Causal Lesion Network Guided Treatment of Bipolar Mania With Transcranial Electrical Stimulation

Mania is a core symptom of bipolar disorder involving periods of euphoria. Decreased inhibitory control, increased risk-taking behaviors, and aberrant reward processing are some of the more recognized symptoms of bipolar disorder and are included in the diagnostic criteria for mania. Current drug therapies for mania are frequently intolerable, ineffective, and carry significant risk for side effects. Presently there are no neurobiologically informed therapies that treat or prevent mania. However, using a newly validated technique termed lesion network mapping, researchers demonstrated that focal brain lesions having a causal role in the development of mania in people without a psychiatric history can occur in different brain locations, such as the right orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex (DLPFC), and right inferior temporal gyrus (ITG). This lesion network evidence converges with existing cross-sectional and longitudinal observations in bipolar mania that have identified specific disruptions in network communication between the amygdala and ventro-lateral prefrontal cortex. The OFC is associated with inhibitory control, risk-taking behavior, and reward learning which are major components of bipolar mania. Thus, the association between OFC with mania symptoms, inhibitory control, risk-taking behavior, and reward processing suggests that this region could be targeted using non-invasive brain stimulation.

Mania is a core symptom of bipolar disorder involving periods of euphoria, delusions, and overactivity. Mania occurs in multiple medical and psychiatric illnesses and can be refractory to existing treatments. Two recent studies using brain lesion mapping of psychiatrically healthy individuals presenting with mania identified causal locations in the brain, including the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and inferior temporal gyrus (ITG), that were associated with new onset mania symptoms. Moreover, these identified brain regions have also been implicated in bipolar mania with specific disruption in network communication between the amygdala and ventro-lateral prefrontal cortex. The OFC is of particular interest because it is a brain structure that is associated with inhibitory control, risk-taking behavior and reward, which are major behavioral components of mania. Thus, the association between OFC with mania symptoms, inhibitory control, risk-taking behavior and reward suggests that this region could be targeted using noninvasive brain stimulation. While several studies have non-invasively targeted the DLPFC for mania, no study to date has non-invasively stimulated the OFC with either transcranial direct current stimulation (tDCS) or alternating current (tACS) in bipolar disorder and examined its effects on mania, inhibitory control, or risk-taking behavior. However, a study in healthy volunteers showed that cathodal stimulation to the OFC enhanced inhibitory control and decreased risk-taking behavior. Recently, researches have showed that targeting the OFC with tACS, personalized to the individual's intrinsic beta-gamma frequency of the reward network, that individuals showed rapid, reversible, frequency-specific modulation of reward-guided choice behavior and learning. Here we aim to answer the question of whether noninvasive brain stimulation when optimally targeted and personalized to an individual's beta-gamma frequency to the OFC can improve emotional cognitive processing and mania symptoms compared to tDCS or sham targeting. The knowledge gained from this study will provide a marker for clinical response and allow personalized treatment for patients with bipolar disorder.

10 passive sham control; Two, twenty-minute sessions of passive sham control to the OFC for a 30 second ramped up and down at the beginning and end of the 20 min period for 5 days (10 total sessions).

Non-frequency dependent transcranial electrical stimulation condition for 5 days of twice a day treatment

Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms

Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms

Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms

The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. 6 or higher indicates a high probability of a manic or hypomanic condition.

The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. 6 or higher indicates a high probability of a manic or hypomanic condition.

The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. 6 or higher indicates a high probability of a manic or hypomanic condition.

EEG measures neural activity recorded from electrodes placed on the scalp. Resting state measures include connectivity as well as oscillatory characteristics within delta, theta, alpha, beta, gamma bands.

EEG measures neural activity recorded from electrodes placed on the scalp. Resting state measures include connectivity as well as oscillatory characteristics within delta, theta, alpha, beta, gamma bands.

EEG measures neural activity recorded from electrodes placed on the scalp. Resting state measures include connectivity as well as oscillatory characteristics within delta, theta, alpha, beta, gamma bands.

The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails.

The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails.

The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails.

The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Total score of SFS ranges between 55 - 145 points. Higher scores mean better social functioning.

The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Total score of SFS ranges between 55 - 145 points. Higher scores mean better social functioning.

The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Total score of SFS ranges between 55 - 145 points. Higher scores mean better social functioning.

30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale.

30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale.

30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale.

The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression.

The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression.

The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression.

The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior.

The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior.

The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior.

The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning.

The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning.

The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning.

Inclusion Criteria: Aged 18-65 years of age Proficient in English Able to give informed consent Meet diagnostic criteria for bipolar disorder or schizoaffective disorder, bipolar type as verified by the SCID History of mania ( >1 lifetime episode) Experiencing mild to moderate symptoms of mania No changes to mood stabilizing medications for a period of 2 weeks prior to participation Has not recently participated in tES/TMS treatments Exclusion Criteria: Substance abuse or dependence (w/in past 6 months) Those who are pregnant/breastfeeding History of head injury with > 15 minutes of loss of consciousness/mal sequelae DSM-V intellectual disability Having a non-removable ferromagnetic metal within the body (particularly in the head) History of seizures