Efficacy of TDCS for Treating Working Memory Dysfunction and Depression in Temporal Lobe Epilepsy

Transcranial direct current stimulation (tDCS) is a powerful technique to modulate brain
activity:

TDCS is based on the application of a weak direct current to the scalp that flows between
two relatively large electrodes—anode and cathode. During tDCS, low amplitude (1-2 mA),
constant currents are applied via the scalp electrodes and penetrate the skull to enter the
brain. Although there is substantial shunting of current in the scalp, sufficient current
penetrates the brain to modify the trans-membrane neuronal potential as shown by two recent
modeling studies (Miranda et al. 2006; Wagner et al. 2007a), and thus influence the level of
excitability and modulate the firing rate of individual neurons. When tDCS is applied for a
sufficient duration, cortical function can be altered beyond the stimulation period (Nitsche
and Paulus 2001) and the direction of the cortical excitability changes depends on current
orientation.

Several well-conducted animal studies on the effects of tDCS dating back to the 1950s and
60s showed that tDCS is a powerful technique to modulate brain function. These studies
demonstrated that polarizing currents applied to the surface of the brain result in a
modulation of the cortical activity. Surface anodal polarization of the cortex increases
spontaneous unit discharges (Burns 1954; Creutzfeld et al. 1962) and initiates paroxysmal
activity (Goldring and O'Leary 1951), whereas cathodal polarization generally depresses
these events. Furthermore, low-level surface polarization facilitates acquisition of learned
motor responses and induces prolonged changes in patterns of evoked cortical unit discharges
(Bindman et al. 1964). Finally, Purpura et al. (1964), studying pyramidal tract cells from
cats, showed that prolonged periods of polarization may produce progressive membrane and
post-synaptic potential changes as well as after-effects (Purpura and McMurtry 1965).

Based on this evidence, recent human studies have been performed and collectively have shown
that motor cortex (M1) stimulation with tDCS changes motor cortex excitability depending on
the stimulation polarity: while anodal stimulation increases cortical excitability, cathodal
stimulation decreases it (Nitsche et al. 2003; Nitsche and Paulus 2000; Nitsche and Paulus
2001). Similar modulatory effects have also been described in the visual cortex (Antal et
al. 2004; Antal et al. 2001). A recent tDCS study has shown that anodal tDCS of the primary
motor cortex not only affects cortical activity, but induces significant changes on thalamic
activity (Lang et al. 2005). It should be noted that application of tDCS in humans has
advanced significantly in the last 10 years and it is therefore different from the human
application used in the '60s and '70s (Wagner et al. 2007b)

Furthermore, tDCS offers several advantages as compared with other techniques of noninvasive
brain stimulation (i.e., repetitive transcranial magnetic stimulation (rTMS)): (1) small
size of the electrodes and stimulator, thus allowing portable use for instance to be used at
home, (2) simple and non-expensive technique that can easily be translated for use in
clinical practice, (3) long-lasting effects - the modulatory effects of tDCS last longer as
compared to rTMS - for instance, 13 minutes of stimulation changes brain excitability for up
to 2 hours (Nitsche and Paulus 2001), and (4) more easily blinded with sham tDCS in the
setting of clinical trials (Gandiga et al 2006)

Prefrontal stimulation has been shown to enhance cognitive function:

There have been several recently published studies demonstrating the enhancement of working
memory when tDCS stimulation is applied to the dorsal lateral prefrontal cortex. Fregni et
al (2005) studied 15 normal subjects. The patients performed a three -back working memory
task during active anodal (stimulatory) tDCS of the left dorsolateral prefrontal cortex
(left DLPFC), sham stimulation over the left DLPFC, cathodal (inhibitory) stimulation of the
left DLPFC, or anodal stimulation over the primary motor cortex (M1). The results of this
study showed a significant improvement in working memory as indexed by task accuracy after
active anodal tDCS of the left DLPFC. The other conditions of stimulation—including sham
tDCS, anodal tDCS of left DLPFC, or anodal tDCS of M1—did not result in a significant task
performance change. Similarly, Boggio et al (2007) have also found significant improvement
in affective go-no-go task performance in patients with severe depression after treatment
with anodal tDCS to the left DLPFC independent of the degree of mood enhancement after 10
consecutive days of tDCS.

Conversely, there has been some evidence that cathodal inhibition of the right DLPFC
enhances working memory performance in the same task in depressed patients (Bermpohl et al
2006). Together these studies suggest that the increased activity of the left DLPFC—whether
directly through anodal stimulation or indirectly through cathodal inhibition of the right
DLPFC—is responsible for improvement in working memory performance.

Transcranial direct current stimulation (tDCS) has a significant antidepressant effect:
Modulation of prefrontal cortex with anodal tDCS is associated with a significant
improvement in depression. Initially a preliminary, randomized, controlled and double blind
trial in which the effects of five days of anodal stimulation of the left DLPFC in 10
patients with major depression was investigated. All patients tolerated tDCS without
complications. At the end of treatment, there were 4 treatment responders in the active
group versus no responders in the sham group. The patients who received active stimulation
had a significant decrease in the Hamilton Depression Rating Scale (HDRS) and Beck
Depression Inventory (BDI) scores compared to baseline which was not observed in patients
that received sham stimulation (Fregni et al. 2006b).

In a follow-up, parallel-group, double-blind clinical trial with 40 patients with major
depression, patients were washed-out of their medications and randomized into three groups
of treatment: anodal tDCS of the left DLPFC (active group); anodal tDCS of the occipital
cortex (active control group) and sham tDCS (placebo control group). tDCS was applied for 10
sessions during a 2-week period. Mood was evaluated by a blinded rater using the HDRS and
BDI. The treatment was well tolerated with minimal side effects that were distributed
equally across all treatment groups. This study showed significantly larger reductions in
depression scores after left DLPFC tDCS (HDRS reduction of 40.4% (±25.8%)) as compared to
occipital (HDRS reduction of 21.3% (±12.9%)) and sham tDCS (HDRS reduction of 10.4%
(±36.6%)). The beneficial effects of tDCS in the DLPFC group persisted for 1 month after the
end of treatment (Boggio et al. 2008).

Similarly, in another longitudinal study on depression by Rigonatti et al (2008), serial
applications of anodal (stimulatory) tDCS applied to the prefrontal cortex (10 sessions of 2
mA each) had a similar effect on reducing depressive symptoms as measured by Beck Depression
Inventory scores as fluoxetine even 6 weeks after treatment. However, the effects of tDCS
were more immediate than that of fluoxetine19.

In summary, tDCS of the left DLPFC seems to be able to induce significant positive affective
and cognitive improvements in normal patients and patients with significant depression. We
will therefore in this proposal test whether prolonged prefrontal stimulation is associated
with clinically meaningful changes in affective and cognitive function without worsening
epileptiform activity or seizure frequency. The results of this pilot study will have a
significant clinical impact for the treatment of the neuropsychiatric comorbidities of
patients with temporal lobe epilepsy.

Inclusion Criteria:

1. age between 18-70 years

2. diagnosis of temporal lobe epilepsy, with seizure focus defined by seizure semiology,
EEG, MRI Brain, PET and/or ictal and interictal SPECT.

3. Must have a stable seizure frequency in the two (2) months prior to enrollment, as
verified by the patient's seizure log and/or clinic notes and without recent
antiepileptic medication changes.

4. Must score above 22/30 on the Montreal Cognitive Assessment (MoCA).

5. Must be able to provide informed consent.

Exclusion Criteria:

1. Patient has a progressive or unstable neurological or systemic disease

2. Patient has an ictal focus over the F3 or F4 (DLPFC) field

3. Patient has a history of severe depression, as determined by a screen inventory test
such as the Beck Depression Inventory or a psychiatrist

4. Patient has a history of severe traumatic brain injury or prior brain surgery with
skull defect

5. Contraindictations to tDCS, including metal in the head or implanted brain medical
devices

6. Pregnancy

7. Any implanted electrical medical device, including pacers and implanted cardiac
defibrillators

8. History of schizophrenia, schizoaffective disorder, other psychosis, rapid-cycling
bipolar illness, alcohol/drug abuse within the past year

9. History of dementia