Table 3 Overview of preclinical deep brain stimulation (DBS) studies

Lee et al. [166]

Theta frequency DBS to improve spatial memory

Cognitive deficits

56 adult male Sprague–Dawley rats, lateral FPI (moderate TBI), awake during DBS

80 µA, 7.7 Hz, 1 ms pulses, for 1 min in exp. 1 and for 15 min in exp. 2

From post-injury days 5 to 7, directly before Barnes maze experiment

Gonzalez et al. [167]

Behavioral and anatomical recovery after TBI

Cognitive deficits

79 adult male Sprague–Dawley rats, FPI (moderate TBI), awake during DBS

30 µA, 8 or 24 Hz, 1 ms pulses, 5 min alternated with 5 min break, over 12 daylight hours

Starting 4–6 h post-injury (or after 7 days in one group), for 8 weeks

Tabansky et al. [175]

Temporally-patterned DBS after multiple TBI

Decreased arousal

25 C57BL/6J mice (6–9 weeks old), weight drop (20 g from 25 cm, up to 5 times, moderate TBI), awake during DBS

150 µA, 200 µs biphasic pulses, 125 Hz, for 10 min every 4 h over 1 day, diff. temporal patterns (varying interpulse intervals)

Starting 4–6 h post-injury, over the course of 1 day

Lee et al. [168]

DBS to improve cognition after TBI

Cognitive deficits

136 adult male Harlan Sprague–Dawley rats, lateral FPI (moderate TBI), awake during DBS

20/80/200 µA, 7.7/100 Hz, 1 ms pulses

exp. 1: for 15/30/60 s; exp. 2 and 3: starting 1 min before task, for 6 min

Exp. 1: 4 and 5 days post-injury, 2x/day;

exp. 2 and 3: 5–7 days post-injury, 2x/day

Chan et al. [171]

Motor recovery with DBS

Motor deficits

32 male Long Evans Rats (7 were withdrawn), FPI in motor cortex contralateral to dominant forelimb (severity unclear), awake during DBS

80% of individual motor threshold, 30 Hz, 400 µs pulses, 12 h per day

Starting 4 weeks post-injury, for 4 weeks

Jen et al. [172]

DBS to modulate bladder function in TBI animals

Bladder dysfunction

22 female Sprague–Dawley rats, weight drop (450 g from 2 m, severe TBI), anesthetized during DBS and cystometry

1.5 V, 50 Hz, 182 µs pulses

One session, 1 week post-injury, during cystometry, triggered by EUS-EMG

Praveen Rajneesh et al. [173]

DBS to treat bladder dysfunction after TBI

Bladder dysfunction

49 male Sprague–Dawley rats, weight drop (450 g from 0.5, 1, 1.5, 2 and 2.25 m, severity unclear), anesthetized during DBS and cystometry

1/1.5/2/2.5 V, 50 Hz, 182 µs biphasic pulses, for 10 s

One session, 1 week post-injury, during cystometry when bladder pressure exceeded threshold

Praveen Rajneesh et al. [174]

DBS to improve bladder function after TBI

Bladder dysfunction

28 male Sprague–Dawley rats, weight drop (450 g from 2 m, severe TBI), anesthetized during DBS and cystometry

1/1.5/2/2.5 V (randomized sequence), 50 Hz, 182 µs pulses, for 10 s

One session, 1 week post-injury, during cystometry when bladder pressure exceeded threshold

Dong et al. [176]

DBS to promote wakefulness after TBI

DoC

55 Sprague–Dawley rats (28 male, 27 female), weight drop (400 g dropped from 40 to 44 cm, severity unclear), comatose but without anesthesia during DBS

2–4 V, 200 Hz, 0.1 ms pulses, switch between left and right side of lateral hypothalamus every 5 min, for 1 h

Once, 2 h post-injury (1 h after electrode implantation)

Aronson et al. [169]

Task-matched DBS to improve cognitive recovery after TBI

Cognitive deficits

65 adult male C57BL/6 mice, CCI (5.2 m/s, 2.65 mm depth, moderate TBI), awake during DBS

50 µA, 130 Hz, biphasic pulses, 80 µs per phase, 500 ms trains, 500 ms between trains

Starting 2 weeks post-injury, during Morris water maze, 5 s after success for 5 s, four times per day, for 5 days

Chan et al. [170]

DBS to enhance cognitive recovery after TBI

Cognitive deficits

33 male Long Evans rats, CCI (2.25 m/s, 2.5 mm depth, severity unclear), awake during DBS

80% of motor threshold, 30 Hz, 400 µs pulses, charge-balanced

Starting 8 weeks post-injury, 12 h daily, for 4 weeks

Lee et al. [166]

Medial septal nucleus

Video-EEG, Barnes maze

Exp 1.: electrode placement, spatial working memory, search strategy;

exp. 2: hippocampal theta power (during stim. and after 15 min)

No persisting effects observed

FPI attenuates hippocampal theta, MSN theta frequency stimulation immediately before trials improves spatial working memory

Gonzalez et al. [167]

Midbrain median raphe and dorsal raphe

Morris water maze, neuroanatomical analysis, cylinder test

Reference memory, working memory, forelimb reaching asymmetry, forebrain volumes, cAMP levels

Not investigated

8 Hz early MR stimulation can restore forelimb reaching, reference memory, working memory and parietal-occipital cortex volume

Tabansky et al. [175]

Central thalamus (bilaterally)

NSS test (circular open maze, hindlimb reflex, beam walk), parental care, elevated plus maze, light–dark transition, pheromenal spatial learning, T-maze, partition test, social discrimination

Injury severity (NSS) and effects of DBS: motor activity deficits, recovery without intervention, nocturnal behavior pattern, behavioral changes

Not investigated

Multiple TBI results in acute deficits for 11–14 days, chaotic simulation increases motor activity more than fixed or random stimulation

Lee et al. [168]

Medial septal nucleus

EEG, object exploration task, Barnes maze, histology

EEG (theta frequency time, phase coherence, peak frequency), behavioral changes (object exploration, search strategy)

No persisting effects observed

FPI diminishes hippocampal theta, no change in phase coherence, shift in peak frequency, MSN stimulation increased hippocampal theta

Chan et al. [171]

Contralateral LCN

Pasta matrix test, cylinder and horizontal ladder tests, histology, RNA microarray assay, immunohistochemistry, western blot

Forepaw dexterity, spontaneous forepaw use, motor coordination, electrode location, lesion volume, various genetic and cellular parameters

Not investigated

LCN DBS can enhance motor recovery after TBI by elevating neuronal excitability and mediating anti-apoptotic and anti-inflammatory effects

Jen et al. [172]

Rostral pontine reticular nucleus (PnO)

EUS-EMG, continuous-infusion cystometry, MRI, assessment of closed-loop control DBS prototype to improve voiding function

Cystometric parameters (volume threshold, contraction amplitude and duration, residual and voided volume, voiding efficiency), electrode position, tissue damage

Not investigated

Designed DBS closed-loop control system prototype for TBI rats and proved its feasibility (detected bladder voiding cycles, significantly improved voiding efficiency)

Praveen Rajneesh et al. [173]

Rostral pontine reticular nucleus (PnO)

Impact height, cystometric measurements, MRI

Effect of impact height on mortality rate, cystometric parameters (volume threshold, contraction amplitude and duration), TBI impact, electrode position

Not investigated

Established weight drop TBI model for significant voiding dysfunction, show therapeutic effects of PnO-DBS on voiding dysfunction and bladder control in rats after TBI

Praveen Rajneesh et al. [174]

Pedunculopontine tegmental nucleus (PPTg)

Cystometric measurements (CMG), external urethral sphincter electromyography (EUS-EMG), MRI

Cystometric parameters, EUS-EMG parameters (burst period, active period and silent period), DBS electrode tip localization

Not investigated

DBS was capable of inducing potential neural regulation that could control bladder functions, PPTg is a promising target of new therapies for lower urinary tract dysfunction

Dong et al. [176]

Lateral hypothalamic area, left and right side

Assessment of consciousness, OX1R antagonist injection, EEG, western blot analysis, immunohistochemistry

Degree of consciousness (I–VI), delta activity, protein expression (OX1R, α1-AR and GABABR)

Not investigated

LHA-DBS-induced wake promotion results in upregulation of α1-AR expression and downregulation of GABABR expression mediated by the orexins/OX1R pathway, LHA-DBS can be used to promote wakefulness

Aronson et al. [169]

Unilateral, cathode in the nucleus accumbens, anode just below the dura

Morris water maze, real-time place preference assay, immunohistochemistry, gene expression analysis

Spatial memory performance, search pattern efficiency, hedonic response, synaptic density and neuronal growth (synapsin-1 and GAP43), neurogenesis

Persistent effects observed 10 days after stimulation cessation

Task-matched DBS of the nucleus accumbens improves recovery of spatial memory in a TBI mouse model, stimulation led to cellular adaptation and upregulation of genes associated with neural differentiation, migration, cell signaling and proliferation

Chan et al. [170]

LCN, unilateral

Barnes maze, baited Y-maze, novel object recognition task, immunohistochemistry, Western blot, Nissl staining

Long-term spatial memory, memory retention, recognition memory, electrode placement, protein expression (CaMKIIα, BDNF, p75NTR), pre- (synapsin I) and post-synaptic (PSD-95) markers

Not investigated

Unilateral LCN DBS is an effective treatment for cognitive deficits in a TBI rat model by enhancing functional connectivity across perilesional cortical and thalamic brain regions