Remembering Hypothalamic DBS

In an ever-lengthening list of recently reported "miracle cures" for Alzheimer's disease [see also perispinal etanercept and the magic NIRS helmet], do we have

Hope for Alzheimer's? Deep Brain Stimulation
Electrical Currents in the Brain May Help Patients Locate Lost Memories

By JOHN McKENZIE
ABC News Correspondent
Jan. 30, 2008

Researchers report what they say is a world first: By implanting a device in a man's brain, they have improved his memory. The discovery, published today in the Journal of Neurology [uh, no it's in the Annals of Neurology -- the "Journal of Neurology" doesn't exist], raises the possibility of using this technique to treat Alzheimer's patients.

Surgeons made this accidental discovery while a 50-year-old-male patient was undergoing "deep brain stimulation," as part of an experimental treatment for obesity.

With the patient under local anesthesia, but fully awake, surgeons traveled into the deepest recesses of the brain, moving gingerly at a quarter of an inch an hour, listening to electrical "pulses," as millions of brain cells communicated with each other.

. . .

Surgeons treating the obese patient hoped that adding electrical signals to his brain would regulate his appetite.

But amazingly, in the midst of the operation, something completely unexpected happened. The patient suddenly reported a flood of intricately detailed memories from an incident decades ago.

Yes, you say. So what, that was a week ago (Hamani et al., 2008) -- time to move on to the next miracle cure. However, most of the points I want to make here haven't been made in other posts on the topic.

(1) This is the first time that DBS of the hypothalmus has been performed on a human to treat obesity. In recent animal studies, the specific target nuclei have been the lateral hypothalamus in rats (Sani et al., 2007) and the ventromedial hypothalamus in monkeys (Laćan et al., 2008).

Hypothalamic stimulation was proposed based on experimental studies of appetite control in rodents, dogs, and nonhuman primates (Stenger et al., 1991; Brown et al., 1984; Takaki et al., 1992), and the experience, albeit limited, of hypothalamotomy for obesity in humans (Quaade et al., 1974; Quaade, 1974).

(2) The memory-enhancing effects were thought to result from stimulation of the fornix, not the hypothalamus. The fornix is a fiber bundle that connects the hippocampus to the mammillary bodies and septal nuclei.

But first, a brief case history:

A 50-year-old man with a life-long history of obesity (420 pounds/190.5 kg; body mass index, 55.1 kg/m) did not respond to multiple treatments, including dietary regimens, psychological interventions, group therapies, and medications. Medical comorbidities included type II diabetes, hypertension, and obstructive sleep apnea. He refused gastric bypass and bariatric surgery believing that he would continue to eat excessively despite these interventions. Given his resistance to treatment, the concern with the long-term health consequences of morbid obesity, and our group's long-standing interest in functional neurosurgery and DBS, he was referred to consider the possibility of a neurosurgical treatment.

We know he experienced...

"déjà vu" with stimulation of the first contact tested (contact 4: 3.0 volts, 60-microsecond pulse width, and 130Hz). He reported the sudden perception of being in a park with friends, a familiar scene to him. He felt he was younger, around 20 years old. He recognized his epoch-appropriate girlfriend among the people.

...which held up under double-blind conditions. He also showed improved performance on standardized neuropsychological tests of memory.

(3) However, there were adverse effects at some of the stimulation sites:

At certain contacts, at intensities of 5 volts or greater, he experienced stimulation dose-dependent adverse effects, including feeling an unpleasant generalized warming sensation that was followed by facial hyperemia and sweating. There were no overt associated changes in the monitored vital signs (blood pressure, heart rate, and electrocardiogram). In addition, when stimulation was rapidly increased from 0 to 5 volts at the most ventral contacts, in closest proximity to the optic tracts, the patient transiently saw flashes of light in the contralateral visual field consistent with current spread to the ipsilateral optic tract.

(4) Because of his weight, the patient could not have MRI or PET scans, but he could (and did) have CT and EEG.


Supplementary Figure (Hamani et al., 2008). Location of DBS electrodes in the hypothalamus. Post-operative CT image at the level of contacts 0 and 4. (A) Electrode locations mapped onto a brain atlas 9 shown in coronal (B) and axial planes (C). The electrode contacts that most readily induced déjà vu experiences with stimulation (0,1 and 4,5) were in close proximity to the fornix (arrows). Red circles - Right electrode contacts 0 and 1. Blue circles - Left electrode contacts 4 and 5. Cm- corpus mammilare; Dm- nucleus dorsomedialis; Fx- fornix; Hpth- hypothalamus...

(5) But most importantly, did DBS help the patient lose weight?

There were no reproducible changes in his subjective sensation of hunger with stimulation on a self-rated 1 to 10 scale with these settings.

So was the procedure helpful at all in treating the patient's obesity? Did he lose any weight? One has to go to the Supplementary Materials to find the answer (which is no, he didn't lose weight...or at least, he gained back all 26.5 lbs):

Change in weight was the primary measure used to evaluate the effectiveness of hypothalamic stimulation on obesity. There was no weight change in the first 6 months of DBS using subliminal monopolar stimulation at high frequency (130 Hz)... Because of the important relationship between stimulation frequency and clinical benefit in other conditions, we then tried stimulation at a lower frequency, 50 Hz... With this new setting, the patient lost 12 kg over 5 months with no clear change in diet or exercise habits. He reported reduced food cravings and a decreased tendency to binge with stimulation. In the last 4 months however, the patient purposely turned the stimulator off some evenings using the hand held controller because he had a desire to eat and he felt it might help him sleep. With the stimulator turned off, nighttime binging activity returned as before surgery and he regained the weight he had lost. Fifteen months after stimulation, his weight was 192 Kg [a net gain of 1.5 kg].

But his California Verbal Learning Test scores were significantly improved!

References

Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, Wennberg RA, Lozano AM. (2008). Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Annals of Neurology, 63(1), 119-123. DOI: 10.1002/ana.21295

Bilateral hypothalamic deep brain stimulation was performed to treat a patient with morbid obesity. We observed, quite unexpectedly, that stimulation evoked detailed autobiographical memories. Associative memory tasks conducted in a double-blinded "on" versus "off" manner demonstrated that stimulation increased recollection but not familiarity-based recognition, indicating a functional engagement of the hippocampus. Electroencephalographic source localization showed that hypothalamic deep brain stimulation drove activity in mesial temporal lobe structures. This shows that hypothalamic stimulation in this patient modulates limbic activity and improves certain memory functions.

Laćan G, De Salles AA, Gorgulho AA, Krahl SE, Frighetto L, Behnke EJ, Melega WP. (2008). Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey. J Neurosurg. 108:336-42.

Sani S, Jobe K, Smith A, Kordower JH, Bakay RA. (2007). Deep brain stimulation for treatment of obesity in rats. J Neurosurg. 107:809-13.