TMS in Schizophrenia I (Auditory hallucinations) - Andrea H

schizophrenia | ˌskitsəˈfrēnēə, ˌskitsəˈfrenēə |a long-term mental disorder involving a breakdown

in the relation between thought, emotion, and behavior
ORIGIN early 20th century: modern Latin, from Greek skhizein ‘to split’ + phrēn ‘mind’.

What are the positive symptoms of schizophrenia?

Positive symptoms can include delusions, disordered thoughts and speech, as well as tactile, auditory,
visual and olfactory hallucinations.

What are auditory verbal hallucinations (AVH)?

One of the symptoms most often associated with schizophrenia, often referred to as “hearing voices”;
affects around 60-80% of people with Schizophrenia at some point in the disease.

--“auditive perceptions involving a verbal aspect in the absence of a provoking external stimulus
(Aleman and de Haan, 1998).”

--can cause “high levels of distress and lead to significant psychosocial impairment.”

-- 25% to 30% of patients diagnosed with schizophrenia experience AVH that are unresponsive to
antipsychotic medication

Subject of these two papers:

TMS has been suggested as a possible way of treating AVH in schizophrenia, and has been shown to be
moderately effective. But there are still many questions and challenges. These papers try to clarify the
benefits, challenges and issues involved.

1. Kubera et al, 2015 = mini-review of TMS for the treatment of persistent AVH in patients with
schizophrenia, with emphasis on phenotypic diversity in individuals with drug-refractory and
persistent AVH (referred to as “P1” below)
2. Slotema et al, 2014 = meta-analysis of 25 randomized controlled trials from 1966 through April
2013, assessing the effects of various rTMS paradigms on AVH, especially comparing effect
sizes to sham treatment for AVH (“P2” below)

rTMS protocol: How is rTMS proposed to be used for AVH?

Supposed to help by inhibiting areas of the brain believed to cause auditory hallucinations. And it is
thought to induce LTP or LDP – to change brain patterns -- though this is not proven, and there is little
or no evidence supporting it (none that was offered here.)

What area is targeted?

1
There is a focus on the area around the primary audio cortex, specifically the superior temporal cortex
(STC), left temporoparietal gyrus (trials have been done on the right, but to no “superior effect” and
stimulation of Broca´s area and “its contralateral homologue” not effective (P1, P2)

Frequency, intensity, duration? Low frequency, rapid succession of pulses (rTMS)

In the various studies of the meta-study, there were positive effect seen in a range from 1 to 30Hz. Most
investigators used a motor threshold below 100% (i.e., usually 90%). No correlation was found between
effect size and MT.(P2)

--the left temporoparietal area was stimulated with a frequency of 1 Hz -- repeated stimulation induced
a longer lasting decrease of the frequency and severity of medication-resistant AVH.

Why is this thought to help (what’s the “rationale”)?

The rationale for stimulating the STC is “to inhibit cortical overactivity and potentially influence
generative phenomena (i.e. AVH) which are thought to be closely associated with regionally increased
cortical activity”. (P1)

Is rTMS recommended for testing auditory hallucinations?

Recommended is too strong a word thus far, but there is evidence that rTMS can provide significant
relief to patients suffering from AVH, especially those with drug-resistant AVH, at least for a certain
period of time. Beneficial long-term effects appear unlikely, but overall, moderate, rTMS does show
efficacy compared with sham treatment.

Meta-analysis effect size was .44. for patients with medication-resistant AVH, the mean weighted
effect size was .45. rTMS applied at the left temporoparietal area with a frequency of 1 Hz yielded a
moderate mean-weighted effect size of .63. rTMS applied at the right temporoparietal area was not
superior to sham treatment. (P2)

Possible problems and future predictions

P1 – therapeutic effects of rTMS in AVH patients are not long-lasting…effect size of rTMS over the left
temporoparietal area has decreased over time (Slotema et al., 2012, 2014). --the stimulation
techniques cd be the problem; bilateral stimulation cd be better, but untried --evidence suggests
AVH are not related only to regional brain dysfunction, cd be abnormal neural network coupling in
various distinct networks; bilateral/ bifocal stimulation could be a promising approach (P1)

--“one size fits all” approach could be the problem: “schizophrenia is a phenomenologically
heterogeneous disorder with several distinct phenotypic presentations at both the clinical and
neurobiological level, and the very same heterogeneity also applies to persons with chronic
AVH”…trying to identify and target more specific regions cd increase efficacy (p1)

“…future studies will need to consider distinct phenotypic presentations of AVH in patients with
schizophrenia, together with the putative functional neurocircuitry underlying these phenotypes.”(P1)

2
P2 – Suggests that the next step should be “to explore the effects of rTMS in medication-free
individuals, for example, during the initial phases of psychosis”

--a stronger effect was found for positron emission tomography–guided rTMS versus the “standard”
procedure so individual neuronavigation may improve rTMS effect. Still, other studies did not have this
same finding and the H coil in deep-brain rTMS has also not yet proved a better alternative to
“superficial” figure-of-eight coil; few studies tried high-frequency

“Most of the studies included patients with medication-resistant AVH. However, given its much milder
side-effect profile, it would be logical to grant rTMS a place much earlier in the treatment protocol.
Because rTMS is safe and tends to be well tolerated, it is surprising to find that no study to date has
investigated rTMS in medication-naïve individuals.” (P2)

“Because rTMS for auditory verbal hallucinations is generally applied at the temporal and parietal
cortices, most rTMS paradigms may in theory have been too weak to achieve any persistent effects.”
(P2)

Supplementary Paper:

A new coil has been developed that could better target the areas associated with AVH and address
some of the issue above. We will briefly discuss this “butterfly coil” and its possible benefits.

Extra:

Review/Opinion regarding the need for personalized treatment for hallucinations, relative to above
problems and recommendations.