Tag Archives: brain stimulation

Brain stimulation holds promise for anorexia

Originally published on the PLOS Neuroscience Community

Anorexia nervosa is a devastating, often fatal disease, in which voluntary food restriction severely compromises physical and mental health. Because current treatments, such as psychotherapy, are only minimally effective, many disease victims fight a lifelong battle and most will never recover. However, recent research into the neural underpinnings of anorexia provides hope that relief may be possible by regulating aberrant neural circuitry. A new study published in PLOS One by Jessica McClelland and colleagues from King’s College London offers preliminary support for repetitive transcranial magnetic stimulation (rTMS) as a viable therapy for anorexia.

Hitting reset to dysfunctional brain circuits

Anorexia is characterized by maladaptive behavior, such as abnormal cognitive flexibility, emotional regulation, and habit learning, which has been linked to dysfunction in frontal, limbic and striatal brain networks. The prefrontal cortex in particular is thought to be a critical hub in this aberrant network, as its hypoactivity may lead to poor impulse control underlying many of the symptoms of eating disorders. Restoring function to the prefrontal cortex therefore holds promise for resetting dysfunctional neural circuits and ultimately ameliorating disease symptoms. Modulating neural function noninvasively can be achieved with brain stimulation techniques such as rTMS, which, by applying repeated magnetic pulses over the scalp, induces an electric current in nearby neurons and alters cortical excitability. RTMS to the prefrontal cortex is FDA approved to treat depression, is effective at treating other psychiatric disorders including addiction and schizophrenia, and has shown early but inconsistent efficacy for alleviating symptoms of eating disorders.

To determine whether rTMS may be similarly beneficial for normalizing brain function in anorexia, the researchers tested 49 women with either restrictive or binge/purge subtypes of anorexia. Twenty-one of the women underwent real rTMS, while 28 underwent sham rTMS, to the left dorsolateral prefrontal cortex. Before and after treatment both groups completed a food challenge test to assess their response to enticing foods and gauge their symptoms. They also performed a temporal discounting task, which measures impulsivity and may therefore be sensitive to the altered inhibitory control that occurs in eating disorders.

A hint of therapeutic promise

The researchers were mainly interested in whether rTMS could attenuate “core” symptoms of anorexia, such as urges to restrict eating, or feelings of fullness and fatness. Core symptoms were reduced after both real and sham treatments, suggesting at least some degree of a placebo effect. However, there was a trend for stronger symptom attenuation at multiple time-points – up to a day after treatment – for those who experienced real compared to sham rTMS. A closer look revealed a trend for lower reports of feeling fat after real rTMS compared to sham. Furthermore, the real treatment was also associated with less impulsivity (as assessed with the temporal discounting task) after rTMS, an effect that was only significant for the restrictive subtype of anorexia.

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Core anorexia symptoms were lower at all time-points after real rTMS than sham. (McClelland et al., 2016)

The path to the clinic

Based on these findings, should practitioners begin prescribing brain stimulation to eating disorder patients? Well, not quite yet. While the study’s results are encouraging, their effects were not overwhelmingly strong, and the authors acknowledge their study was possibly underpowered. Before rTMS translates to the clinic, its therapeutic potential needs to be further evaluated and the target patient population and optimal protocol should be better characterized. Even if these results hold up, it’s still not clear whether the benefits of rTMS are specific to anorexia, perhaps by resetting underactive neural function to normal levels, or whether rTMS similarly modulates healthy brain activity and behaviors. For example, would altered impulsivity and emotional responses to food also occur in healthy individuals after rTMS? McClelland admits that “Including healthy controls in this study would have been useful as a comparison group, to see if the rTMS in people with anorexia encourages more ‘normal’ responses,” and her group plans to include a healthy comparison group in future studies.

Furthermore, other brain stimulation tools may be equally or more effective, so comparative studies are needed to determine the ideal therapeutic technique. McClelland explains that

“We selected rTMS because there is more literature on its use and efficacy in other neuro-circuit based psychiatric disorders. Transcranial direct current stimulation (tDCS) is a slightly newer technique and hasn’t yet been investigated in eating disorders as widely as rTMS. This doesn’t mean that tDCS may not be as, if not more, effective than rTMS.”

And because the neural mechanisms of eating disorder subtypes presumably differ, the efficacy of rTMS may depend on the patient’s particular set of disease symptoms and illness duration. Targeting therapies at the individual patient level could be an ideal treatment approach, but will require further research to determine what stimulation protocols are optimal for particular symptom profiles.

According to McClelland, “Our single-session study was experimental and therefore only looked at the short-term, transient effects of rTMS in people with anorexia. We wouldn’t expect a single-session of rTMS to have long lasting therapeutic effects.” Therefore, in a critical step along the path to the clinic, McClelland and colleagues are currently doing a randomized clinical trial of 20 sessions of either real or placebo rTMS in individuals with anorexia.

Although preliminary, this study offers early hope for the millions of Americans presently suffering from anorexia. Effective relief from an otherwise debilitating, unrelenting disease may be just around the corner.

References

Bartholdy S et al. (2015). Clinical outcomes and neural correlates of 20 sessions of repetitive transcranial magnetic stimulation in severe and enduring anorexia nervosa (the TIARA study): study protocol for a randomised controlled feasibility trial. Trials. 16:548. doi:10.1186/s13063-015-1069-3

Grall-Bronnec M, Sauvaget A (2014). The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: a critical literature review of efficacy, technical and methodological considerations. Neurosci Biobehav Rev. 47:592-613. doi:10.1016/j.neubiorev.2014.10.013

Lam RW, Chan P, Wilkins-Ho M, Yatham LN (2008). Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry. 53(9):621-631.

McClelland J, Bozhilova N, Campbell I, Schmidt U (2013). A systematic review of the effects of neuromodulation on eating and body weight: evidence from human and animal studies. Eur Eat Disord Rev. 21(6):436-455. doi:10.1002/erv.2256

McClelland J et al. (2016). A Randomised Controlled Trial of Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Anorexia Nervosa. PLOS ONE. 11(3): e0148606. doi:10.1371/journal.pone.0148606

Oberndorfer TA, Kaye WH, Simmons AN, Strigo IA, Matthews SC (2011). Demand-specific alteration of medial prefrontal cortex response during an inhibition task in recovered anorexic women. Int J Eat Disord. 44(1):1-8. doi:10.1002/eat.20750

Shi C, Yu X, Cheung EFC, Shum DHK, Chan RCK (2014). Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A meta-analysis. Psychiatry Res. 215(3):505-513. doi:10.1016/j.psychres.2013.12.019

Steinhausen HC (2002). The outcome of anorexia nervosa in the 20th century. Am J Psychiatry. 159(8):1284-1293. doi.:10.1176/appi.ajp.159.8.1284

Zhu Y et al. (2012). Processing of food, body and emotional stimuli in anorexia nervosa: a systematic review and meta-analysis of functional magnetic resonance imaging studies. Eur Eat Disord Rev. 20(6):439-450. doi:10.1002/erv.2197

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@PLOSNeuro #SfN14 Highlights: Intracranial EEG and Brain Stimulation

Originally published on the PLOS Neuroscience Community

Despite their many advantages, traditional tools to study neurocognitive function in humans, such as EEG or fMRI, carry several disadvantages compared to those usable on animals. Perhaps the most significant limitation is the challenge of imaging neural activity of live human brains during mental functions, which inherently requires the application of invasive neuroimaging techniques. Recently, the cognitive neuroscientist’s tool-belt has rapidly expanded, with the growing prevalence and usability of powerful imaging methods such as intracranial EEG – or electrocorticography (ECOG) – and electrical brain stimulation, that permit direct recording or stimulation of neuronal activity in live, conscious humans.

The SfN symposium Studying Human Cognition with Intracranial EEG and Electrical Brain Stimulation (previously previewed here, including an interview with speaker Josef Parvizi) explored current advances in these evolving methods along with their applications to the human cognitive experience.

Knight

UC Berkeley’s Bob Knight opened the symposium by highlighting the unique perks of ECOG over more traditional imaging techniques — points which were later recapitulated by other speakers — including its remarkably high spatial and temporal resolution and exceptional signal to noise ratio. ECOG is in fact so precise that it can reliably measure signal down to the single trial level – a feat neither EEG nor fMRI can boast. In just his brief introduction, Knight shared some impressive clinical and cognitive applications of these electrophysiology techniques. For instance, intracranial EEG signal from the auditory cortex was effective (with 99% accuracy!) at reconstructing words, holding clear implications for patients with speech impairments. My personal favorite highlight of the session, however, was the reconstruction of Pink Floyd’s “Another brick in the wall” from intracranial auditory cortex recordings.

Parvizi

First up, Josef Parvizi from Stanford University presented his lab’s multimodal approach to neurocognitive assessment, incorporating fMRI, ECOG and electrical brain stimulation. Parvizi shared a series of cases illustrating the powerful – and entertaining — applications of brain stimulation. In response to stimulation of the “salience network”, which had been previously mapped using fMRI, one patient responded that he felt like he was “riding in a storm”, but “felt nothing” after sham stimulation. A second patient reported the sense that “something bad is going to happen,” confirming in both patients emotionally driven reactions to “salience network” stimulation. In a final, particularly compelling, demonstration, Parvizi showed the effects of fusiform face area stimulation: “You just turned into somebody else,” the subject reported. “That was a trip!”

Malach

Next, Rafael Malach of the Weizmann Institute discussed his lab’s use of intracranial EEG to measure spontaneous neural activity at rest. FMRI is most commonly used to study resting-state activity; however, the BOLD signal may be contaminated by non-neural signal, and — due to its poor temporal resolution — is effectively blind to rapid events. Using ECOG, which overcomes both of these hurdles, Malach demonstrated how high frequency gamma activity accurately reflects neuronal firing rate and can assess functional connectivity. Surprisingly, spontaneous activity between recording sites on opposite hemispheres is more highly correlated than between adjacent recording sites. So ECOG may be a powerful tool for measuring spontaneous activity, but this is only valuable if we can identify the signal’s associated mental processes. Using the comical and celebrated example of the entorhinal cortex “Simpsons neuron”, which selectively fired in response to images of the Simpsons or immediately before spontaneous recall of the cartoon, Malach suggested that spontaneous activity exceeding an awareness threshold might indeed represent conscious thoughts.

Lachaux

Jean-Philippe Lachaux, from the Lyon Research Council, took a slightly different angle on the applications of ECOG, highlighting its unique suitability for evaluating naturalistic behavior. Because of its robustness against artifacts problematic in EEG or fMRI — like motion, blinking or signal distortion — ECOG can be more flexibly used in a variety of environments. These applications can be enhanced by integrating it with other tools such as eye-tracking, to more accurately associate natural behavior with neural activity in real time. Furthermore, Lachaux illustrated the power of ECOG at unraveling the temporal dynamics of functional interactions. Lachaux presented data questioning the common assumption that inter-region communication is typically a one-way street, proposing instead that such interactions may be more akin to reciprocal “shared conversations”.

Kastner

Sabine Kastner of Princeton University wrapped up the session with her lab’s comparative studies of attention in humans and monkeys. Combining human intracranial EEG with single-unit and LFP measures in monkeys during attention (Flanker task), she reported similar attention modulation in human and monkey intraparietal sulcus. Intriguingly, while attention modulated high gamma in both species, it also increased low frequency oscillations in humans. At the heart of cognitive neuroscience is the question of how neural activity translates to thoughts and behavior. To directly address this issue, Kastner is using electrophysiology to identify the optimal neural code for attention. In both humans and monkeys, she finds that spike phase better predicts behavior than spike rate, inching us one step closer to resolving the brain-cognition relationship.

Judging by the responses to my live-tweeting of this symposium, I’ll conjecture that the Neuro community is as intrigued and excited as yours-truly about the potential applications of ECOG and brain stimulation. In the words of @WiringTheBrain,

“This stuff is so COOL! And scary. But mainly COOL!”

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