Table 1.

A summary of fornix DBS studies presented in this review

Subject	Type of stimulation	Memory task	Effect	References
Human (patients with TBI) N = 4	Continuous DBS using a burst pattern (200 Hz in 100 ms trains, 5 trains/s, 100 µs pulse width, 7 mA, bipolar and bilateral stimulation)	Rey auditory verbal learning test, Medical College of Georgia Complex Figure Test, Boston Naming Test	Burst stimulation of the fornix was associated with a robust reversible improvement in immediate and delayed performance on the Medical College of Georgia Complex Figure Test	Miller et al. [58]
Rats (model of TBI) N = 21	Low-frequency (5 Hz), high-frequency (130 Hz), and theta-burst stimulation (200 Hz in 50 ms trains, five trains per second; 60 µA biphasic pulses)	Swim T‐Maze, Morris Water Maze	Deficits in learning and memory after TBI are improved  following DBS of the fornix	Sweet et al. [60]
Human (patients with intractable epilepsy) N = 11	Bilateral, high amplitude, low pulse width, low frequency (8 V, 0.2 μs, 5 Hz), for 4 h	MMSE	An increase of MMSE scores during stimulation. Hippocampal spikes were significantly reduced during and outlasting each stimulation session. Seizure odds (n = 7) were reduced by 92% in the 2 days that followed stimulation	Koubeissi et al. [63]
Mice (model of RTT) N = 21	Bilateral, 130 Hz, 60 µs pulse duration, for 1 h per day for 14 days	Fear conditioning, Morris water maze, open field, light–dark box, wire hang and dowel walk, accelerating rotarod, three-chamber interaction, and pain threshold	Forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory	Hao et al. [65]
Human (morbid obesity patient) N = 1	Bilateral, 3–5 V, 130 Hz and 60 μs pulse width, continuous for 3 weeks	Neuropsychological tests, e.g., verbal learning test, WAIS attention index, spatial associative learning, etc	Significant improvements on the California Verbal Learning Test and Spatial Associative Learning Test	Hamani et al. [50]
Human (AD patients) N = 6	Bilateral, 3.0–3.5 V, 130 Hz, and 90 μs pulse width, continuous for 12 months	ADAS-cog, MMSE	Possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients	Laxton et al. [72]
Human (AD Patients) N = 6	Bilateral, 3.0 V, 130 Hz and 90 μs pulse width, continuous for 12 months	ADAS-cog, MMSE	Local volume increase in parahippocampal gyri, right superior temporal gyrus, left parietal lobule and bilateral precuneus as well as thalamus and superior frontal gyrus	Sankar et al. [73]
Human (AD patient) N = 1	Bilateral, 2.5 V, 130 Hz and 210 ms pulse width, continuous for 12 month	ADAS-cog, MMSE, Free and Cued Selective Reminding Test	Cognitive scores worsened after 6 months but returned to baseline after 12 months of chronic DBS	Fontaine et al. [74]
Human (patients with mild AD) N = 42	Bilateral, 3.0–3.5 V, 130 Hz, with a pulse width of 90 microseconds at the top, or second from top, of the 4 electrode contacts, continuous for 12 month	ADAS-Cog-13, CDR-SB, California Verbal Learning Test-Second Edition (CVLT-II), the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale (ACDS-ADL)	Participants aged ≥ 65 years show less cognitive decline while there was possible worsening in patients below 65 years with stimulation	Lozano et al. [75]
Rats (model of experimental dementia) N = 10	Bilateral, 100 and 200 μA, 10 and 100 Hz, 100 μs pulse width, acute stimulation	OLT	Memory enhancement in high current densities (frequency-independent)	Hescham et al. [78]
Rats N = 29	Bilateral, 100 Hz, 100 µA and 100 µs pulse width for 1 h	N/A	Fornix DBS induced a selective activation of cells in the CA1 and CA3 subfields of the dorsal hippocampus, a substantial increase in the levels of extracellular hippocampal acetylcholine	Hescham et al. [79]
Rats (transgenic rat model of AD, tgF344) N = 10	Permanent, bilateral, and unipolar stimulation (130 Hz, 80 µs, 100 µA)	N/A	Amyloidosis, inflammatory responses, and neuronal loss decreased in both cortex and hippocampus after DBS in the fornix	Leplus et al. [76]
Mice (transgenic mouse model of AD, 3xTg) N = 50	Monophasic, 1 h (100 Hz, 100 μs pulses, 100 μA)	Morris water maze	Fornix DBS improved learning and long- term memory after 3 and 6 weeks with significant differences driven mostly by males	Gallino et al. [77]

The table shows the subjects involved, the type of stimulation, memory task, and the behavioral outcome of the surgical intervention

ADAS-cog Alzheimer's Disease Assessment Scale-cognitive subscale, CDR-SB Clinical Dementia Rating Scale Sum of Boxes, OLT object location task, DBS deep brain stimulation, MMSE mini-mental state examination, WAIS Wechsler Adult Intelligence Scale