Efficacy of TDCS for Treating Working Memory Dysfunction and Depression in Temporal Lobe Epilepsy
Efficacy of TDCS for Treating Working Memory Dysfunction and Depression in Temporal Lobe Epilepsy
Memory difficulty ranks among the most common complaints for patients with temporal lobe
 epilepsy. While these cognitive problems may affect quality of life more than seizure
 frequency, no effective therapy exists. Transcranial Direct Current Stimulation (tDCS) is a
 method of safe, noninvasive, and painless brain stimulation delivering low intensity direct
 current through scalp electrodes to modulate brain activity. Several recently published
 studies demonstrate the enhancement of working memory and mood with stimulation of the
 frontal region of the brain. Furthermore, tDCS has never been reported to have induced a
 seizure. The aim of our study is to determine whether real tDCS can improve memory function
 and mood. The investigators are enrolling patients with well-controlled temporal lobe
 epilepsy who have not undergone brain surgery.
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