Neurophysiological Biomarkers to Optimize Deep Brain Stimulation in Movement Disorders

Figures & data

Table 1. Common neuronal firing patterns and stimulation-induced effects encountered during deep brain stimulation surgery for movement disorders.

Structure	Neuronal firing pattern	Stimulation-induced effects
Striatum (caudate, putamen)	Low density and background, low amplitude and very low frequency activity. No sensorimotor activity	NA
Thalamus: dorsal or VOa	Low density, background and sporadic low amplitude, low frequency activity. No sensorimotor activity	None
Thalamus: VOp	Moderate density, low background and frequency. Sensorimotor activity. Bursting cells that may correlate with tremor	Possible tremor improvement at high amplitudes
Thalamus: Vim	Sensorimotor activity. Bursting cells that may correlate with tremor	Tremor improvement Dysmetria at high amplitudes Dysarthria (medial Vim)
Thalamus: Vc	Proprioceptive (anterior Vc) or tactile (posterior Vc) sensory-responsive activity	Contralateral paresthesia Dysmetria at high amplitudes
Zona incerta	Low density, background and sporadic low amplitude, low frequency activity	Improvement of Parkinsonism
STN (in PD)	Very high density and background, high amplitude and frequency. Bursting cells that may correlate with tremor. Sensorimotor activity (dorsolateral STN)	Dyskinesia (dorsolateral STN) Improvement of Parkinsonism (dorsolateral STN) Mood changes (medial STN)
SNr	High frequency (regular), moderate density, background and amplitude	Mood changes, worsening of Parkinsonism
GPe (more evident in PD than in dystonia)	Moderate background. Brief interruptions of moderate frequency, continuous activity (pausing cells). Brief bursts of high frequency activity (bursting cells)	Dyskinesia
GPi	High density, amplitude and frequency, low to moderate background. Bursting cells that may correlate with tremor. Sensorimotor activity	Dyskinesia (dorsal GPi), improvement of Parkinsonism (in PD)
Medial lemniscus	Absent or markedly reduced (white matter)	Contralateral paresthesia
Internal capsule	Absent or markedly reduced (white matter)	Contralateral muscle pulling, twitching, posturing, gaze deviation, dysarthria
Red nucleus	Similar to STN	Nausea, sweating, warm/cold sensation, dizziness, etc.
Oculomotor nucleus	NA (Not part of trajectory or target)	Ipsilateral esotropia or esophoria (with or without diplopia)
Optic tract	Absent or markedly reduced (white matter). May be evoked by light stimulus	Contralateral phosphenes

DBS: Deep brain stimulation; ET: Essential tremor; GPe: Globus pallidus pars externa; GPi: Globus pallidus pars interna; NA: Not applicable; PD: Parkinson’s disease; SNr: Substantia nigra pars reticulata; STN: Subthalamic nucleus; Vc: Ventralis caudalis nucleus of the thalamus; Vim: Ventral intermedius nucleus of the thalamus; VOa: Ventral oralis anterior nucleus of the thalamus; VOp: Ventral oralis posterior nucleus of the thalamus.

Table 2. Local field potentials associated with movement disorders.

Movement disorder	Local field potentials (frequency peak)
	Increased synchronization	Reduced synchronization
Akinetic-rigid syndrome in PD (untreated)	▪ Low >high beta (13–20 Hz) (longer bursts) ▪ Gamma^† (35–250 Hz) (at lower frequency within this range)	▪ Gamma (35–250 Hz) (shifts to higher frequency within range)
Akinetic-rigid syndrome in PD (treated)	▪ High-frequency^† (250–350 Hz) ▪ Gamma^† (35–250 Hz) (at higher frequency within this range)	▪ Low >high beta^†(13–20 Hz) (shorter bursts)
Tremor in PD (untreated)	▪ Theta/alpha (4–13 Hz) ▪ Gamma^† (35–250 Hz) (at higher frequency within this range) ▪ High-frequency (250–350 Hz) (at higher frequency within this range)	▪ Beta^† (13–35 Hz)
Tremor in PD (treated)		▪ Gamma (35–250 Hz) (at lower frequency within this range) ▪ High-frequency (250–350 Hz) (at lower frequency within this range)
Essential tremor	▪ Theta/alpha (4–13 Hz) ▪ Beta^† (13–35 Hz)
Levodopa-associated dyskinesia	▪ Theta/alpha (4–13 Hz) ▪ Gamma^† (60–90 Hz) (coherent between STN and motor cortex)	▪ Beta^† (13–35 Hz)
Dystonia (tonic)	▪ Delta (0–4 Hz) ▪ Low beta (13–20 Hz) (shorter bursts) ▪ Gamma (60–90 Hz)
Dystonia (phasic)	▪ Theta/alpha (4–13 Hz) ▪ Low beta (13–20 Hz) (shorter bursts) ▪ Gamma (60–90 Hz)
Tics	▪ Theta/alpha (4–13 Hz)

† Also associated with initiation and facilitation of normal voluntary movements.

PD: Parkinson’s disease.

Figure 1. Measurement of local field potentials of the left subthalamic nucleus during initial deep brain stimulation programming in a patient with Parkinson’s disease.

Conventional monopolar review based on acute clinical responses during initial DBS programming yielded equivalent therapeutic windows for contacts E0 and E1. Consistent with the monopolar review, the LFP survey demonstrated low beta (13–20 Hz) frequency peaks of higher amplitude in the regions between contacts (A) E0 and E1, (C) E0 and E2 and (D) E0 and E3. There were no significant beta peaks in the regions between contacts (B) E1 and E2, (E) E1 and E3 and (F) E2 and E3. Thus, initial DBS settings were programmed using contact E0 since the three regions with low beta LFPs shared contact E0 and the highest amplitude (1.89 μVp) was found in the region between contacts (D) E0 and E1. LFP measurements were obtained in the dopaminergic medication OFF state by the Percept DBS system (Medtronic).

DBS: Deep brain stimulation; LFP: Local field potential.

Figure 2. Optimization of left subthalamic deep brain stimulation therapy for the same patient with Parkinson’s disease described in Figure 1.

(A) During surgical implantation of the left STN DBS lead, microelectrode recordings and stimulation defined a physiologically optimized trajectory and target in the dorsolateral region of the anatomically defined left STN. (B) During the initial programming session described in Figure 1, contact E0 was chosen to deliver DBS to the region with the highest peak of low beta LFPs. Upon subsequent DBS amplitude increase, the patient developed subtle side effects due to lateral spread of stimulation toward the IC, which limited the benefits of DBS. (C) With directional stimulation using segmented leads, this lateral spread of stimulation could be theoretically avoided and DBS therapy could be further optimized. Reconstruction of neuroanatomical structures and DBS lead localization were performed by merging pre-operative brain MRI and post-operative CT using BrainLab.

CT: Computed tomography; DBS: Deep brain stimulation; IC: Internal capsule; LFP: Local field potential; STN: Subthalamic nucleus.