Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex in Alcoholism
Condition: Alcohol Dependence; Executive Dysfunction; Abnormal Craving for Drugs
MeSH terms: Alcoholism
Study type: Interventional
Phase: Phase 2

Summary: 
      Alcohol dependency is the most frequent addiction leading to a massive burden of both,
      patients health, and economy. Present therapeutic concepts suffer from limited efficacy, and
      thus new innovative therapies are needed. Neuroscientific studies have shown that prefrontal
      function in alcohol-dependent patients is impaired, leading to cognitive disturbances, and
      continuation of dependent behaviour. The results of pilot studies demonstrate that activation
      of prefrontal cortices via non-invasive brain stimulation improves cognitive performance in
      healthy subjects, and diminishes dependency-related behaviour in patients. The investigators
      aim to develop a stimulation protocol suited to induce a clinically relevant improvement of
      prefrontal functions in patients suffering from alcohol dependency. Therefore, the
      investigators will develop stimulation protocols which are able to modulate prefrontal
      activation for a much longer time course than those currently available, and will explore if
      the induced physiological alterations translate to respective cognitive improvements and
      reduction of addictive behaviour.
    

Detailed description: 
      A hallmark of alcoholism is the deficiency of the frontal lobe, characterized by deficits in
      attention and working memory and executive dysfunction. This condition is especially marked
      by an inability to abstain from alcohol, having direct implications for the treatment of
      alcoholism (Goldstein and Volkow 2002).

      In a previous study, we examined the frontal function by the Frontal Assessment Battery (FAB)
      and mental state through the Mini-Mental State Examination (MMSE) in 170 patients with
      alcoholism classified according to Lesch's typology (Zago-Gomes and Nakamura- Palacios 2009).
      In a global analysis, the alcoholics showed total scores on MMSE and FAB significantly
      smaller compared to non-alcoholics subjects. Type IV alcoholics showed lower scores on MMSE
      and FAB in comparison with non-alcoholics and all other types (Lesch's types I, II and III)
      of alcoholics. In a more specific analysis, even in alcoholics Type IV who had mental
      function (MMSE) preserved, the executive function (FAB) was significantly reduced (Zago-Gomes
      and Nakamura-Palacios 2009).

      Moselhy et al. (2001) suggest that the frontal cognitive deficits observed in alcoholic
      patients are important predictors of therapeutic results. According to Lesch et al (1989,
      1990, and in personal communication), Type IV alcoholics, who showed more severe frontal
      deficits are the ones who have the worst prognosis, with great difficulty in abstaining from
      alcohol, but still being treatable under intensive and multiple approaches. Therefore,
      investigations of new perspectives for the treatment of these alcoholics are especially
      needed.

      A technique of neuromodulation that has been increasingly used and tested is the transcranial
      Direct Current Stimulation (tDCS). In this method, a weak direct current is induced in the
      cerebral cortex through two electrodes usually placed on the scalp (Nitsche et al 2008).
      Several studies have shown that this noninvasive method of brain stimulation is associated
      with significant changes in cortical excitability - increasing or decreasing it according to
      the polarity of stimulation (Nitsche and Paulus 2000, Nitsche and Paulus 2001; Zaghi et al
      2009). Animal studies from the 50s and 60s showed that the effects of tDCS are associated
      with changes in the threshold of neuronal membrane at rest (Bindman et al 1964b; Purpura and
      McMurtry 1965). There is evidence that anodal transcranial stimulation improves cognitive
      function in man, and this effect seems to be due to a strengthening of glutamatergic synapses
      (Fregni et al 2005, Iyer et al 2005, Nitsche et al 2003).

      In a recent study we examined the clinical and electrophysiological (indicated by the P3
      component) effects of tDCS application over the left dorsolateral prefrontal cortex (DLPFC)
      in different types of alcoholics according to Lesch's typology (data submitted for
      publication). We enrolled 49 alcoholics aging between 18 and 75 years old during the subacute
      period of abstinence. These individuals were submitted to event-related potentials (ERP)
      under the presentation of sounds related or non-related to the use of alcohol before, during
      and after active tDCS (1mA, 35 cm2, for 10 minutes) or sham procedure at a randomized and
      counterbalanced order. We observed a significant improvement in the FAB performance after the
      active tDCS compared to sham in Type IV alcoholics. There was an increase in the amplitude of
      P3 mainly in frontal site (Fz). This change was also more pronounced in Type IV alcoholics.
      Thus, we found clinical and electrophysiological evidence of increased frontal activity
      induced by tDCS specific to the type IV alcoholics. Considering that the frontal dysfunction,
      may contribute to the loss of control over drinking behavior, these results suggest that a
      local increase in frontal activity induced by tDCS may have a beneficial clinical impact.

      Therefore, in this project we intend to continue this study, aiming now to investigate the
      potential beneficial effects of tDCS applied repeatedly (once a week for 5 consecutive weeks)
      on the left DLPFC in the treatment of alcoholism in the course of protracted withdrawal. The
      frontal function will be examined by the application of FAB and other cognitive tests. A
      clinical follow-up will be carefully conducted.

      General objective: The main objective of this study is to examine the potential beneficial
      effects of repetitive transcranial direct current electrical stimulation over the left
      dorsolateral prefrontal cortex in the treatment of alcoholism in the course of its protracted
      withdrawal.

      Specific objectives: Of the specific objectives include the verification of the effects of
      repetitive transcranial electrical stimulation (5 applications) on: (1) the records of
      event-related potentials over 32 brain regions, (2) craving, (3) the performance of the
      frontal assessment battery, (4) the performance of two-back visual-spatial working memory
      task, (5) the performance of two-back auditory working memory task, (6) the performance of
      the inhibitory control behavior in a Go / No-Go task, (7) the performance of error detection,
      mental flexibility and inhibitory control in a counting Stroop test, (8) the quality of life.

      This study recruited thirty three alcoholics with diagnosis confirmed by Diagnostic and
      Statistical Manual of Mental Disorders in its Fourth Edition (DSM-IV) who present themselves
      voluntarily for treatment of Alcohol Dependence Syndrome in the outpatient public service at
      University Hospital Cassiano Antonio de Moraes from Health Sciences Center from Federal
      University of Espirito Santo (PAA / HUCAM / CCS / UFES), which were clinically stable and not
      requiring hospitalization, with significant history of consumption of at least 35 weekly
      doses of alcohol on average last year, and an active intake of at least 35 weekly doses of
      alcohol in the last 90 days before starting the study, and yet, being in a minimum of seven
      days of abstinence until beginning of the study protocol. They signed a consent form and were
      distributed randomly in two groups (sham and tDCS groups). Registrations of visual-cued
      (neutral or alcohol-related images) event-related potential (ERPs)were done before and after
      repetitive bilateral (left cathodal/right anodal) transcranial Direct Current Stimulation
      (tDCS, 5 x 7 cm2, 2 mA, double application - 13 min duration with 20 min interval in
      between)over the dorsolateral prefrontal cortex or sham procedure. tDCS or sham tDCS were
      applied once a day for 5 consecutive days. Cognitive tests (frontal assessment battery - FAB,
      mini-mental status examination - MMSE, verbal n-back task, visuospatial n-back task, go/no-go
      task) were done at the beginning of the session 1 and session 6. They were weekly followed up
      for 4 additional weeks and monthly over the following 5 months. Treatment of acute withdrawal
      followed the routine in the outpatient service (diazepam, vitamins and general support). They
      were examined weekly at the outpatient service for 4 weeks after the end of the protocol.
    

Intervention name(s): transcranial Direct Current Stimulation
Intervention type(s): Device
Intervention description(s): transcranial Direct Current Stimulation (tDCS, 5 x 7 cm2, 1 mA, during 10 min) will be applied over the left dorsolateral prefrontal cortex once a week for 5 consecutive weeks.
Other intervention name(s): non-invasive brain stimulation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Alcoholism; Lesch's typology; tDCS; ERP; P300; FAB; MMSE; Cognitive tasks