in the EARLYSTIM trial with secondary behavioral outcomes of apathy, behavior, and depression evaluated at 2-year follow-up. This study reported a reduction in neuropsychiatric fluctuations and an improvement in the Ardouin Scale of Behavior (bilateral STN DBS plus medical therapy group alone). The scores of apathy and depression did not differ between treatment groups. A smaller number of antidepressant and antipsychotic medications were used in the DBS-plus-medical therapy group but the study was not powered to examine this relationship. Two suicides occurred in the DBS-plus-medical therapy group and one in the medical therapy-only group ( ).
A pilot trial was completed comparing bilateral STN DBS plus optimal medical therapy to optimal medical therapy alone. It was conducted in 30 subjects who were between the ages of 50 and 75 years old, off-medication Hoehn and Yahr stage 2 (severity rating). Patients were treated for more than 6 months and for less than 4 years and without a history of motor fluctuations ( ). There were 15 subjects who underwent bilateral STN DBS placement. Co-primary endpoints were: time to reach a 4-point worsening from baseline, the off-therapy UPDRS- III score, and the change in levodopa equivalent daily dose from baseline to 24 months. Total and part III UPDRS scores were not significantly different on or off therapy at 24 months. The DBS plus optimal medical therapy group required less medication at all time points, with the maximum difference reached at 18 months. Overall, the safety and feasibility study of DBS plus optimal medical therapy in early PD patients in whom motor complications had not yet occurred , found a 50%–80% reduction in the relative risk of worsening compared with optimal medical therapy alone when followed at 2 years ( ). A recent follow-up study suggested that DBS in early PD may possibly have an impact on the progression of rest tremor ( ).
Until recently, few fundamental technological advances in DBS have occurred in the era of modern usage. Traditional DBS has used a single-source voltage-driven system, which has the potential limitation of changes in the electrical field due to fluctuations in tissue impedance. Recently, constant-current devices have been developed and this technology has the theoretical advantage of improved field stability. The St. Jude Medical DBS Study Group investigated the impact of a constant-current DBS device implanted in bilateral STN on the change in “on” time without dyskinesia. The control group received the DBS with a delayed 3-month activation. The improvement of quality “on” time was observed in both groups, with greater benefit in the stimulated group. These findings confirmed the effect of lead implantation alone, in addition to the efficacy of constant-current devices.
Additional innovations in design have led to finer control over the electrical field’s shape and direction of spread. A new development has been the use of multiple independent current sources, which facilitates the delivery of current to one or more DBS contacts. This approach has a goal of improved precision in electrical field shaping and a limitation of side effects. The VANTAGE study was a prospective, nonrandomized, unblinded, multicenter trial of unilateral and bilateral STN DBS in 40 PD patients in Europe, which evaluated the use of a new constant-current system and utilized eight circumferential contacts with independent current sources. This technology was manufactured by Boston Scientific ( ). The primary endpoint was mean change in the UPDRS-III score at 26 weeks, and this was improved with a significant mean difference of 23.8 points, which was a 62% change. The use of anti-Parkinsonian medications was reduced; the amount of “on” time and also the quality of life was improved. This system was not formally compared with conventional DBS, but the frequency and severity of side effects were comparable to those reported in prior trials of STN DBS. This system was approved for use in Europe in 2012. The long-term results of the VANTAGE study at 5 years were recently presented, and it was shown that quality-of-life measures continued to improve from baseline ( ). More recently, this system was evaluated in the INTREPID study, the results of which were recently presented. This was a multicenter, prospective, double-blind randomized controlled trial (RCT) of STN DBS that was conducted in the United States. The study met the primary outcome of change in mean hours per day of on time without troublesome dyskinesia ( ). Based on this most recent study, the US Food and Drug Administration (FDA) approved the use of this device for PD in December 2017.
Traditional DBS leads utilize cylindrical contacts, which produce a circumferential field. Recently developed directional devices use radially segmented leads, which take advantage of independent current sources to activate one or more segments to create asymmetric field shapes. The therapy was designed so that the electrical current could be directed away from nontargeted structures and toward intended fiber bundles, thereby minimizing side effects. The PROGRESS trial is an ongoing nonrandomized, double-blind crossover trial comparing classic stimulation with directional stimulation of the STN in PD patients using a different constant-current device which incorporates radially segmented leads. The device was developed by Abbott. The primary outcome measure will be “the proportion of subjects for which at least one lead’s therapeutic window (evaluated by a blinded evaluator) is greater using directional stimulation than omnidirectional stimulation; tested against a performance goal of 60%” (NCT02989610). This system was approved in the EU in 2015 and by the US FDA in 2016.
The DIRECT DBS trial is a multicenter study of STN DBS in PD utilizing a constant-current device with segmented leads and eight contacts with independent current sources. This device was developed by Boston Scientific. Preliminary results were presented showing the potential for directional stimulation–related differences in clinical responses ( ).
Dystonia
Dystonia is characterized by sustained co-contraction of agonist and antagonist muscles. Sufferers may experience involuntary repetitive movements that result in twisted and sometimes painful postures. Dystonia may be focal, segmental, or generalized based on the body region affected. A 2013 consensus document revised the classification of dystonia into two axes ( ). Axis I categorizes dystonia by its clinical features and axis II by etiology. Lesion surgery (i.e., pallidotomy and thalamotomy) has been successfully employed for various primary and secondary dystonias ( ), though most centers prefer DBS, as ablation is irreversible and bilateral lesions may result in speech or cognitive issues ( ), while stimulation parameters may be adjusted for benefit and to limit side effects.
DBS therapy is mainly performed in the GPi target, as stimulation in this region has provided a reasonable alternative to lesion therapy. Most DBS cases have responded best if the dystonia has been of primary origin, although select secondary dystonias as well as tardive dystonias have had meaningful improvements in small series ( ). There have been multiple large randomized trials that address primary generalized dystonia, and each has demonstrated sustained improvement of dystonia rating scales up to 5 years after implantation ( ). A recent longitudinal study including 61 patients with idiopathic inherited and also acquired dystonia who underwent GPi DBS observed overall sustained clinical improvements. Those with idiopathic and inherited isolated dystonia and acquired dystonia did best, while those with dystonia secondary to neurodegenerative disorders did poorly ( ). Additionally, the number of indications has been expanding within dystonia (e.g., cerebral palsy) and the number of brain targets continues to expand, with recent trials indicating the potential for STN DBS ( ).
One interesting and unique aspect of DBS for dystonia has been the phenomenon that, in many cases, the effects seem to be delayed and appear gradually after stimulation initiation (weeks to months). It has been hypothesized that this phenomenon may be the result of neuroplasticity, with recent work suggesting the role of normalization of abnormal cortical plasticity by the electrical stimulation provided by DBS ( ). The mechanisms underlying the benefit(s) of DBS in dystonia remain unknown. The other evolving story in dystonia DBS has been the utilization of lower stimulation frequencies for select cases ( ). Selecting which cases may respond to lower frequencies remains an area of investigation.
Tremor
Tremor has been broadly defined as an involuntary and rhythmic oscillation of a body part and has been classified according to its etiology and/or by its characteristics (e.g., phenomenology, physiology, etc.; ). It has been hypothesized that physiological disturbances in the cerebellothalamic and pallidothalamic pathways may be the genesis of some tremor subtypes.
Pre-surgical Evaluation in Essential Tremor.
The ventralis intermedius (VIM) nucleus of the thalamus, which takes its input from the cerebellum, forms a vital piece of this regulatory network, and has been frequently targeted for HFS to address various medication-refractory tremors, with the most common being essential tremor (ET; ). DBS therapy has been reported to have similar efficacy as thalamotomy ( ) and fewer short-term side effects, but more long-term device-related adverse effects when compared to lesion therapy.
Typically, unilateral VIM DBS has been employed to control medication-refractory tremor in a contralateral extremity ( ). Unilateral DBS may result in side effects of ataxia and speech problems, and these issues may be more commonly encountered when bilateral DBS is utilized ( ). Midline tremor, head tremor, and voice tremor seem to less consistently respond to DBS ( ). Longitudinal follow-up studies have revealed good long-term benefits, although there has been an emerging concern in the field about waning efficacy over time, with tolerance and disease progression among suspected causes ( ). A paper by revealed that in ET, disease progression and not tolerance is the more common mechanism underpinning worsening tremor over time.
Post-surgical Evaluation in Essential Tremor.
The largest prospective study in ET was recently published using the Abbott constant-current device for unilateral thalamic DBS. In this prospective, controlled, multicenter study, 127 patients were implanted with VIM DBS. The primary efficacy outcome at 180 days in 76 patients revealed a mean improvement of 1.25 ± 1.26 points in the target limb tremor rating scale (TRS). Improvements were also found in secondary outcome measures of quality of life, depression, and activities of daily living (ADLs). There were 47 patients who underwent placement of a second contralateral VIM DBS, with significant reduction in contralateral tremor at 180 days. The rate of adverse events was comparable with prior studies, with serious adverse events including three infections, three intracranial hemorrhages, and three device explants ( ).
While VIM DBS is preferred for pure ET and select cases of PD tremor, cerebellar/midbrain tremor, posttraumatic tremor, and MS tremor have had worse efficacy with this target when compared with ET. These more complex tremor disorders have been treated in small case series by either single or multiple leads in VIM, ventralis oralis posterior (VOP), or by zona incerta (ZI; ). The exact target(s) for these disorders remain to be investigated.
Dementia
Several reports of DBS implantation in Alzheimer disease (AD) over the last decade have suggested a possible role for DBS. The two primary targets studied have been the nucleus basalis of Meynert (NBM) and the fornix. The report of serendipitously evoked autobiographical memories in a case of bilateral hypothalamic DBS to treat obesity prompted the discovery that the fornix may be a potential DBS target. Early reports of DBS targeting the fornix revealed the possibility of improving symptoms and changes in temporal and/or parietal lobe hypometabolism ( ). Similar findings of increased functional connectivity and increased cortical metabolism were seen after 1 year in a study of five AD patients with stimulation of the fornix ( ). A larger phase II RCT of DBS in the fornix of 42 patients with mild AD failed to meet its primary outcome. Patients in this trial older than 65 may have possibly benefited ( ).
A marked cholinergic deficit due to degeneration of the NBM, which is located in the basal forebrain, is thought to play a significant role in the cognitive and behavioral dysfunction in AD. Excitation of NBM output using low-frequency stimulation may be a method to improve cholinergic output to the cortex. This notion has been supported by work in animal models ( ). An early attempt of using NBM DBS in a patient with AD demonstrated no significant clinical benefit ( ). Another pilot trial of NBM DBS in AD suggested stable or possibly improved cognition in four of six patients ( ). There was possible benefit in two younger AD patients with a higher level of baseline functioning ( ). A study of eight younger AD patients similarly suggested earlier-stage disease may respond better to NBM DBS.
A small study of two patients evaluated the effect of DBS on auditory processing, and supported the potential beneficial effects of NBM DBS on recognition of familiar stimuli ( ). Seeking to better define predictors of response, a recent study of NBM DBS utilized magnetic resonance imaging (MRI) to define preoperative cortical thickness and to identify networks modulated by stimulation. This study observed that preserved fronto-parieto-temporal cortical thickness and retained interplay were both associated with better outcomes ( ). Expanding to a new target, there was a recently reported phase I open-label trial of ventral capsule/ventral striatum (VC/VS) in three AD patients. Two of three patients demonstrated meaningfully less decline in the primary outcome measure, with minimal to increased metabolism evident on 2-deoxy-2-[ 18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) imaging of frontal cortical regions.
DBS for Parkinson disease dementia (PDD) is similarly an emerging area of exploration. The degeneration of the NBM in PDD typically leads to a cholinergic deficit that is greater than that observed in AD. The results of the first case of NBM DBS for PDD were potentially encouraging ( ). This was followed by a pilot double-blind RCT of bilateral NBM DBS in six patients with PDD and, while it was found to be safe, no improvements were seen in the primary cognitive outcomes ( ). Future research directions may explore subregions of the NBM and the effects of different stimulation parameters.
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